The Theory of Endobiogeny: Volume 1: Global Systems Thinking and Biological Modeling for Clinical Medicine 0128169036, 9780128169032

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Preface to volume 1 It is nearly 50 years since that spring day in 1972 when the late Dr. Christian Duraffourd and I, two young physicians, first met and decided to work together. How could we have imagined that our meeting would one day result in publications on the theory of Endobiogeny by Elsevier, one of the premier publishers of scientific publications? During his medical studies, Christian had been struck by the dissociation which existed between the physiological complexity of the organism as taught by our medical professors and the simplistic practice of giving the same treatment for all. It was a kind of therapeutic funnel focused only on symptoms despite recognizing multiple different pathophysiologic and physiological mechanisms that play a role in starting and maintaining the disease. Christian would say, “Little head or big head, always the same (sized) hat.” We graduated from University of Paris Faculty of Medicine. Despite our training in the largest and most specialized hospital service, the choice we made to practice general medicine could have seemed surprising to some. After all, we started our medical practice at an age in which great French researchers received the Nobel Prize for their work in genetics. However, faced with this reality of daily clinical medicine, genetic science at its peak development never provided an effective response to illness in everyday life. That is why the need we faced, namely to help our patients as much as possible, led us to reflect jointly on how to arrive at a scientific approach to medicine that truly addressed our patients’ need for better treatment, adapted to their individual physiology and terrain. In order to do that we conceived an intellectual framework for the integration of physiological systems, in order to better understand the functional globality of the individual's terrain, and, to make the link between the analytical approach that underpins current medical science and a synthetic vision that considers the individual in his uniqueness. The groups of doctors we formed around us1 met regularly over the years to participate in the development of this new approach, initially called "endocrine theory of terrain," proposed by my colleague Christian Duraffourd, and later called “the theory of Endobiogeny” (cf. Chapter 1). In 2002, we published A Treatise on Clinical Phytotherapy,1 which

laid the main principles of our vision of clinical and laboratory research used to rationally determine the selection of medicinal plants in clinical practice. Since that time, the objective to be reached was clear: to formally present the theory of endobiogeny to the wider scientific community in order for it to be subject to validation. The development of this essentially clinical approach was and is being diffused across the world thanks to the collaboration of passionate and committed physicians around us. At the same time, I started disseminating new concepts on clinical phytotherapy and an introduction to the study of endobiogeny in various countries, particularly the United States. It was in 2007 during a seminar that I hosted in the university town of Pocatello, Idaho, that I met Dr. Kamyar Hedayat. He was at the time, head of Pediatric Intensive Care and Integrative Medicine at Sutton Children's Hospital. At the end of the first morning, he asked me a sharp question: "Where are the scientific proofs?” Indeed, all the clinical research that we had done in France had been carried out within a small group of clinical physicians, without scientific references to support them and without publications to ensure their validity. During that seminar, we decided to work together. Kamyar asked me to become his mentor in this new knowledge of endobiogeny. My joy was immense. Finally, I was in front of a keen scientific mind. Surely, I believed, his intellectual interest in our work would allow us to move faster in validating and disseminating our approach. This first meeting very quickly revealed itself to be capital. Based on a deep friendship, it inaugurated a major upheaval in the direction of our development of Endobiogeny. It had and will continue to have important consequences on our ability to provide objective evidence for validation by the scientific community, and, present a teaching methodology that meets the needs of a new generation of doctors demanding scientific evidence while seeking to broaden their therapeutic choices. And what we were not able to achieve in France found its fulfillment in the United States: the first official scientific publication in an international peer-reviewed journal exposing the foundations of the theory of endobiogeny.2, 3 This publication would be followed by others,4–6 validating

1. First, in 1975, the Société Française de Phytothérapie et d’Aromathérapie (French Society of Phytotherapy and Aromatherapy), transformed in 1980 to the Société Française d’Endobiogénie et Médecine (French Society of Endobiogeny and Medicine).

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aspects of the theory of Endobiogeny based on current scientific, experimental, and statistical criteria. At the same time that we were developing in France the endobiogenic clinical approach, my friend Kamyar and I had maintained a constant series of intellectual exchanges and engagements throughout the years that to pass on a knowledge acquired from my years of collaboration with Christian Duraffourd. Kamyar is part of a line of researchers who can allow a qualitative and disruptive leap in the definition, development, and promotion of complex systems theory as represented by endobiogeny. His original contributions cover several areas by further systematizing Christian's original concepts and introducing new ones that further expand the field of endobiogeny (cf. Chapter 1). Thus, this first volume presents an evolutionary vision of endobiogenic thought since its origin, proposed in 1972 by Dr. Christian Duraffourd. Thanks to the original synthesis carried out by Kamyar in the development of Christian's work, this book provides the reader with a new overview of fundamental endobiogenic principles that allow us to place it in a global physiological and integrative perspective, never realized until today. All the information provided by listening to the patient, semiology, clinical examination, imaging, and laboratory testing related to the biology of functions can now be seamlessly integrated to create a web of information regarding the patient and their individual terrain. This makes it possible to develop a truly personalized therapeutic strategy, centered on the patient in their complex reality and not on the only disease.

The orientation of the future validation of endobiogeny over the next 50  years will have to be organized around the principles as they are now defined and proposed to the scientific community by Dr. Kamyar Hedayat. This vision integrates the mechanisms at work that allow for the expression of life: adaptation of the individual’s internal environment to that of the external environment. I know that the task is huge, but the challenge for patients is such that I have no doubt that this goal will one day be achieved. This is my dearest wish. Jean-Claude Lapraz

References 1. Duraffourd C, Lapraz JC. Traité de Phytothérapie Clinique: Médecine et Endobiogénie. Masson ed. Paris: Masson; 2002. 2. Lapraz JC, Hedayat KM. Endobiogeny: a global approach to systems biology (part 1 of 2). Glob Adv Health Med. 2013;2(1):64–78. 3. Lapraz JC, Hedayat KM, Pauly P. Endobiogeny: a global approach to systems biology (part 2 of 2). Glob Adv Health Med. 2013;2(2):32–44. 4. Buehning  LJ, Hedayat  KM, Sachdeva  A, Golshan  S, Lapraz  JC. A novel use of biomarkers in the modeling of cancer activity based on the theory of endobiogeny. Glob Adv Health Med. 2014;3(4):55–60. 5. Hedayat K, Lapraz JC, Schuff BM, et al. A novel approach to modeling tissue-level activity of cortisol levels according to the theory of Endobiogeny, applied to chronic heart failure. J Complex Health Sci. 2018;1(1):3–8. 6. Hedayat  K, Schuff  BM, Lapraz  JC, et  al. Genito-Thyroid index: a global systems approach to the neutrophil-to-lymphocyte ratio according to the theory of Endobiogeny applied to ambulatory patients with chronic heart failure. J Cardiol Clin Res. 2017;5(1):1091–1097.

Chapter 1

Origins of Endobiogeny what is possible.2 Over the last 500 years the braided relationship of these disciplines has been severed, resulting in The theory of Endobiogeny offers a completely new vision a true turning point. Medical inquiry, long interdisciplinary, of human physiology, health, and illness. It traverses every holistic science has descended into increasing levels of relevel of human function and interaction within itself and ductionist thinking. The patient has been removed from the with its surrounding world: subcellular to global systems, question of clinical practice, replaced by a study of organs, internal regulation to external interaction, and physiologic then cells, then genetics, and soon quantum biology. to mental/emotional activity. The theory of Endobiogeny From the Hippocratic oath “first do no harm” has come was developed to return intellectual flexibility and openness the goal to suppress symptoms and correct biomarker levto the biomedical approach. It is not a replacement for, or els. A century of fantastic insights, exciting discoveries, abandonment of, modern science. It is applied global sys- and seemingly miraculous treatments have been considtems biology. It is functional biomathematics. It is a medi- ered as proof of the validity of this approach. But now we cal paradigm that seeks to expand the current conceptual find that this approach too has reached a plateau, and in boundaries of biomedicine to reflect contemporary under- some cases, devolved. Disorders once believed to be constandings of complexity and chaos theory and the notion trolled such as infection,3 cancer,4 and autoimmune disthat mathematics can describe physiologic activity in daily ease5 are now presenting with greater frequency, severity, clinical practice. and recidivism. In contrast to this, in the last 60 years sysThe history of Endobiogeny lies within the history of tems theory has reversed the reductionist trends in many medicine, like the fractal growth of a long-distant seed. fields of inquiry—except clinical medicine—returning to It is a flower germinated by an ancient qualitative holism the Aristotelian observation that the “whole is greater than and a modern quantitative rational discipline. To arrive at the sum of its parts.” Endobiogeny we survey contemporary medicine and trace Reductionist experimentation can be a valuable tool in its trajectory from ancient times. The chapter concludes understanding the individual components of complex phewith a brief history of Endobiogeny and the physician-­ nomena. In fact, this approach has proven key not only in philosophers and clinician-scientists who theorized, culti- the foundation of modern medicine but also in the foundavated, and distributed its fruits. tion of systems biology, which may 1 day expand the concepts of clinical medicine beyond the current reductionist approach. An isolated study of phenomena is neither probDevolution of holism and the limits of lematic nor flawed if it is part of a more comprehensive reductionism process of integration of the global intrinsic function of the organism and its interaction with its external environment. Reductionism is the attempt to explain complex phenomNaïve reductionism, on the other hand, is contrary to the ena by defining the functional properties of the individual very existence of life as a phenomenological event. Wings components that compose multicomponent systems…“naïve do not fly—a bird does—within the context of air pressure, reductionism,” the belief that reductionism alone can lead temperature, wind, etc. A syncytium of myocytes does not to a complete understanding of living organisms, is not tencirculate blood—a heart does—within the milieu of global able. Organisms are clearly much more than the sum of their demands of the organism. parts, and the behavior of complex physiological processes The principles of reductionism originated in 17th cencannot be understood simply by knowing how the parts work tury Europe. During this time, the focus of scientific inquiry in isolation. shifted from “why” to “how,” from cause to mechanism, Kevin Strange, Department of Anesthesiology, Molecular and from understanding the whole to dissecting the parts.2 Physiology and Biophysics and Pharmacology.1 Quantitative analysis of isolated subsystems supplanted Historically, philosophy, science, culture, and medicine qualitative analysis of relationships of subsystems to the were intertwined, each informing the other of what is, and whole. The macrocosm and microcosm were ­characterized

Introduction

The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00001-X © 2019 Elsevier Inc. All rights reserved.

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by three qualities: order, predictability, and control. Newton’s physics posited that objects follow defined, predictable rules of behavior. French philosopher Laplace posited a type of determinism in which the past and future of all behaviors of objects could be precisely determined.6 French philosopher Descartes first described the reductionist method of inquiry.7 In his first work, A discourse on the method for conducting oneself with reason, and searching for truth in the sciences, he writes: The second (method I use) is to divide each difficulty…into the smallest components into which it can be divided in order to better resolve it. The third is to conduct my thoughts in an orderly manner, beginning with the objects that are most simple and easy to know, then progressing little by little, as if by degrees, to the knowledge of the most complex ones, even assuming an order between objects that do not logically precede one another in a natural way. Ref. 7

It is worth noting that Descartes was not a “naïve reductionist”—merely a reductionist. His goal, as he explains, was to build back up to a global level of knowledge. The shortcoming of his thought process was in seeing the body as a collection of parts as opposed to a system of integrated and interrelated units composing a dynamic whole. Contemporary medicine, as Dr. Strange notes in the opening quote, suffers from “naïve reductionism,” which can be characterized as follows: the body is a collection of organs, composed of tissues which are composed of cells, which are managed by genes. Therefore, the object of study is genetics, and the proteins and cellular activity that it guides. The true role and effect of each cell can only be discovered studying each variable in isolation, so as to rule out the effects of other variables. The sum of the effects of each individual variable is an accurate reflection of the function of the whole organism because it is merely a collection of parts. Because the cell is the ultimate unit of function and the genes contain the code that runs the cell, diseases arise from faulty information contained in genes, or due to faulty translation of genetic information. Therefore, genes are the cause of disease, not its mechanism.8–23 According to this approach, symptoms express the loss of control and order within the body due to faulty genes. Because, as the 17th-century philosophers noted, order is the hallmark of perfection and functionality, order must be restored to an unruly body. In order to restore order to the organism, symptoms must be controlled. Therefore, to control symptoms is to treat disease. The best treatment is the one that has the most precise control over the most specific single variable of dysfunction. The best treatment will be predictable in action and noncompetitive in its control. In this paradigm, only a single-compound drug, with a single mechanism of action on a single locus of activity can reliably control, ergo, “treat” disease.

In the last 60 years a shift has taken place in science and philosophy away from the reductionist trends of the last 500 years. More recent studies in physiology have revealed the existence of complex supersystems of physiologic regulation.24–36 Experimental and clinical studies have revealed the multifactorial nature of disease, as well as the high degree of interrelatedness of physiologic factors and systems.1, 37, 38 The conclusion of a growing number of researchers is that the body functions like a system, not as a collection of isolated parts, and therefore must be studied as a system. A paradigm shift in health care toward a systems analysis may offer a scientific approach to diagnosis and treatment that makes progress where the current paradigm has reached a plateau. The theory of Endobiogeny proposes such a paradigm shift.

A return to epistemology in medicine Science without epistemology is—insofar as it is thinkable at all—primitive and muddled. Albert Einstein.39

Medicine as a cultural product Healing is one of the earliest human endeavors. Neanderthals successfully performed trephination, patients surviving and healing from the procedure.2 In ancient civilizations such as Egypt, India, China, Greece, and Iran, medicine was understood to be a cultural endeavor. That is to say, it was the product of cosmological and philosophical considerations that produced a certain set of values and worldviews. The nosology and pharmacopeia were products of a coherent set of interdisciplinary constructs. From our perspective, contemporary medicine remains a cultural endeavor with a scientific method of analysis, not a scientific endeavor expressed through a cultural lens. This distinction is important. Stating that medicine is a cultural endeavor does not make it unscientific, unrigorous, or subjective. It simply acknowledges that it arises from an a priori set of cultural beliefs and biases that fundamentally create the constraints of what questions are asked and how diseases are categorized—if they are determined to exist at all. As Chilton Pearce noted in 1971 in The Crack in the Cosmic Egg, A question determines and brings about its answer just as the desired end shapes the nature of the kind of question asked. This is the way by which science synthetically creates that which it then ‘discovers’ out there in nature…We pick and choose, ignore or magnify, illuminate or dampen, expand upon or obscure, affirm or deny as our inheritance, adopted discipline, or passionate pursuits dictate. Ref. 40, pp. 6, 11.

Science may be an impassionate, objective observer, but scientists are not. Some wish to see science as a new

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religion, and scientists as its priests and priestesses, but neither is true (cf. scientism below). Religion explains why something is, but science is a method to understand how it is. An objective assessment of truth would not change over time, yet the consensus of the scientific community does change over time. Why? Because facts change. And what determines the subjects of study that generate facts? It is the cultural conditioning of the scientist in each age. As culture changes over time, so do philosophy and science, and thus, medicine. If we are to understand why our current method of medical practice is not sufficient and how it can change, we must remove ourselves from the context of our practice and learn how we know. In other words, we must acquire knowledge of how we acquire knowledge. Thus the first step in the success of endeavors lies in an epistemological analysis. All knowledge is the intersection of an absolute truth and our a priori beliefs, as demonstrated in the Euler diagram (Fig. 1.1). The more we know how we know, the more we can expand our beliefs about what is possible. The more we do that, the greater the intersection between the truth and the belief, viz. knowledge. Thus, after millennia of human civilization, philosophy still precedes medicine.

Five epistemological methods in medicine Traditionally, four methods of knowing have been identified: traditional, empirical, rational, and intuitive. To this we add in Endobiogeny a fifth method: synthetic. A synthetic approach utilizes two or more of the general m ­ ethods

Propositions Poorly justified true beliefs

Truths

Beliefs Knowledge

FIG. 1.1  Euler diagram: knowledge as the intersection of truths and beliefs. (From Wikimedia Commons by user Krishnavedala [CC0].)

to create a dynamic, holographic method of knowing. One method is not inherently superior to another. The value of each approach is based on how applicable the method of knowing is to question to be answered and the level at which we wish to understand it (cf. Table 1.1).

Traditionalism The traditionalist approach considers what has historically or traditionally been done. Its value is self-evident to those who practice it. Their reasoning is that if it were not effective, it would not have been continued to be practiced. In other words, there is a belief that a communal wisdom exists that retains what is expedient, good, and wise and discards that which is not. Traditional healing systems, such as

TABLE 1.1  Summary of epistemological methods, advantages, disadvantages and indications for use Method

Advantage

Disadvantage

Essence

Best use

Traditional

Anticipated results

Cloistered, self-referential knowledge

It’s right because this is how it has always been done

Symptomatic treatments

Empirical

Self-validation

Selection bias

It’s right because I see the results

Personalizing care Rare cases without clear treatment guidelines Working in areas of specialized knowledge

Rational

Objective, dispassionate, reproducible Knowledge

Can disregard other approaches

It’s right because I have proven all other ways as not right

Selecting precise treatment Sharing results with colleagues

Intuition

Grasps the whole

Hermetic knowledge

It’s right because I have experienced its rightness

Treating the person as a whole

Synthetic

Uses best elements of all ways of knowing

Requires reflection, intellectual flexibility

It’s right because I have intuited, rationally evaluated, then empirically observed what I tested, then established its relationship to tradition

All cases: full application of theory of Endobiogeny

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Ayurveda and Chinese five-element theory, rely in part on this approach. In the face of demands for “scientific proof” a traditional practitioner might say, “Isn’t thousands of years of continuous use and results proof enough? I don’t need a double-blind randomized trial to demonstrate that Triphala (Phyllanthus emblica, Terminalia belerica, Terminalia chebula) is effective for digestive health, or, that a needle in Lung point 2 is beneficial for dyspnea.” For those not learned in these traditions, the challenge of accepting a traditionalist proof is the observation that all forms of knowledge are bound to particular cosmologies and terminologies. “Excess cold with deficient moisture” is not a term that resonates with a contemporary, materialist thinker. What contemporary thinkers do not realize is that they are themselves in a form of traditionalism. There is a cosmology, an ideology of molecular biology and the scientific method that is held to be the Truth. In other words, while research findings are up for debate, the methodology of research and the underlying assumptions are not. According to Harvard professor of evolutionary biology Richard Lewontin, this is particularly true for biology, and by extension, medicine (in our opinion). Professor Lewontin writes: All of physical science seemed blocked by the repeated conflict between classical formulations and the new observations of radioactivity, of light, and of astronomy. Without relativity and quantum theory, physics and theoretical chemistry would have ground to a halt. On the other hand, biology, far more diverse in its subject matter, far more loosely tied together into a coherent science, has undergone a radically uneven development…Developmental biology, the study of cognition and memory, and evolutionary biology, on the other hand, have profited only marginally from these rapid advances. Rather, they are stalled by their attempt to use outdated concepts to confront a rich phenomenology to which these concepts clearly do not apply. Evolutionary biology suffers particularly because it is the nexus of all other biological sciences, so that a lack of progress in developmental biology, in ecology, in behavioral science, all are fatal to a proper understanding of evolution. Ref. 41

Scientific reductionists demand that traditionalists prove to their satisfaction the truthiness of their traditional beliefs without realizing that reductionism is itself now a traditional belief system with all the associated dogmatism that can come with traditionalism. Even when a clinical study demonstrates efficacy of a traditional approach, reductionists merely suspend their skepticism of if it works. They retrain their skepticism as to how it works, because they only accept mechanistic, materialistic explanations of how biological activity occurs. Physicians trained in the biomedical paradigm like to believe that they do not use a traditional approach to knowledge,

but studies in medical economics and medical education beg otherwise. In the United States, there are highly regionalized practice styles with respect to rates and types of surgical intervention. In addition, over 80% of a physician’s knowledge base is acquired during training with less than 20% added over the next 30–40 years of practice. In other words, we tend to practice how we were taught during our training, which is how someone else was taught to practice during their training. The majority of physicians practice in the same region of their highest level of training, which merely reinforces the perception that the (traditional) community standards are indeed the best way to practice medicine. The strength of traditionalism with respect to nonmodern and prerational knowing is that it offers a starting point for further investigation and clarification for the rational thinker. This is true in clinical Endobiogeny. The basis for evaluating the Endobiogenic effects of medicinal plants arose from traditional usage by both prepharmaceutical physicians of the earlier centuries, as well as ethnobotanical reports (cf. history of Endobiogeny below). Not infrequently an established medical practice becomes accepted as tradition, rejected by later studies, and then readopted decades later. Something we refer to as revivalism. The ketogenic diet is a good example. It was first evaluated for seizures as early as 1921.42 Despite its impressive efficacy over the early and crude antiepileptics—a 50%–66% rate of resolution or reduction in seizure activity—it was abandoned when new antiepileptics entered the market. Then it was rediscovered decades later. Even now, perhaps based on certain prejudices, the ketogenic diet remains a third-line treatment, despite few side effects compared to antiepileptics.43–45 In summary, the traditionalist approach values continuity and communal wisdom. For rationalist thinkers, traditional approaches should be approached with an open mind and as a starting point for further investigation.

Empiricism To be radical, an empiricism must neither admit into its construction any element that is not directly experienced, nor exclude from them any element that is not directly experienced. William James, MD, Philosopher-Psychologist, Father of American Psychology.46

Empirical knowledge is knowledge that is gathered through the senses, particularly observation. In the context of this discussion, we will define empiricism as a nonmethodical, nonexperimental method based on the use of senses. In other words, we refer to the daily experience of practitioners in forming an impression, implementing treatment, and observing results at a later time. The rational experimentation of scientists, also using their senses (or devices read by their senses) will be discussed in the next section.

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For most physicians and healers, empiricism is the method of knowing most relied upon. Results are all the proof required for the empirical physician. It allows for a personalized and contextualized practice of medicine. It can be compassionate and passionate, yet factual and based on cultural coherence and scientific rationalism. When it is practiced, as the great philosopher, physician, and psychologist William James proposed, in its “radical” truth-seeking method, it can be an epistemological method of great value. Radical empiricism requires that the observer accept dispassionately results that were (1) anticipated and verified, (2) not anticipated but verified, or (3) anticipated but negated, to alter practice where indicated. Radical empiricism respects the context of clinical practice but demands an openness to change. The particularities of the patient, the physician, and the culture at a particular point in space and time are valued. It is what allows a practitioner to say, “In my experience, for a woman of your age, treatment “x” would be better.” For example, a nursing mother who suffers from poor sleep quality would not be prescribed a benzodiazepine or melatonin for sleep by an empiricist. It is relatively contraindicated for two reasons. The first is exposure of the infant through nursing to the metabolites of these substances. The second is impairment of the mother’s alertness for on-demand feeding. The Endobiogenist, using an empirical approach, might recommend a lifestyle intervention, such as breathing techniques or binaural hemispheric synchronization music. In addition, they might recommend medicinal plants that regulate autonomic tone while supporting breast milk production, such as essential oils of lavender and fennel in a base of vegetable glycerin. These treatments have anticipated effects based on traditional usage, repeated personal experience, and experimental evidence. As valuable as the empirical approach is, senses can be deceived. Moreover, our self-limiting beliefs of what is possible and what is probable creates a self-referential, echolalia of concurrence from a chorus of believers standing between two mirrors reflecting upon themselves, reinforcing the validity of what we already believe to be true. In other words, it is not “seeing is believing,” but “believing is seeing.” This may be why on average it takes 20  years for conclusive evidence in disease management to be applied by the average private practice physician. They feel that they know through empirical experience what works. They do not feel that they need someone else to tell them how to practice good medicine. They resist change, even when studies demonstrate that another way—within their own paradigm—has superior outcomes. This self-serving empiricism closes us off to new ideas, which brings up a paradox. Today’s traditionalism was founded on yesterday’s empiricism. The only way to not fall into rigid traditionalism is to constantly question what

we believe we have empirically experienced, and to be ­prepared to change our minds if the facts prove otherwise. In summary, radical empiricism respects the individual knowledge of the practitioner when applying traditional or rational knowledge in the context of their specific patient’s health-care needs.

Rationalism Rational knowledge is the third way of knowing. It is the foundation of the scientific approach and hence the theoretical foundation of biomedical medicine. It is a particular type of empiricism referred to as logical positivism. The logical aspect of positivism refers to its use of deductive reasoning: the systematic and logical reduction of ideas to their most simple form. As noted in the introduction, Descartes promoted deductive reasoning as only one method of knowing in order to establish foundational concepts. He also promoted inductive reasoning to reassemble the basic facts. There are a number of valuable aspects to the scientific method. It is quantitative and repeatable. It allows third parties to empirically and rationally evaluate one’s findings. Finally, it allows findings to be communicated with clarity and precision. The use of biomarkers such as hemoglobin A1c and physiologic data such as blood pressure are good examples of the success of this approach. Their validation through statistical sampling of population-based data is also testament to the value of mathematics in the rational method. The basic elements considered in the theory of Endobiogeny are the fruit of positivistic scientific research: the discovery of the endocrine system, membrane receptors, hepatic metabolism, digestive enzymes, etc. The discovery of life-saving medications, surgeries, and devices are all derived from this type of research. The traditionalist approach to knowledge will not substitute for electrocautery or mechanical ventilation. A community physician’s personal experience with walking pneumonia did not help discover human immunodeficiency virus or lead to the development of retroviral medications. Rationalism has a unique potential in the expansion of scientific observations and the generation of objective data. It is only in modern times with the advancement of biology, then genetics, then molecular biology that the reductionist approach has become naïve reductionism. You cannot determine how a bird flies by killing it and dissecting it. With dissection, you only evaluate the structural component of its wings and not the method by which the bird knows how and where to fly. The adage “know thyself” cannot be extended to the biochemistry of the Krebs cycle. To know the Krebs cycle is not to know oneself as a global system! There are emergent properties that occur in the transition from physics and chemistry to biology. If we have a defective Krebs cycle, are we a defective human being? The absurdity is clear.

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The term “positivism” refers to the study of what is detectable—the gathering of empirical data. Science relies on the senses to receive data—positive empiricism. Even in the case of highly sensitive devices, scientists rely on the devices to sense for them. According to the rationalist approach, the phenomenon must be sensed and noted not from within but from without—by multiple parties. It is not that the undetectable does not exist, merely that it is not worthy of study, according to logical positivists. Thus, dreams, intuitions, or remote viewing are not phenomena considered worthy of scientific study. As the founder of quantum physics, Werner Heisenberg noted, The positivists have a simple solution: the world must be divided into that which we can say clearly and the rest, which we had better pass over in silence. But can anyone conceive of a more pointless philosophy, seeing that what we can say clearly amounts to next to nothing? If we omitted all that is unclear we would probably be left with completely uninteresting and trivial tautologies. Ref. 47

Many cultures have had systematic ways of knowing but not a scientific way of knowing. The scientific method is based on a proposition that knowledge can be objectively and systematically determined. It seeks to disprove its own assumptions and only when it fails to disprove itself does it accept findings and revise its assessment of reality. In other words, it seeks not to prove the truth, but to disprove falsehood. This has been a true advance in human understanding, when practiced with integrity. It offers an approach to knowledge that is not dogmatic or ideological. It is based on facts, not speculations, assumptions, or tautological statements. The problem is that science has become an ideology based on the particular beliefs of materialism and reductionism, of the authority of scientists, and the personification of science as a living entity of independent intelligence, referred to as “scientism.”48 Adherents of scientism reject criticism from all disciplines considered insufficiently scientific, including philosophy. Ironically, professor of philosophy Alex Rosenberg is among the most vocal proponents of scientism, writing, “If we’re going to be scientistic, then we have to attain our view of reality from what physics tells us about it. Actually, we have to do more than that: we’ll have to embrace physics as the whole truth about reality” (p. 20, emphasis by author).49 Scientific research that does not fit their strict materialist criteria is decried as pseudoscientific. It is not enough in their view to use the scientific method or draw from experimental observations. One’s conclusions must fit into their cosmology to be considered scientific. Endobiogeny is a defender of the value of rationalistic inquiry on two conditions. The first is that it is used with

other epistemological methods. The second is that the deductions of logical positivism are recontextualized by inductive thinking into the whole. The challenge we see today is not with the scientific method, but scientists themselves. Setting aside the adherents of scientism, many scientists have good intentions but remain insufficiently trained in epistemology to bring awareness to how or why they choose to study, and that implicit biases affect their study design and conclusions. Another problem is poorly conducted scientific trial. Many clinical trials have inappropriate use of statistics, or conclusions not supported by the sample size. There is also a lack of imagination, with studies that repeat prior studies, concluding that “further research is required.” Worse, we have studies that fail to be replicated—a significant proportion of all published studies.50–54 Even worse is the increasingly frequent occurrences of plagiarism in science55–60 and retracted studies due to falsified data.61 Ironically, Alex Rosenberg acknowledges the fallibility of scientists but holds on to the infallibility of science to produce “the whole truth about reality.”49 In effect, we have a panel of cats tasking themselves with defining the reality of what it means to be a dog. We recommend some humility on the part of scientists about how close we can arrive at a complete sense of reality. Another challenge facing scientists is that science is a social, cultural, and economic endeavor. Scientists need money to conduct experiments. We are not in the age of Lord Kelvin and other brilliant minds who were self-funded thanks to inherited wealth. The two major sources of funding are governments and industry. Industry has imbricated itself for nearly 100  years into the workings of government and the direction of funding.62–64 What gets funded is “sexy” research. Research that reviewers and funding agencies consider worthy of study is not necessarily what piques a scientist’s curiosity. Richard Lewontin observes, “Science is molded by society because it is a human productive activity that takes time and money, and so is guided and directed by those forces in the world that have control over money and time.”65 One of many examples of the confluence of factors in scientism is the case of Harvard molecular biologist David Sinclair. In an interview with the Washington Post in 2015 he stated that he has been concerned about the “gravity of life” since he was 4  years old. What motivates his research? Clinical care? Careful observation? A philosophical approach to the nature of life and the formation of living organisms? No. It is his personal fear of death and his mother’s bout with lung cancer.66 His research goal is to find a single pill to prolong life and prevent multiple degenerative illnesses. He has started several biotech companies to profit from taxpayer funded research and is working with the US Food and Drug Administration to classify aging as a treatable disease, so that he can study something found in nature,

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put it in a pill, and make money from it with his company. He recommends taking the pill from 30 years of age with a goal of extending life to 150 years of age. What drug company and shareholder would not like to see healthy people taking their drug for 120 years? This type of research is not dispassionate and objective, but personal and motivated by a confluence of economic and psychological motivations. Reason is a philosophical and cultural choice. When it is applied to the scientific method, science then becomes a cultural phenomenon. When scientists see their work as free of culture, personal beliefs, traditionalism, and empiricism, it becomes a rigid ideological phenomenon with Jacobean consequences against dissenters. One need only consider the scientific “defrocking” of luminaries, Nobel Prize winners and thinkers of stunning originality.67, 68 Consider, e.g., Rupert Sheldrake, PhD, who discovered key plant growth factors. He was vigorously criticized for proposing a theory of formative causation. In an unprecedented move a prominent journal allowed anonymous scientific criticism (against the dignity of peer review) and had his TED talk blocked from being disseminated on the internet due to pressure from his critics.67, 68 Luc Montagnier is a 2008 Nobel laureate in Physiology and Medicine for his role in the discovery of the HIV virus. Late in his career he published studies detecting electromagnetic signals of bacteria in high-dilution water that no longer contained any detectable levels of the living bacteria. A theoretical chemist stated: “If [Montagnier’s] results are correct, these would be the most significant experiments performed in the past 90 years, demanding re-evaluation of the whole conceptual framework of modern chemistry.”69 But rather than consider re-evaluating the framework of modern chemistry, Montagnier faced what he called “intellectual terror,” had all funding proposals rejected in his home country of France, and decided to move to China to research and publish there. Nobel laureates are not immune to defrocking. Another Frenchman, immunologist Jacques Benveniste discovered platelet-activating factor in 1979 and later became the head of a major research institution in Paris. In 1988 he produced research, published in the prestigious journal Nature on the activity of high-dilution IgE on degranulation of basophils. The article was published with an editorial of incredulity. Benveniste lost his research funding after failure of others to replicate his results. Further research on this phenomenon was rejected from publication and one article that went to press was stopped by the French Academy of Science and all copies destroyed.1 At the most pragmatic level one must consider if a ­naïve-reductionist methodology is really the only or best way to expand human knowledge. Based on their own 1. Benveniste en mémoire, La chronique d’Eric Fottorino, Eric Fottorino, Le Monde 6 octobre 2004.

c­ riteria, one may simply evaluate the results. Consider the success rate of new chemical entities (NCEs, i.e., pharmaceuticals) that make it to market. Over the last 30 years 15% of NCEs tested in phase 1 clinical trials ultimately went to market.70–72 In other words, with millions of scientists, billions of dollars of research, and decades of studies, the reductionist, rational scientific method has an 85% failure rate. If farmers had an 85% failure rate, we would have starved to death. If only 15% of automobile prototypes were considered safe enough to be driven, auto companies would have gone out of business. What we have discussed so far is the approach of scientists with other scientists. Logical positivism also grapples with perceived validity of non-Western healing practices and the wisdom of community physicians. Logical positivism tends to show “contemptuous disregard for the resources of tradition”73 considering precartesian thought as superstitious and illogical. This is not inherent in the method, but in the practitioners of the method and a smug sense of superiority. The editors of the Journal of the American Medical Association (JAMA) famously wrote, “There is no alternative medicine. There is only scientifically proven, ­evidence-based medicine supported by solid data or unproven medicine, for which scientific evidence is lacking.”74 In essence saying, “If I cannot prove it, it doesn’t work no matter what your experience with it is.” Despite such a categorical statement, they were able to acknowledge in the same article that, “many therapies used in conventional medical practice also have not been as rigorously evaluated as they should be.” However, their conclusions were not to discontinue all standard Western medical practices derived from the empirical experience of physicians or from studies paid for by pharmaceutical companies. In the same editorial, the editors of JAMA expressed concern for patient safety and costs for receiving something like acupuncture or a homeopathic remedy. However, the vast majority of spending occurs through the health-care system and technological medicine that remains unsatisfactorily proven, driven by industry bias and profit motives. An example is the treatment of prostate cancer. Expensive, money-generating procedures are favored by hospitals and surgeons even when less invasive, safer, and equally efficacious methods are available.75 In psychiatry, there remains a serious overprescription of antipsychotics to the elderly and children, problems with kickbacks from drug companies, and the use of newer and more expensive antipsychotic medications that have not proven superior to older, less expensive generic medications.76 Finally we note the ever-rising fines paid by drug companies in the order of billions of dollars for malfeasance relating to their promotion of medications while not disclosing risks.77 Finding the right role of rationalism vs empiricism (e.g., experience) is challenging. In the science fiction television show Star Trek, the ship’s chief surgeon, Dr. “Bones”

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McCoy represents the empirical physician. His recurrent tête-à-tête with the hyperlogical chief science officer Mr. Spock embodies this conflict: MCCOY: I know you, Mister Spock. You’ve never voiced it, but you’ve always thought that logic was the best basis on which to build command. Am I right? SPOCK: I am a logical man, Doctor. MCCOY: It’ll take more than logic to get us out of this. SPOCK: Perhaps, Doctor, but I know of no better way to begin…I will do whatever logically needs to be done. Star Trek, Season 1, Episode Galileo 7, January 5, 1967 airdate.

In summary, the rational positive model of scientific inquiry offers advancement in human thought that eschews bias and personal motive or desired outcome. It offers an objective, testable method of verifying and reproducing certain types of events. When misapplied, it denies the value of all other forms of knowing. When used along with other types of thinking, it can offer a rich foundation of knowledge. Good scientists are logical positivists. Great scientists are intuitive, using logical positivism to elaborate and establish the verity of their intuition (cf. below).

Intuition Certainly, those who can conceive the causes of phenomenon in their minds before the phenomenon themselves have been revealed are more like the Architects (of the Universe) than the rest of us, who consider causes only after they have seen the phenomenon. Do not, therefore, Galileo, begrudge our predecessors their proper credit…you refine a doctrine borrowed from Bruno. Johannes Kepler in a letter to Galileo Galilei Dissertatio cum nuncio sidereo, nuper ad mortales misso Galilaeo Galilaeo, mathematico Patavino, 1610 regarding the scientist Giordano Bruno, burned at the stake for heresy.78

The fourth method of knowing is intuition. Intuition is a suprarational method of understanding. It does not use analytical reason to know. It grasps the whole and the relationship of the parts to the whole instantaneously. It occurs without ratiocination and in a manner that was neither selfevident nor accessible by pure reason.79 Rationalism rejects intuition because the absence of a shared point of objectivity, making it unverifiable by others. However, intuition does not reject rationalism. In fact, it depends on it to make clear to others what is instantly grasped by the recipient of intuitive knowledge. Immanuel Kant stated it like this: “All human knowledge begins with intuitions, proceeds to concepts, and ends with ideas.”80 Many of the greatest ­scientists have relied on intuition. Einstein’s special theory of relativity, Kekulé’s discovery of the benzene ring, Pauling’s discovery of hemoglobin’s deformed shape in sickle cell

anemia were all dreams or flashes of suprarational knowing, later proved through rigorous experimentation. The ability to understand and apply intuition is based not only on the depth of one’s formal, rational, and empirical knowledge, but also on the traditional knowledge (viz. culturally normative beliefs). We cannot receive and retain intuitively what we have no basis to perceive or grasp intellectually. A healer’s intuition allows him to grasp the wholeness of the patient, the healer’s state, and the environment in which the patient and their illness exist. Nevertheless, it is neither a reproducible experience nor can it be taught to or evaluated by others using rational means. In the manner of Kant, we can conclude that intuition is a spring of wisdom that nourishes, sustains, and revivifies the roots of traditional knowledge, strengthening the trunk of empiricism and sweetening the fruit of rationalism. However, there is a fifth epistemological method that integrates the four levels of knowledge called syntheticism. Syntheticism creates a truly dynamic method of knowing.

Syntheticism: The fifth way Thoughts without content are empty. Intuitions without concepts are blind…Understanding intuits nothing. Senses think nothing. Only through their union can knowledge arise. Immanuel Kant, Critique of Pure Reason, p. 93.80

Synthetic thinking is a method of utilization of all forms of knowing in various proportions to expand the breadth and depth of knowledge. It increases certainty and brings us ever closer to veracity. Syntheticism results in a dynamic, fractal, and holographic assessment. We consider it to be the preferred way of knowing. It offers greater degrees of freedom for the clinician to assess and select a treatment plan for the patient. Good clinicians utilize one or two epistemological methods, but great clinicians are synthetic, even if they are not aware of their process of knowing. Whether a skilled interventional radiologist, ayurvedic hakim, acupuncturist, therapist, or Endobiogenist, one will find them to be synthetic in their approach. For example, you determine that a patient requires liver drainage. Do you use milk thistle? Agrimony? Dandelion? Artichoke leaf? Yarrow? A combination? At what dose? For how long? You start with a rational assessment of the terrain,2 and consider the chief complaint and conclude that milk thistle and dandelion should be used. But empirically, you have found that 10% of your patients have experienced biliary colic due to dandelion’s impressive drainage effects. 2. Endobiogeny is a theory of terrain. Dr. Duraffourd defined terrain as all the structural and functional elements that interact in a dynamic fashion to create, maintain and adapt an organism in its expression of Life. See Chapter 2: A general overview of systems theory, integrative physiology, and the theory of Endobiogeny for a full discussion.

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You consider the traditional use of agrimony. And you recall how you have a long-standing relationship with a compliant patient who prefers a slower but safer method of healing to a rapid and aggressive one. With all this in mind, you determine that using milk thistle and agrimony is the most expedient and rational treatment. In a matter of 2 min, you have used a synthetic, Endobiogenic approach to clinical medicine. In conclusion, there are four methods of knowing and a fifth way for integration, summarized in Table 1.1.

A brief history of the theory of Endobiogeny The theory of Endobiogeny originated with Christian Duraffourd (1943–2017), MD and was developed over 40 years thanks to the tireless efforts of two generations of physicians, all performed without private or governmental grants. The growth of Endobiogeny can be divided into six distinct phases, described below.

Phase 1, Pre-1970: Loss and revival of medical phytotherapy France of the early to mid-20th century saw the development of the triumph of Pasteurian thinking: a single chemical treatment for a single cause of a single disorder. With this rise of “pharmaceuticalism” and the standardization of medical care, the grand French tradition of use of medicinal plants by physicians had been effectively eliminated. In the 1950s, Dr. Jean Valnet, a military surgeon, was exposed to the use of medicinal plants and medical aromatherapy during his time serving in the French Indochina war. With the publication of various books and articles between 1964 and 1971, Dr. Valnet reawakened an interest in the role of medicinal plants in medicine.81, 82

Phase 2, 1970s: The age of empirical clinical phytotherapy Clinical phytotherapy is the application of medicinal plants based on a systematic assessment of traditional usage, empirical observations, in vitro, in vivo and clinical evaluation of therapeutic actions. At the dawn of the decade, two significant events occurred. Two young doctors, Jean Claude Lapraz and Christian Duraffourd, were soon confronted with the limits of an approach based exclusively on contemporary scientific information in taking care of their patients.81 In 1971, Dr. Valnet, along with Paul Duraffourd, pharmacist and father of Christian Duraffourd, founded the Association d’études et de recherche en a­ romathérapie et phytothérapie, renamed in 1975 as Société Française de Phytothérapie et d’Aromathérapie (French society of Phytotherapy and Aromatherapy). The role of the

association was to inform physicians of the role that medicinal plants might play in medicine. During this time, Drs. Duraffourd and Lapraz began working with Dr. Valnet and Paul Duraffourd. The two young doctors started what would be over four decades of teaching and writing.82 The structuration of clinical phytotherapy and medical aromatherapy were precisely defined with clear rules on the use of internal and external routes of administration, most notably in a course in an international congress organized in 1978 with the faculty of medicine of Tours, France. This new information was brought to the attention of the French ministerial commissions on which the two physicians participated. At the same time, they conducted experimental studies into the active therapeutic effects of medicinal plants based on the modern principles of pharmacology. The various levels of action and novel modalities of application were identified along with new therapeutic properties. This last endeavor proved to be quite impactful on the future of Endobiogeny. Between 1973 and 1980, the group standardizes the methods and interpretations of the aromatogram, similar to an antibiogram. It was an attempt to evaluate the “strength” and specificity of individual essential oils against the organisms cultured from their patients during infectious states. The goal was to more precisely use essential oils comparing their activity against that of antibiotics. Impressive and convincing clinical results were obtained. However, calculations of the pharmacokinetics and tissue concentration of essential oils were confusing and showed that the antiinfective effects could not be explained by mechanisms of activity comparable to those governing that of antibiotics. The very small concentration of active ingredients contained in the essential oil preparations absorbed by the patients could not explain the positive results. They hypothesized that mechanisms other than those involved in the antiinfectious activity of antibiotics must be in play. These mechanisms, they reasoned, must necessarily involve the capital importance of the reactivity of the patient in response to the global activity on the human body of the multiple active ingredients contained in the essential oil. The notion of terrain then appeared to be fundamental to understand how the medicinal plant acts on this organism. Clinical phytotherapy placed the plant at the center of clinical reflection and its use was symptomatic and mechanistic. The plant was considered to be a utilitarian object to replace the harmful effects of pharmaceutical products or offer amelioration of recidivistic conditions.81 As the decade progressed it become progressively clear to Drs. Duraffourd and Lapraz (Fig. 1.2) that a new theory must be developed that placed the patient and their terrain at the center of the clinical reflection. The use of medicinal plants must be the result of the reflection, not its foundation. Furthermore, it would need to be applied to the particular characteristics of the individual’s terrain and not exclusively to the presenting

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phytotherapy. This decade also saw international participation in conferences and seminars throughout Europe. They published a series of system-specific books detailing the results of their research and clinical observations in the use of medicinal plants, Cahiers de phytothérapie Clinique in five volumes between 1982 and1984.83

Phase 4: 1990s: Advances in clinical Endobiogeny and international teaching

FIG.  1.2  Christian Duraffourd (right) and Jean Claude Lapraz. Paris, France, 1978.

symptoms. By the end of the decade, the young physicians began to develop a theory of terrain and integrative physiology, but had not yet arrived at the fullness of the theory later referred to as Endobiogeny.

Phase 3: 1980s: Formalization of a new theory, official ties, and rational clinical phytotherapy In the 1980s, the term “terrain” was in vogue in France and was being used by various healing traditions without a precise and scientific definition. Based on observations going as far back as medical school, Dr. Duraffourd began to develop a theory of terrain. It was based firmly within contemporary scientific notions of physiology while incorporating systems thinking to avoid reductionist tendencies. It also eschewed the terminology of premodern, prescientific medical systems since the age we live in and our reference point is scientific and physiologic. In 1989 he coined the neologism “Endobiogeny”3 to distinguish a specific theory of the terrain originated by him and developed with Lapraz and their now growing team of physicians. In 1990, the term was used in public lectures for the first time, replacing the general term, “theory of the terrain.” The term Endobiogeny literally means “how life is managed by internal processes.” By 1983, the concept of clinical phytotherapy began to garner the attention of academics. Drs. Duraffourd and Lapraz began to teach at the universities of Lille and Montpellier in France. They worked with the French Ministry of Health and participated in various national and European commissions, advocating for rational clinical

3. Dr. Lapraz recounts, “Christian called me and said, ‘I am going to call my new theory ‘Endogeny’. We discovered that the term was already in use in biology, referring to internally derived, or, endogenous processes. So Christian changed the name to ‘Endobiogeny’.”

The 1990s witnessed the growth of Endobiogeny and the diffusion of its teachings beyond continental Europe. During this time, a group of physicians working with Drs. Duraffourd and Lapraz organized teachings based on Dr. Duraffourd’s theory of Endobiogeny. The notion of endocrine axes of alternating catabolic and anabolic action was developed. The relationship between central and peripheral hormones and the clinical applications of these ideas to various disorders were formalized from the 1990s into the 2000s. With a clear set of clinical teachings developed under Dr. Duraffourd’s guidance, Dr. Lapraz and his team began to travel across the United States (Lapraz) and United Kingdom (Lapraz, Colin Nicholls), Mexico and North Africa (Lapraz, Drs. Alain Carillon and Jean-Christophe Charrié) introducing clinicians to the concepts of Endobiogeny and the original teachings. With growing confidence in their theory, a series of case studies were presented in France, and in Mexico along with the faculty of medicine of Mexico, the National Institute of Anthropology and History, and the Mexican Society of Clinical Phytotherapy with Dr. Paul Hersch Martinez,4 an instrumental researcher-physician and supporter of Endobiogeny in Mexico. Another sign of the growing confidence in Endobiogeny was the humanitarian work performed from 1997 to 2000 in multiple African countries. The Ministry of Health of Senegal invited Drs. Duraffourd and Lapraz to conduct a clinical trial using medicinal plants and illite clay in patients with leprosy. The Ministry of Health of Madagascar invited them to help address an epidemic of acute diarrhea and dehydration (conducted with Drs. Carillon and Charrié). The official ministerial reports confirmed the objective reality of the results obtained in this type of pathology using the approach of clinical Endobiogeny. From 1989 to 1996, Drs. Duraffourd and Lapraz began a fruitful period of consultation on oncology p­ atients in

4. Dr. Hersch Martinez is doctor in medicine and social health sciences, member of the National Academy of Pharmaceutical Sciences, researcher at the National Institute of Anthropology and History, President of the Mexican Society of Clinical Phytotherapy, member of the National Society of Researchers, of the National Academy of Pharmaceutical sciences, of the Permanent Pharmacopeia Commission and the International Plant Conservation Commission.

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conjunction with Professor J. Renier at Hôpital Bouçicaut in Paris. During this time, Drs. Duraffourd and Lapraz published a series of briefs on their work in oncobiology. Arising from this work, Dr. Duraffourd sought a way, using standard blood work, to evaluate the relativity capabilities of physiologic activity. He called this analysis the biology of functions, and the first of what would become over 150 indexes was developed, called the Genital ratio (cf. Chapter 15). The decade culminated with an international congress held in Tunisia by Professor R. Chemli of Tunisia, and Drs. Duraffourd and Lapraz (1997).

Phase 5: The 2000s: Maturation of Endobiogeny With the new millennium came the evolution of the phytotherapy society to La Société Française d’Endobiogénie et Médecine (SFEM): the French Society of Endobiogeny and Medicine. Endobiogeny was now front and center as a new scientific theory. In 2001, Drs. Duraffourd and Lapraz published their magnum opus Traité de Phytothérapie Clinique (A treatise on clinical phytotherapy).84 Endobiogeny as a theory of terrain was introduced to the general public and practitioners alike. The summary of 30  years of work in clinical phytotherapy was reorganized and classified according to principles of integrative physiology. This work represented the first time in the known history of medicine the application of medicinal plants not by symptoms but integrative physiologic principles in order regulate the critical terrain of disease. The year 2004 saw the creation of a clinical and educational home for Endobiogeny in the United States in Pocatello Idaho, thanks to the patronage of the late Anne Marie Buhler of Time Labs and the support of Dr. Jean Bokelmann of Idaho State University Department of Family Medicine, Peter Buhler, and, Eric and Annette Davis. This decade also witnessed the adoption of Endobiogeny as an official form of medicine covered by the Mexican Ministry of Health. In 2007, the authors of these books first met at a conference in Idaho. Dr. Kamyar M. Hedayat was chief of pediatric intensive care and integrative medicine in Shreveport, Louisiana. This meeting was a major turning point in the history of Endobiogeny as it laid the foundation for the use of rational scientific deduction and induction to align the theory of Endobiogeny with the avant garde of mathematics, physiology, and philosophy. The first question Dr. Hedayat asked Dr. Lapraz is, “Where is the scientific evidence?” This was the beginning of a long and fruitful collaboration and friendship. Dr. Lapraz closely worked with Dr. Hedayat in order for him to gain an in-depth understanding of Endobiogeny and apprenticed him in teaching Endobiogeny throughout the world.

FIG. 1.3  Alain Carillon, teaching in Mexico City, Mexico, 2009.

In 2008, Dr. Lapraz, along with Drs. Carillon and Charrié formed a new professional society called Société Internationale de la Médecine Endobiogénique et Physiologie Intégratif (SIMEPI: The International Society of Endobiogenic Medicine and Integrative Physiology) (Fig. 1.3). It reflected Dr. Lapraz’s vision of emphasizing the international role of Endobiogeny in medicine, and the scientific importance of integrative physiology as a method of assessment. The SIMEPI has gone on to develop new institutions aimed at establishing Endobiogeny as a movement of community physicians and citizens interested in better health.

Phase 6: 2009–present: A new theoretician, new indexes, and new publications This current period is the time of scientific developments and publications. The first goal was to establish the theory of Endobiogeny and the role of biological modeling in clinical medicine. This was accomplished with theoretical articles,85, 86 followed by retrospective studies with our academic colleagues.87–89 The second goal, ongoing, is prospective studies on the predicative and prognostic possibilities of the biology of functions performed at an international level. The challenge remained to comprehensively elaborate the entire theory of Endobiogeny, which is more than the modeling tool the biology of functions. Starting in 2013, Dr. Hedayat, with the guidance and support of Dr. Lapraz undertook this task, the fruit of which are the four-volume series of The Theory of Endobiogeny. With this, we hope to finally place Dr. Duraffourd’s theory in the vanguard of integrative physiology.

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Dr. Hedayat’s contributions have focused in four areas: theoretical concepts, biology of function indexes (cf. Chapter 15), new applications of medicinal plants (cf. The theory of Endobiogeny, volumes 2–4), and pedagogy. The theoretical concepts include incorporation and elaboration of chronobiology and cosmobiology, characterization and classification of phenotypic subtypes in neuropsychiatric disorders (e.g., spasmophilia, depression, and autism). In the biology of functions, he has introduced new biomarkers into calculations, age and sex-specific normative values, new indexes modeling physiology, and phenomenological aspects of cognition and psychological tendencies. New applications of medicinal plants, mushrooms, and amino acids based on biology of functions indexes and evolutionary endocrinology have been introduced. In pedagogy, new teaching methods have been developed linking historical, physical examination, and biology of function findings to each other in clinical disorders. This decade also witnessed the growth in the group of Endobiogeny researchers and a flourishing of activity (Fig.  1.4). There are publications for the general public81, 90, 91 as part of a collaborative movement between citizens and physicians advocating for better health practices, and for practitioners.81, 92 In the social realm, Endobiogeny is recognized as an official form of medicine within the public health system of Mexico, and is the exclusive form of medicine used to treat US active duty and military veterans with posttraumatic stress by the charitable organization Mission 22. In summary, over the past four decades, the vision of Dr. Duraffourd has developed and been developed by a growing number of researchers into a clearly elaborated scientific approach to global systems applied to clinical medicine. Endobiogeny is a synthetic method derived from a rational scientific analysis of physiologic data with respect for traditional and empirical knowledge within a humanistic con-

FIG.  1.4  Jean Claude Lapraz, Kamyar M. Hedayat (middle), JeanChristophe Charrié (right). Taking a break discussing new developments in Endobiogeny. Paris, France, 2018.

text. It evaluates complexity and integrates data on multiple levels while maintaining the notion of interconnectivity and interrelatedness. It is an integrating medicine, to be distinguished from integrative medicine.

Integrative vs integrating medicine The Integrative medicine (IM) is a term coined by academic physicians to enlarge the number of acceptable concepts and therapeutic approaches within the current biomedical model while staying within acceptable norms of rational probity. It seeks to integrate, i.e., layer over, current approaches, additional therapies, especially where satisfactory pharmacologic treatments or surgical interventions are not available. It is more syncretic than synthetic. It neither explains why certain biomedical approaches are not effective, nor does it try to reform or reenvision the scope of medical science through a comprehensive and coherent theory of life. There are three general approaches adopted by IM researchers. The first is to compare complementary or “alternative” approaches to medicine to standard biomedicine in terms of quality of life or patient well-being.93 The second is to investigate “mind-body” approaches such as meditation or energy therapies which lack clear deterministic mechanisms of action but have proven clinical results. This is with the understanding that the use of these modalities (as opposed to medicinal plants with pharmacologic actions) will not encroach upon the dominion of academic medicine.94–96 The third approach has been to focus on diet and nutritional supplementation, avoiding the question of pharmacology and “pseudoscientific” treatments altogether.97–99 The IM approach has numerous merits and successes on which to rest its laurels. In the last 30  years it has made inroads into numerous academic centers (Duke, Cleveland Clinic, Harvard, Stanford, etc.), creating an office at the National Institutes for Health for funding, and published numerous peer-reviewed articles. It has also created a true shift in practice for community physicians. For example, in 2010 it was not considered respectable for physicians to recommend probiotics or fish oil to their patients. Physicians have had opportunities for postgraduate education that allow them to feel confident to offer symptomatic use of nutritional supplements for their patients, avoiding side effects of certain medications. The IM has played a role in slowly and incrementally increasing the possibility of having a dialogue with researchers on expanding the boundaries of scientific inquiry. What we wish to point out is that Endobiogeny is not within that tradition for all its efforts and results. It is a fundamental reexamination of the principles of science, the philosophy of life, and the use of mathematics to quantify physiology and psychology. Endobiogeny is neither an uncritical embracing of, nor movement away from modern principles of scientific inquiry. Neither is it an uncritical embracing of

Origins of Endobiogeny Chapter | 1  13

prerational methods. It does not seek to find “gentler” or more “natural treatments” merely to avoid side effects of medication or surgery or radiation therapy. Endobiogeny seeks to integrate and interrelate physiologic phenomenon in a way never done before in medical history in order to explain how a complex and dynamic system such as a human being can come into existence, develop and undergo the massive and dramatic changes from infant to adult, adapt to circadian, seasonal and circannual demands, and manage itself against internal and external aggressions. It offers this rational, deductive, and inductive approach in order for physicians to have a more precise understanding of their patients. The physician is free to use whatever therapy he wishes, from steroids to bee pollen, from surgery to acupuncture, and from hypnotherapy to hyperbaric oxygen therapy. Thus, the theory of Endobiogeny is an integrating form of medicine that is truly synthetic and not syncretic in its approach. There is no discipline of health care, from surgery to geriatrics, dentistry to physical therapy, and public health to medical anthropology that cannot be assessed according to an Endobiogenic global systems analysis. Physical illness has structural or functional elements of disadaptation. Physical illness exists within material, cultural, and institutional environments through which the individual exits, moves, and interacts with.

rather than the person. Historically, medicine, as a cultural endeavor has been influenced by and in turn influences philosophy and science. The current system continues to function based on 17th-century philosophy, disregarded in most fields of science, and 19th-century concepts of physiology. Many other fields of scientific inquiry have combined quantitative and qualitative analysis based on the concept of systems theory. We believe it is time for medicine to benefit from these concepts. The theory of Endobiogeny grew out of early work in clinical phytotherapy. Endobiogeny is the original concept of the late Dr. Christian Duraffourd. Its teachings were developed by him and Dr. Jean-Claude Lapraz over a 30-year period of time with their group in France. Later elaboration of the theory and establishment of a scientific lineage was done by Drs. Kamyar M. Hedayat and Jean-Claude Lapraz. Endobiogeny is a form of integrating medicine that uses a synthetic, multilevel analysis in order to increase the greatest probability of veracity and accuracy in clinical care. Using this synthetic approach, we can come to new conclusions about the nature of life, the formation of the human body, the purpose of its structures and functions, the logic of its activity, and the keys to ensuring good health and correcting illness.

What this text is and is not

1. Strange  K. The end of "naive reductionism": rise of systems biology or renaissance of physiology? Am J Physiol Cell Physiol. 2005;288(5):C968–C974. 2. Lyons AS, Petrucelli R. Medicine: An Illustrated History. New York: Harry N. Abrams; 1987. 3. Fang  FC, Casadevall  A. Reductionistic and holistic science. Infect Immun. 2011;79(4):1401–1404. 4. Hanin L. Why victory in the war on cancer remains elusive: biomedical hypotheses and mathematical models. Cancer. 2011;3:340–367. 5. Jackson ND. The Autoimmune Epidemic: Bodies Gone Haywire in a World Out of Balance—And the Cutting-Edge Science that Promises Hope. 1st ed. Touchstone; 2008. 6. Laplace  P-S. Essai philosophique sur les probabilités. p. 4. éd. Bachelier; 1840. 7. Descartes R. Discours de la méthode: pour bien conduire sa raison, et chercher la vérité dans les sciences [A discourse of the method for conducting oneself with reason, and searching for truth in the sciences]. p. 142. Vol Cinquième: éd. Cousin, 1637. 8. Verduijn  M, Jager  KJ, Zoccali  C, Dekker  FW. Genetic association studies: discovery of the genetic basis of renal disease. Nephron Clin Pract. 2011;119(3):c236–c239. 9. Woods MO, Younghusband HB, Parfrey PS, et al. The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. Gut. 2010;59(10):1369–1377. 10. Moller  CC, Pollak  MR, Reiser  J. The genetic basis of human glomerular disease. Adv Chronic Kidney Dis. 2006;13(2):166–173. 11. Day IN, Gu D, Ganderton RH, Spanakis E, Ye S. Epidemiology and the genetic basis of disease. Int J Epidemiol. 2001;30(4):661–667. 12. Partridge M. Oral cancer: 1. The genetic basis of the disease. Dent Update. 2000;27(5):242–248.

This text offers a systematic, philosophical, scientific, rational, and clinical approach to Endobiogenic medicine. Its purpose is to elaborate the concepts of applied systems biology according to the theory of Endobiogeny. Its goal is to demonstrate that because the endocrine system is the manager of the terrain, every disorder, be it physiologic, physical, mental, or emotional, directly or indirectly implicates a certain level of endocrine dysfunction. This book will not elaborate mechanisms of endocrine action or endocrinopathies in any great detail. There are many reference works on this subject. This is a text intended for researchers in global systems theory and medicine, and for clinicians interested in new concepts to expand their framework for health care. It is heavily referenced to satisfy the needs of rational thinkers and skeptics alike. As a clinical guide, it is written for the benefit of the practicing clinician in order to satisfy two needs: that of the clinician for a deeper approach to healing, and that of the patient for a deeper experience of healing.

Conclusions The basis of contemporary clinical medicine is the rational, reductionist scientific method. This approach has been successful but brings with it numerous side effects and depersonalization of the patient by treating the symptoms

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Chapter 2

A general overview of systems theory, integrative physiology, and the theory of Endobiogeny Systems theory Aristotle's statement ‘the whole is more than the sum of its parts’ is a definition of the basic system problem which is still valid. Aristotelian teleology was eliminated in the later development of Western sciences, but the problems contained in it, such as the order and goal-directedness of living systems, were neglected and by-passed rather than solved. Hence, the basic system is still not obsolete. Ludwig von Bertalanffy, PhD, biologist and founder of the General Systems Theory.1

A system is a collection of parts that form a whole (Fig.  2.1). A [living] system is self-generating, cohesive, closed unto itself, but open to interaction with its environment. Its functionality is determined at four levels: (1) the individual units of activity in and of themselves, (2) their relationship with each other, (3) the global level of functionality of the system, and (4) the system’s relationship to its external environment (Fig. 2.2). Describing this system, we can observe the following according to the diagram: ●

●

Unit 1 has a strong, frequent, positive unidirectional effect on Unit 3 (Large, solid blue line). Units 3 and 2 have weak, infrequent, positive bidirectional relationships with each other. They promote each other (small, broken blue line): ● Unit 1 directly promotes Unit 3. ● Units 2 and 3 promote each other independent of Unit 1 but this relationship is infrequent in time and relatively weak in nature. ● Unit 1 indirectly promotes Unit 2 via Unit 3 but the effects are not commensurate because Units 3 and 2’s relationships are not strong or frequent.

1. Adapted from Lapraz JC, Hedayat KM. Endobiogeny: a global approach to systems biology (part  1 of 2). Global advances in health and medicine: improving healthcare outcomes worldwide. 2013;2(1):64-78. The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00002-1 © 2019 Elsevier Inc. All rights reserved.

FIG. 2.1  General schematic of a global system and subsystems. (© 2014 Systems Biology Research Group.)

●

●

●

●

Subunits 1.1 and 1.2 have a constant reciprocal relationship with each other. As one increases, the other increases. As one diminishes, the other diminishes. Subunit 2.3 has a strong, frequent, positive unidirectional promotion of Subunit 1.2 (thick black line). Subunit 1.2 has a weak but frequent and unidirectional promotion of Subunit 3.1 (thin black line). Subunit 3.1 has a strong and frequent inhibitory effect on Subunit 1.2 (large, broken black line): ● The more Subunit 2.3 promotes 1.2, the more Subunit 3.1 inhibits 1.2. ● The more Subunit 2.3 directly promotes 1.2, the more Subunit 1.2 directly promotes 1.1. ● Subunit 2.3 has an indirect promotional effect on 1.1. 17

18  The Theory of Endobiogeny

FIG.  2.2  Types of relationships within a system: The diagram shows the function of a global system (red circle) containing three units (blue circles). Each unit contains three subunits (black circles). Blue lines, influence of units on each other; black lines, influence of subunits on each other; solid line, stimulates; broken line, inhibits, degree of influence commensurate to thickness of arrow, direction of influence indicated by location of arrowhead. (© 2014 Systems Biology Research Group.)

According to James Miller, MD, PhD, originator of the seminal tome Living Systems, every system, from a cell to a supranational organization must possess 19 properties divided into two general categories: matterenergy, and information. The properties of matter-energy are: (1) ingestion of material, (2) distribution of material, (3) conversion of material into structure or energy, (4) production of material, (5) storage of material, (6) extrusion of waste, (7) movement of the system, (8) support and maintenance of spatial relationships of the subunits, (9) reproduction, and (10) maintenance of internal and external boundaries. The properties of information are nine: (1) external input transduction: conversion of light, chemical, tactile, and temperature information into a form recognized by the system, (2) internal input transduction of information about changes in one component or subsystem to other components or subsystems, (3) channeling and distribution of information within the system, (4) decoding and translation of information, (5) learning and association (first stage of learning), (6) memory (second stage of learning), (7) d­ ecision-making based on information from all subsystems of the system, (8) encoding information for external interpretation, and (9) output transduction.2 In a system, the quantitative abilities alone do not determine the functionality of the system because each unit of activity depends on, influences, and is influenced by

the activity of other units. While quantitative measurements determine the minimum and maximum potential of an individual unit of function in isolation from all the other parts, qualitative relationships determine the functional capabilities of the system and its various subsystems. Based on this understanding of systems dynamics, order and cohesiveness do not arise from rigid control, but from dynamic management of the needs of the systems at the individual, regional, and global levels by the system itself. The prospect of orderly self-regulation from such complex systems with variable demands sounds unlikely. Yet we found that this is the mode of interaction in the cosmos. This type of function is not exclusive to natural systems. The most successful artificial systems follow similar patterns. Consider the internet. Who owns the Internet? No one. Everyone. Who runs the Internet? No one. Everyone. It is a network of millions of nodes of independent activity (Fig. 2.3). The system does have codified rules for conformity of process and language, such as the universal resource locator (URL) but little else in terms of mechanisms of control. And yet, it functions with a high degree of freedom and flexibility. Neurophysiologist P.K. Anokin, a student of Pavlov, was the first to describe feed-forward, feedthrough, and feedback loops, which laid the foundation for the concept of biological system regulation, as opposed to operation by reflex alone. In 1935 Anokin published his theory of functional systems.3 The biologist Ludwig von Bertalanffy developed his General Systems Theory in 1937, which influenced the applications of systems theory across multiple disciplines. James Miller, MD, PhD, published his theory of living systems in 1955.4 Since then, systems theory has been applied to biology,5 social psychology,6 resource management,7 economics,8 and other areas of material and human sciences, demonstrating the universal applicability of this concept. Advances in cellular biology have demonstrated how at every level—cell, tissue, organ, and organism—the human being meets the criteria of being a system.9–21 With this new understanding of physiology, if medicine is to continue to progress a similar paradigm shift will be critical. The shift starts by moving away from a quantitative, binary model of biochemistry that states. Elevation in serum liver enzymes = liver dysfunction, therefore, if liver enzymes are not elevated, then there is no liver dysfunction

to a qualitative evaluation of relationships that states. Despite normal liver enzymes, there is hepatic strain due to a global insufficiency of oxidative activity relative to reductive activity,22 which compromises glutathione recycling and hepatic detoxification pathways,23, 24 which is rooted in an insufficiency of insulin sensitivity25 which is impairing mitochondrial respiration and ATP production25, which may ­explain the recent devolution in the patient’s cardiac

A general overview of systems theory Chapter | 2  19

FIG. 2.3  Order and cohesiveness can be expressed through dynamic, nonhierarchical management. The diagram represents the connectivity between various nodes, each representing an IP address on the world wide web. (By the Opte Project [CC BY 2.5] via Wikimedia Commons.)

function and/or lipid metabolism, and/or neurocognitive status,26 all of which are related to oxidative impairment, which therefore will necessitate support of hepatic function despite normal liver enzymes.

The therapeutic approach in systems analysis is based not on control, but on the modification of physiology, on supporting the reengagement of endogenous mechanisms of management rather than a permanent substitutive one. In order to apply such a therapeutic approach, the level of physiologic activity most responsible for the loss of ­cohesiveness and ­integrity of

the system must be determined. Thus, we may consider the liver as a system unto itself with subsystems (Fig. 2.4). But the liver as an organ is also a subsystem in a network of organs and activities that influence hepatic function, which are influenced by hepatic function in turn (Fig. 2.5).

Determining the level and method of study Biological information is encoded in a multi-scale information hierarchy: DNA, RNA, proteins, interactions, biological

20  The Theory of Endobiogeny

If the human organism is to be studied as a system, the level of study and the method of bioinformatics should be carefully considered so as not to confuse cause with mechanism of disease. There are three levels of activity within the system that can be studied in four ways: 1. Cell, e.g., cell metabolism for ATP production 2. Organs, e.g., hepatic metabolism of urea 3. Global system, internal regulation, e.g., role of perfusion pressure in global metabolism 4. Global system’s interaction with its environment, e.g., seasonal adaptation of metabolism

FIG. 2.4  Liver as a system with subsystems. (© 2014 Systems Biology Research Group.)

FIG. 2.5  The liver is a subsystem within networked subsystems within the global whole. Each system influences and is influenced by the others. (© 2014 Systems Biology Research Group.)

networks, cells, tissues, and organs, individuals and, finally, ecologies. The important point is that the environment impinges upon each of these levels of the hierarchy and modulates the digital informational output from the genome. Thus, systems-level investigations demand the collection of data at each relevant level of the hierarchy between the phenotypic measurement (features of the cell) and the core digital genome. Leroy Hood et al., Institute for Systems Biology.27

For the first half of the 20th century, “naïve reductionism” focused primarily on the first level: the cell. The clinical result was the production and use of drugs that either inhibit or stimulate (i.e., antiinflammatory, aromatase inhibitors, diuretic, beta-agonist, etc.), or replace deficient physiologic products (i.e., cortisol, estradiol, insulin, thyroxin, etc.). The mid-20th century gave rise to molecular biology and an intense study of the role of DNA. Advances in high-throughput assays and bioinformatics since the late 20th century have allowed for the complexity and ­systems-behavior of the cell to be clearly demonstrated. The response of many researchers has not been to move up to higher levels of organization to view how the body functions as a whole, but to move to the lowest level of activity: the genome (genomics), and the attendant “–omics” that arise from such study: proteomics, transcriptionomics, metabolomics, etc.28–32 Still, this approach can be seen as an improvement in the study of human physiology because it moves away from “naïve reductionism” (cf. Chapter 1). However, it does not represent a paradigm shift in the concept of how life is managed. The complex reductionist approach arose out of advances in molecular biology and it continues to be a genecentered approach to disease. What is different is that the paradigm has expanded to look at many different proteins and metabolites related to a specific disease or cell. Thus, the paradigm still reads like this: Gene “x” encodes for a single protein, that affects the cell’s metabolism, that affects the function of tissues and organs, that affects the whole system, that leads to disease “y.” Ergo: gene “x” is the cause of disease “y.”

There are two compelling arguments against this paradigm, one nosologic and the other clinical. Nosology, the science of disease categorization, was traditionally based on classifying disease based on a group of symptoms (i.e., myocardial infarction), pathologic findings (i.e., amyloidosis), or localization of disease (i.e., breast cancer) (Fig. 2.6). With the shift to genomics, diseases have been categorized by single-gene mutations or polymorphisms. Genetic issues become the foundation of assessing histopathologic phenomenon related to physiologic disturbances.

A general overview of systems theory Chapter | 2  21

FIG.2.6  A typical example of current nosologic approach to the diagnosis of temporary loss of consciousness (TLOC, transient loss of consciousness, HT, hyperventilation test, HUTT, head-up tilt test, EPS, electrophysiological study, CSM, carotid sinus massage, NMS, neurally mediated syncope, ILR, implanted loop recorder, EEG, electroencephalography). (Reproduced from Mereu R, Sau A, Lim PB. Diagnostic algorithm for syncope. Auton. Neurosci. 2014;184:10–16. doi:https://doi.org/10.1016/j.autneu.2014.05.008, Elsevier.)

Medications are selected based on their primary physiologic actions. Or they are repurposed based on incidental actions, such as the use of the antibiotic doxycycline to regulate matrix metalloproteinases (MMP) with respect to vascular remodeling. New network-based classification methods, such as the human disease network, aka the “diseasome”33 have found that disorders should not be grouped by symptom or single gene mutations, but based on clusters of underlying physiologic dysfunction related to multiple simultaneous genetic polymorphisms and epigenetic changes (Fig. 2.7).34–42 From the clinical perspective, this helps explain a number of observations. One observation is the partial or weak associations between disorders, such as endocrinopathies and liver cancer in patients with one or the other. A second is why two patients with an “identical” cancer by location, e.g., breast, will have different responses to identical chemotherapy regimens. A landmark study of 2000 specimens of breast cancer suggests that it can be subclassified into 10 distinct groups based on various genomic and transcriptomic properties.43 Even with a highly specific ­classification

of breast cancer such as “triple negative,” there are sufficient variations in combinations of gene mutations that such a classification does not aid in evaluating drivers of growth or optimal therapy.43Another compelling argument for the diseasome concept is that it offers intriguing explanations into how cancer of the breast and pancreas can be more similar physiologically due to shared genetic polymorphisms38, 44 than two “identical” cancers of the breast based on staging methodology and location. In vitro, in vivo, epidemiologic and small-scale c­ linical studies of single-gene polymorphisms yielded what appeared to be compelling evidence for the single-gene, single-disease view of physiology.45 However, repeated ­ clinical studies have failed, prospectively, to link single genes to the development of a single disease.46–54 The human disease network approach may help explain why ­disease development is (1) multifactorial, (2) dependent on both multiple genetic factors, (3) multiple neuroendocrine factors, and (4) multiple environmental factors. Genes are the basis of the possibility of disease but do not appear to be the sole determinant of its probability.

22  The Theory of Endobiogeny

Ear, nose, throat diseases Metabolic diseases

Endocrine diseases

GHRHR

SLC26A4

TNFSF4

MAN2B1

DCX

Cardiovascular diseases

Dermatological diseases TNNT3

CTH

LDHB

Neurological diseases

ACADSB

ARHGEF10

PRNP

Immunological diseases

MMP1 FH

XBP1

Bone diseases

PRODH UROS

Psychiatric diseases

Respiratory diseases

PEX6

Liver cancer

NCF2

SLURP1

APOC2

CYP27B1

IL10 LIG4

COL5A1 NFKBIL1

Connective tissue diseases

Multiple diseases

NEB F10

Muscular diseases

Hematological diseases

FIG. 2.7  Multifactorial relationship of liver cancer to noncancer disorders and shared gene expression. Circular nodes (light red color) represent different categories of disorders. Diamond shaped nodes (teal) represent different genes that are common with other disorders. The size of a disease node is proportional to the number of dysregulated genes shared between disorders. For example, liver cancer is related to psychiatric disorders (lower left corner) through two genes: XBP1 and PRODH. PRODH is also related to metabolic disorders (upper leftcorner), thus creating a link between liver cancer, psychiatric, and metabolic disorders. (Reproduced from Xu H, Moni MA,Liò P. Network regularised cox regression and multiplex network models to predict disease comorbidities and survival of cancer. Comput. Biol. Chem. 2015;59(Part B):15–31. doi:https://doi.org/10.1016/j.compbiolchem.2015.08.010, Elsevier.)

A more holistic application of systems theory has been suggested in which the tripartite interaction between the genome, the cell, and the environment are evaluated as an ensemble.27, 33, 55 We agree with this approach but differ on the level of organization and management to be studied. If the inquiry is, “how did this disease develop?” the genome will contribute to a mechanistic understanding of pathophysiology. If the question is to be “why did this disease develop in this individual, and, what factors managed its appearance?” the level of study cannot be the genome. The genome is the mechanistic basis of life and disease—the “how”—not the “why.” Genes need to be told when, how often, and for how long to allow transcription of their information. Therefore, there is something that manages when and why certain segments of the genetic code are transcribed or not. At the microscopic level, the locus of management lies with the cell membrane. The membrane evaluates the internal functioning of the cell relative to (1) functioning of adjacent cells and (2) the extracellular environment. This information imposes demands on the nucleus to create or modify enzyme production or activity to adapt cell function. Thus, the membrane manages the cell, not the nucleus. The nucleus responds to the demands of the membrane. The membrane is why a gene is transcribed. The genome is how, and the nucleus

where this management occurs.56 At the macroscopic level, the global system is like the membrane: the system manages cells that manage genes, not vice versa. Thus, the development, expression, and continuation of disease are managed at the global level by nongenomic factors (Fig. 2.8). If we are to understand the person who has a disease and not just the disease a person has, as Sir William Osler said, we must understand what manages life and not limit ourselves only to its mechanisms. If, as evidence suggests, biology operates as a system and not a series of individual parts, then the future of medicine lies with a systems approach that studies the global manager of the system and not the individual mechanisms alone.

Endobiogeny: A global systems approach to medicine Definition of Endobiogeny Endobiogeny is a general theory of Life expressing itself in an organized manner. At the level of a living organism (a living system), Endobiogeny is a global systems theory of terrain. To understand the terrain is to understand the theory of Endobiogeny.

A general overview of systems theory Chapter | 2  23

Systems biology Cellula

Nucleo

Global systems medicine DNA

Cromosoma

Why disease develops in this individual at this time

How disease develops

FIG. 2.8  The image shows a global system (large circle) with four subsystems (smaller dark circles) that are integrated and interrelated in their functions (redcircle). There is input (orange arrow, far right) into the system, such as a response to an external aggression. Then, there is output (dark arrowleft of circle) from the system, such as a waste product or a response. Finally, there is some internal process that results in the expression of disease (large blue arrowpointing downward). (© 2015 Systems Biology Research Group.)

Terrain and metabolism The terrain appears under two aspects: a potential structure—its quantitative aspect, and a functional expression of this potential structure—its qualitative aspect…the way in which each person’s organs functionally express themselves is unique for each of us. Duraffourd, Lapraz and Valent.57

For the theory of Endobiogeny, terrain is capital. Terrain ultimately manages metabolism. From the Greek word for “change,” metabolism is the sum of all factors that allow the organism to create, maintain, repair, and renew its structural elements, and to constantly adapt the functionality of those elements and calibrate its adaptive capabilities in ceaseless change.

Structure As Christian Duraffourd defined it, terrain is “the functional expression of the structural constitution in its internal equilibrium in the face of endogenous and exogenous aggressions,” (personal discussion, JCL). Let us briefly evaluate each aspect of this statement: ●

●

●

Structural constitution: The material elements of the cell, tissue, and organs: cell membrane, organelles, DNA, connective tissue, muscle, neurons, etc. Functional expression: The basal and adaptive activity of this structure: membrane fluidity to regulate nutrient entry, DNA transcription, myocardial contraction, neuronal firing, etc. Internal equilibrium: How the organism maintains a balance between the various demands of breakdown and build up, increase and decrease, inhibition and

●

●

e­ xcitation, all of which function simultaneously to varying degrees. Endogenous aggression: The demands that body makes on itself to alter its function, i.e., a teenager needing more dehydroepiandrosterone (DHEA) in the first phase of puberty, dissolving an asymptomatic clot and metabolizing the fibrinous particles in the liver, etc. Exogenous aggression: A demand from outside the body that solicits an adaptation of the internal function, i.e., waking up in the morning, an infection, jumping into cold water, etc.

Simply put, Dr. Duraffourd’s definition of the terrain is the sum of all the physical elements of life and how they function to maintain the structure and adapt it to internal and external challenges or demands. The terrain has two aspects: structure and function. Structure is derived from the genetic inheritance of each individual but reflects the phenotypic expression of this genetic potential in its current, dynamic materialization (Fig. 2.9). Structure refers to the most basic elements of biologic life: DNA, the cell nucleus, organelles, the cell wall, the cytoskeleton, etc. Structure through the genome determines the maximum and minimum expression of the fullness of material life at every level: enzymatic rates of function, cytochrome efficiency, receptor density, cell structure, organ size, muscle oxidative capacity, exomorphic shape, personality, etc.

Function We define it as such: Function is the dynamic expression of genetically determined possibility in a nondeterministic field of probability. Simply put, there is a maximum and minimum possible range of activity that is possible based on

24  The Theory of Endobiogeny

Terrain

How much is constructed

Elements DNA, organelles, enzymes

What is constructed

Phenotype

When constructed

Structure

Genotype

Metabolism

Structural metabolism of cell Cell in its basal function

Function

Structuro-functional metabolism Cell in adaptation

Adaptation of System Tissue, organ, body in adaptation

FIG. 2.9  Summary of terrain. The terrain consists of two basic elements: structure and function. Structure is derived from the genotype but expressed as phenotype. Structure is the material elements that constitute the organism. Function refers to how these material elements are maintained or adapted. The sum of all this is the terrain. The terrain regulates metabolism. (© 2014 Systems Biology Research Group.)

genetic inheritance. This is possibility. Probability refers to what is likely to occur, not simply possible. Nondeterministic means that what is probable is not set or strictly defined. It is variable. In mechanistic terms, this includes epigenetic modification of the genetic code, persistent organic pollutants, the quality of symbiosis with symbionts, coherence of physiologic function, psychological factors, etc. In other words, the functioning of a living being is constantly fluctuating and adapting to internal and external demands, internal and external assistors, constrainer, or detractors. Moreover, while each person has a unique set of capabilities, what is actual expression cannot be fully determined ahead of time. There is a lot of room for variation. Consider the performance of a sprinter. The sprinter may come from a family of Olympiads—there is a genetic inheritance favorable to the type of muscle fibers and oxidative capacity optimal for sprinting. How does the sprinter perform? As a novice, perhaps better than the average person. With physical and mental performance training, her performance becomes more and more optimal. How will she perform at the Olympics? It is not certain. She may suffer from jet lag, not tolerate cooler weather, feel angry, be menstruating, etc. We can only characterize her performance a posteriori, not a priori. The essence of function is metabolism. There are three types of metabolic activity according to the theory of Endobiogeny: structural, structuro-functional, and functional (Fig. 2.9). 1. Basal maintenance of structure (structural metabolism) a. Definition: The metabolism that maintains the elements of the cell already existing and ensures their basic level of function (i.e., enzymes, organelles, etc.). b. Example: Maintenance of membrane fluidity.

2. Function of structure (structuro-functional metabolism) a. Definition: The adaptation of level of function of cellular metabolism based on intrinsic cellular demands. b. Example: Augmentation of ATP protection in preparation for cell growth or division. 3. Function of the organism (adaptation) a. Definition: Adaptation in coordination of the metabolism local, regional, or global functioning in the face of internal or external demands or aggressions. b. Example: Augmentation of the rate of glucose absorption by the pancreas, distribution by the liver, circulation by the heart, entry by insulin, and oxidation via thyroid hormones for ATP production when talking a long walk in the cold winter air.

Manager of the terrain The terrain assures its own functioning through permanent movement: a constant and unceasing adjustment of its internal equilibrium in the face of inductive and reactive elements. The manager of this terrain must similarly be dynamic, ubiquitous, and constant in its association with every aspect of the organism. It must also be selfregulating. A number of complex networks have been studied and proposed as managers of the organism.58 The most widely studied are the autonomic nervous system (ANS), immune system, and endocrine system. A brief evaluation of these systems will reveal why we conclude that the endocrine system is the manager of the terrain.

A general overview of systems theory Chapter | 2  25

The ANS consists of the sympathetic (Σ) and para-­ sympathetic (πΣ) nervous systems. It calibrates the qualitative, quantitative, and chronologic duration of diverse areas of autonomic function, from cardiac output to movement to digestion and sleep. The ANS is distributed throughout the body and synapses with every organ and tissue. It meets the first criterion: ubiquity. However, it does not possess criterion 2: constancy of relationship. The ANS depends on other systems to solicit its activity because it acts as a means of calibration, not management. It also lacks criterion 3: autoregulation. The ANS ends by autolysis or enzymatic degradation, not feedback. The immune system participates in host defense against internal and external aggressions through the use of anti- and pro-inflammatory compounds, innate and learned immunologic activity, and various signaling molecules. It meets criterion 3: autoregulation. In an optimal state, the anti- and pro-inflammatory aspects of the immune system are regulated through negative feedback. However, the immune system lacks the first two criteria: ubiquity and constancy of action. The immune system is not present throughout the entire body. It must be mobilized. It neither plays a managerial role in the formation of the structural elements of the cell nor in its basal functioning. Its existence, rate of function, and downregulation is dependent on other systems. In contrast, the endocrine system meets all the three criteria. 1. Ubiquity. Hormones: messengers that regulate function. They are ubiquitous. Cells excrete hormones with paracrine and autocrine activity on themselves or neighboring cells. Otherwise they are excreted from ductless glands into circulation where they are distributed to every cell in the body. 2. Constancy of relationship. Long before there is a nervous system or immune system, the endocrine system manages the foundation and growth of structure during embryogenesis and fetogenesis. The endocrine system manages all programmed phases of life: childhood, puberty, genital pause, senescence, and the deinstallation of life at death. 3. Autoregulation. The endocrine’s system’s use of feedforward, feedthrough, and feedback loops serves as the direct mechanism of self-regulation. In conclusion, the endocrine system is the manager of the terrain and hence metabolism (Fig.  2.10). Thus, the theory of Endobiogeny is the theory of how the endocrine system manages the terrain.

An overview of the elements of the terrain Endocrine system From the unitary notion of metabolism arises the dualistic phenomenon of opposing but complementary activities:

FIG.  2.10  Endobiogeny is a theory of the terrain. The terrain is the dynamic expression of genetic potential in ceaseless function, expressed through metabolism. Metabolism is regulated by the endocrine system. The endocrine system is the manager of the terrain. Thus, the theory of Endobiogeny is the theory of how the endocrine system manages the terrain. (© 2014 Systems Biology Research Group.)

catabolism (breaking down of material) and anabolism (building up of material). Within this dualism lies a further division of coupled and alternating pairs of catabolic and anabolic activity. Thus, there are four endocrine axes, each one responsible for a catabolic or anabolic activity (Fig. 2.11). The endocrine system has vertical feed-forward, feedthrough, and feedback loops that regulate the production of hormones within a particular endocrine axis of function. The term vertical refers to the concept of a cascading series of “top to bottom” and “bottom to top” levels of influence. For example, within the corticotropic axis, there is a vertical feed-forward loop: hypothalamic CRH stimulates

FIG.2.11  A general overview of the Endobiogenic notion of endocrine metabolism arranged in alternating axes of catabolic and anabolic activity. Within each outlined red or blue box, the top line is the hypothalamic hormone, the middle pituitary, and the bottom peripheral glands containing various hormones. Corticotropic: CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; adrenals=adrenal cortex. Gonadotropic: LHRH=GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone, gonads=ovaries/ testicles. Thyrotropic: TRH, thyrotropin-releasing hormone; TSH, thyroidstimulating hormone. Somatotropic: GHRH, growth hormone-releasing hormone; GH, growth hormone; PL, prolactin, pancreas=endocrine pancreas=insulin, glucagon. (© 2014 Systems Biology Research Group.)

26  The Theory of Endobiogeny

pituitary ACTH, which stimulates the end organ adrenal gland. Vertical feedback would go bottom up, so to speak. Adrenal Cortisol inhibits both pituitary ACTH and hypothalamic CRH. ACTH inhibits CRH. An original concept in the theory of Endobiogeny is the concept of horizontal and radial endocrine management of itself. Horizontal regulation is defined as the regulation of adjacent endocrine nuclei within the hypothalamus and pituitary within the brain in a specific sequential fashion. It is called horizontal because it refers to activity within the same gland or “level” in the vertical cascading control concept. The hypothalamus and pituitary glands contain numerous hormones which in turn regulate specific lines of hormone function. An example of horizontal management is the manner in which Dr. Duraffourd hypothesized that anterior pituitary hormones influence each other in sequential action: ACTH → FSH → TSH → GH You will note that this sequence is the sequence of alternating catabolic (ACTH)-anabolic (FSH)-catabolic (TRH)Anabolic (GH) shown in Fig.  2.11. An example of radial regulation would be the regulation of hormones across ­different levels (i.e., central vs peripheral) according to the vertical notion of regulation, and across different axes according to the Endobiogenic classification. Examples of radial regulation include the manner in which cortisol effects the excretion of FSH to adapt the level of anabolic estrogen to the level of catabolic cortisol activity to ensure a net neutral state of metabolism. In summary, (1) metabolism has two parts: catabolism and anabolism, (2) the endocrine system manages

­ etabolism with four axes of function that have a generally m catabolic or anabolic function, (3) hormones of the endocrine system manage themselves in three ways, creating a complex web of relationships: (a) vertically: within its own axis of functions: top to bottom, and bottom-up, (b) horizontally: within a specific gland, and (c) radially: across different glands and levels of function (Fig. 2.12).

Autonomic nervous system The ANS is the branch of the nervous system that originates in the brain stem. Its role is to stimulate and calibrate endocrine function in both its basal and adaptive activities. The ANS is ubiquitous, dynamic, and ceaseless in its actions. The ANS can be seen as a series of dualities: 1. Two divisions a. Para-sympathetic (πΣ) b. Sympathetic (Σ). The sympathetic is further divided into two parts: i. Alpha: αΣ ii. Beta: βΣ 2. Two areas of function a. Central: with the brain, further divided into two parts i. Central ii. Peripheral b. Peripheral: the rest of the body 3. Two ways in which it regulates metabolism a. Basal metabolism b. Adaptive metabolism: further divided into two parts i. Structuro-functional ii. Functional

FIG. 2.12  Vertical, horizontal, and radial endocrine regulation according to the theory of Endobiogeny. The cartoon shows the progression from left to right of the four endocrine axes during the “second loop,” which is discussed further in Chapter 4. (© 2015 Systems Biology Research Group.)

A general overview of systems theory Chapter | 2  27

Thus, in practical terms, it is the neuroendocrine system that regulates the terrain. We briefly summarize three general types of functional capacity through neuroendocrine activity (cf. Chapter 6 for more details):

FIG.  2.13  The autonomic nervous system (ANS) and its autacoids in sequential relationship. Para-sympathetic is the basal aspect of the ANS. Serotonin is its autacoid. It delays the onset of alpha-sympathetic. Alpha is the start of the sympathetic branch of the ANS. Its autacoid is histamine, which prolongs its actions. Beta-sympathetic does not have an autacoid. It is a neurohormone that autolyzes within the blood stream. (© 2015 Systems Biology Research Group.)

Three points are crucial to understanding the ANS. 1. Its function is timed and sequential, indispensable for biorhythms. 2. It calibrates the timing and sequencing of endocrine function, thus the ANS is indispensable for the proper functioning of the endocrine system as a whole. 3. Its own function is calibrated by autacoids that regulate the intensity and duration of function of the ANS at the most localized level appropriate. Autacoids regulate the ANS regulation of the endocrine system. Thus, last shall be first and the first shall be last (Fig. 2.13).

Neuroendocrine integration: Adaptation states The endocrine system is the manager of the terrain, but the ANS regulates the endocrine system’s management of the terrain. It is the permanent and dynamic interaction of neuroendocrine activity that ultimately assures the proper regulation of metabolism and survival of the organism (Fig. 2.14).

1. Basal capacity: Basal metabolic function for the maintenance of structure and function of structure. 2. Adaptation syndromes: A series of normal physiologic reactions that install a change in the functional equilibrium and which result in a return to the prior state once the demand is resolved. 3. Adaptability: A state of physiologic function that is contrary to a person’s optimal physiology. It can serve as a method of economizing adaptation syndromes by maintaining the minimum number of elements of the terrain in an altered physiologic state in order to allow the remaining elements of the terrain to return to their prior state. Hashimoto’s thyroiditis is an example of adaptability.

Emunctories An emunctory is an organ that drains and excretes waste products. These products may be from catabolism (or external toxins), thus they are under the control of the catabolic axes: the corticotropic and thyrotropic (cf. Chapter 6). The same emunctories implicated in drainage and detoxification have crucial nonemunctory functions in the body, i.e., endocrine, digestive, etc. Thus, the impairment of drainage due to a relatively excessive or prolonged catabolism, endogenous insufficiency of metabolic capability, vascular or lymphatic congestion, anatomical alteration in the liberal flow of waste products, or any combination of the above may compromise the other activities of the emunctories. A good comprehension of emunctory and nonemunctory function of glands, and their relationship to neuroendocrine activity is capital according to the theory of Endobiogeny1 (Fig. 2.15).

FIG. 2.14  Integrated neuroendocrine management of metabolism. Alpha-sympathetic (αΣ) stimulates and calibrates the intensity and duration of the endocrine management of metabolism. At the cellular level, para-sympathetic (πΣ) stimulates the general cellular anabolic tendency through influence on the rate of production of elements, alpha-sympathetic calibrates it, and beta-sympathetic (βΣ) completes it. (© 2015 Systems Biology Research Group.)

28  The Theory of Endobiogeny

FIG.2.15  Catabolic axes and their emunctories. The two catabolic axes are the corticotropic axis, which contains hormones such as cortisol, and the thyrotropic axis, which contains hormones such as TRH and T4 (thyroxine). The corticotropic axis solicits the skin, kidneys, liver, and intestines as emunctories. The thyrotropic axis solicits the lungs, liver, and intestines. (© 2018 Systems Biology Research Group.)

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Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes. 2006;55(suppl 2):S9–S15. Dhanasekaran M, Ren J. The emerging role of coenzyme Q-10 in aging, neurodegeneration, cardiovascular disease, cancer and diabetes mellitus. Curr Neurovasc Res. 2005;2(5):447–459. Hood  L, Rowen  L, Galas  DJ, Aitchison  JD. Systems biology at the institute for systems biology. Brief Funct Genomic Proteomic. 2008;7(4):239–248. Strange  K. The end of "naive reductionism": rise of systems biology or renaissance of physiology? Am J Physiol Cell Physiol. 2005;288(5):C968–C974. Fang  FC, Casadevall  A. Reductionistic and holistic science. Infect Immun. 2011;79(4):1401–1404. Ideker T, Galitski T, Hood L. A new approach to decoding life: systems biology. Annu Rev Genomics Hum Genet. 2001;2:343–372. Auffray C, Adcock IM, Chung KF, Djukanovic R, Pison C, Sterk PJ. An integrative systems biology approach to understanding pulmonary diseases. Chest. 2010;137(6):1410–1416. Taylor  BS, Varambally  S, Chinnaiyan  AM. A systems approach to model metastatic progression. Cancer Res. 2006;66(11):5537–5539. Schwenk K, Padilla DK, Bakken GS, Full RJ. Grand challenges in organismal biology. Integr Comp Biol. 2009;49(1):7–14. Barrenas  F, Chavali  S, Holme  P, Mobini  R, Benson  M. Network properties of complex human disease genes identified through ­genome-wide association studies. PLoS One. 2009;4(11):e8090. Bosco A, McKenna KL, Firth MJ, Sly PD, Holt PG. A network modeling approach to analysis of the Th2 memory responses underlying human atopic disease. J Immunol. 2009;182(10):6011–6021. Chavali  S, Barrenas  F, Kanduri  K, Benson  M. Network properties of human disease genes with pleiotropic effects. BMC Syst Biol. 2010;4:78. Dudley  JT, Butte  AJ. Identification of discriminating biomarkers for human disease using integrative network biology. Pac Symp Biocomput. 2009;27–38. Goh  KI, Cusick  ME, Valle  D, Childs  B, Vidal  M, Barabasi  AL. The human disease network. Proc Natl Acad Sci U S A. 2007;104(21):8685–8690. Jiang JQ, Dress AW, Chen M. Towards prediction and prioritization of disease genes by the modularity of human phenome-genome assembled network. J Integr Bioinform. 2010;7(2). Lee DS, Park J, Kay KA, Christakis NA, Oltvai ZN, Barabasi AL. The implications of human metabolic network topology for disease comorbidity. Proc Natl Acad Sci U S A. 2008;105(29):9880–9885. Loscalzo J. Systems biology and personalized medicine: a network approach to human disease. Proc Am Thorac Soc. 2011;8(2):196–198. Zanzoni A, Soler-Lopez M, Aloy P. A network medicine approach to human disease. FEBS Lett. 2009;583(11):1759–1765. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;489 (7403):395–399.

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Urbach  D, Moore  JH. Mining the diseasome. BioData Min. 2011;4:25. Iakoubova  OA, Robertson  M, Tong  CH, et  al. KIF6 Trp719Arg polymorphism and the effect of statin therapy in elderly patients: results from the PROSPER study. Eur J Cardiovasc Prev Rehabil. 2010;17(4):455–461. Assimes  TL, Holm  H, Kathiresan  S, et  al. Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies. J Am Coll Cardiol. 2010;56(19):1552–1563. Mathew J, Narayanan P, Sundaram R, et al. Lack of association between Glu(298) asp polymorphism of endothelial nitric oxide synthase (eNOS) gene and coronary artery disease in Tamilian population. Indian Heart J. 2008;60(3):223–227. Tsantes AE, Nikolopoulos GK, Bagos PG, Vaiopoulos G, Travlou A. Lack of association between the platelet glycoprotein Ia C807T gene polymorphism and coronary artery disease: a meta-analysis. Int J Cardiol. 2007;118(2):189–196. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Lack of association between the P2Y12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease. Thromb Res. 2005;116(6):491–497. Schmoelzer I, Renner W, Paulweber B, et al. Lack of association of the Glu298Asp polymorphism of endothelial nitric oxide synthase with manifest coronary artery disease, carotid atherosclerosis and forearm vascular reactivity in two Austrian populations. Eur J Clin Investig. 2003;33(3):191–198. Sigusch HH, Surber R, Lehmann MH, et al. Lack of association between 27-bp repeat polymorphism in intron 4 of the endothelial nitric oxide synthase gene and the risk of coronary artery disease. Scand J Clin Lab Invest. 2000;60(3):229–235. Anderson JL, Muhlestein JB, Habashi J, et al. Lack of association of a common polymorphism of the plasminogen activator inhibitor-1 gene with coronary artery disease and myocardial infarction. J Am Coll Cardiol. 1999;34(6):1778–1783. Garg  UC, Arnett  DK, Folsom  AR, Province  MA, Williams  RR, Eckfeldt JH. Lack of association between platelet glycoprotein IIb/ IIIa receptor PlA polymorphism and coronary artery disease or carotid intima-media thickness. Thromb Res. 1998;89(2):85–89. Fujimura T, Yokota M, Kato S, et al. Lack of association of angiotensin converting enzyme gene polymorphism or serum enzyme activity with coronary artery disease in Japanese subjects. Am J Hypertens. 1997;10(12 Pt 1):1384–1390. Halanych KM, Goertzen LR. Grand challenges in organismal biology: the need to develop both theory and resources. Integr Comp Biol. 2009;49(5):475–479. Lipton  B. The Biology of Belief: Unleashing the Power of Consciousness, Matter, & Miracles. 13th ed. Hay House; 2011. Duraffourd C, Lapraz JC, Valnet J. ABC de Phytothérapie dans les maladies infectieuses. Paris: Editions J. Grancher; 1998. Revici Method. CA Cancer J Clin. 1989;39(2):119–122.

Chapter 3

The autonomic nervous system Introduction As postulated by the theory of Endobiogeny, the endocrine system is considered to be the manager of the terrain. According to this theory, the autonomic nervous system (ANS) regulates this manager of the terrain: the endocrine system. Thus, a study of the ANS precedes a study of the endocrine system. When the ANS is contextualized within its role in global functioning of all branches of the nervous system, the logic of its relationship to the endocrine system becomes more apparent. In Miller’s theory of living systems (Chapter 1), all living systems are characterized as having two general types of activities: energy-matter transformation and information processing (Fig. 3.1).1 Energy matter is transformed directly by the endocrine system and associated digestive and emunctory glands (cf. The Theory of Endobiogeny, Volume 3, Chapter 9). Information processing is managed by the various branches of the nervous system. The autonomic branch of the nervous system (ANS) links these two activities and all the organs implicated. The ANS remains permanently in close physical, physiologic and teleological proximity to them. In other words, the purpose of the ANS is to allow all other systems to serve their intrinsic purpose more efficiently.

A general overview of the nervous system There are four branches of the nervous system: central nervous system (CNS), peripheral nervous system (PNS), enteric nervous system (ENS), and autonomic nervous system (ANS). The central, peripheral, and enteric systems are involved in nine types of information transduction and processing described in Miller’s theory of systems (Fig. 3.2).1 In contrast, the ANS affects the quantitative, qualitative, and chronologic qualities of these nine information-related activities (cf. Chapter 2). From the perspective of Endobiogenic integrative physiology, the nervous system is best classified with respect to two factors: (1) type of information processed, and (2) location of processing. The divisions of the nervous system are functional in nature and not anatomical. An anatomical approach would be arbitrary and illogical. For example, the

The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00003-3 © 2019 Elsevier Inc. All rights reserved.

CNS consists of neurons found within the cortex, subcortex, brain stem, and spinal cord. On the other hand, the peripheral and enteric and autonomic branches arise, in part or in whole, from the CNS. Furthermore, various portions of cranial nerves (CNs) contribute to both the PNS and ANS (Fig. 3.3).

Central nervous system Location This branch is referred to as “central” because it is the centralized location for the processing of information, not because it is located in the anatomical center of the body. The CNS is composed of gray and white matter and structurally includes the hemispheres, the cerebellum, pons, medulla, thalamic nuclei, and spinal cord.2 The pineal, hypothalamus, and pituitary endocrine glands are enveloped by, but, not part of the CNS (Fig. 3.4).

Function The CNS prioritizes the quantitative and qualitative physiological needs of the organism and integrates them into a qualitative, value-based program of the organism. The CNS processes all the physical exchange of information arising from the peripheral, enteric, and autonomic nerves from the interior or exterior. With respect to the global system, the CNS is not the manager or head of the organism. It is a coordinator and executor of demands originating elsewhere. It does not have the capability of influencing the metabolic rate of the periphery because its neurotransmitters do not cross the blood-brain barrier.3 It is only with respect to hierarchies and global awareness that the CNS intervenes in peripheral function. It can do this through the transmission of information through the PNS, ANS, or ENS with local or regional function. Or, through the limbic system, where it meets the endocrine system, it can provide information about the qualitative and quantitative demands that the organism is facing.4 The endocrine system can then calibrate its response both intrinsically and via the ANS to this information.

31

32  The Theory of Endobiogeny

FIG.  3.1  Two general functions of the autonomic nervous system (ANS): Energy-matter transformation and information processing. The ANS touches every aspect of the terrain. It is a sequential, calibrating system that calibrates all of other systems and activities by ensuring proper sequencing of their activity. (© 2014 Systems Biology Research Group.)

With respect to itself, the CNS functions as a semiautonomous structure that manages its own needs. It is only semiautonomous because it is completely dependent on the periphery to provide it with nutrients and remove its waste products, as it has neither input nor egress for processing alimentation or any emunctory function. It is also the most protected and thus the most restricted organ in the body with respect to tolerance of congestion or edema. Thus, it is both highly influential and highly vulnerable to peripheral disorders as well as direct external aggressions such a closed or open head injury.3, 5–7

Peripheral nervous system Location

FIG. 3.2  The nervous system and nine types of functions according to the systems theory of James Miller. All nine types of function can be represented by the various aspects of the autonomic (ANS), central (CNS), peripheral (PNS), and enteric (ENS) nervous systems. (© 2014 Systems Biology Research Group.)

It is called the peripheral nervous system because it manages information from the periphery, that is, that which is not central and that which is not visceral. It would be more accurate to call it the exterior nervous system, because it manages that which is on the exterior of the organism and that which is beyond the exterior of the self. Anatomically, the PNS is composed of CNs involved in sight, hearing, smell, touch, and proprioception. It is also composed of sensory and motor nerves arising from the spinal cord of the CNS (Fig. 3.3).

FIG. 3.3  Organization of the four branches of the nervous system. There are four branches of the nervous system: autonomic (ANS), central (CNS), peripheral (PNS), and enteric (ENS). Anatomically and structurally, they arise from various central and peripheral areas. Functionally, they interrelate. (© 2014 Systems Biology Research Group.)

The autonomic nervous system Chapter | 3  33

FIG. 3.4  Neuroanatomical aspects of the central nervous system (CNS) are shown. (© 2014 Systems Biology Research Group.)

Purpose

Autonomic nervous system

The purpose of the PNS is to sense the external environment, conduct this information to the CNS and then respond to the external environment with gross physical movement. Thus, the PNS codes and decodes external information: electromagnetic light, mechanical sound waves, and chemical and electromagnetic odor information packet all into electrical impulses.8 It also senses and responds to aggressions and changes in internal states, thus it has two branches: sensory and motor.8 The sensory aspect detects changes in the temperature, pressure, and pain in order to inform the organism of a potential threat to its structural integrity. It also allows the organism to mechanically respond to these changes in its internal equilibrium or to an external aggression. The PNS determines the quantitative nature of the threat. The CNS determines the qualitative nature of the threat and the ANS affects the intensity of the response.

Introduction

Enteric nervous system Location The enteric nervous system is located in the periphery, in the interior, and in the abdominal viscera. It is derived from visceral nerves arising from the spinal cord.9 This is opposite to the central location of the CNS or the peripheral, exterior nonvisceral location of the PNS (Fig. 3.3).

Purpose The purpose of the ENS is to regulate the general functioning of the enteric viscera, which is dedicated to the primary function of any living system: energy-matter transformation. It is considered to be a “second brain” that regulates the functioning of the viscera in a semiautonomous way from the activity of the CNS. However, it remains integrated into the global functioning of both the nervous system and the endocrine system, with respect to information relay, ­energy-matter transformation, and the adaptation syndromes (cf. Chapter 12).9

The ANS links management of the terrain to internal and external demands. By its very nature, the ANS maintains projections throughout the entire body and have relationship to every system. Thus, the area of function of the ANS is both central and peripheral, interior and exterior and its domain of influence includes the nervous and endocrine systems, the emunctories and viscera (abdominal and thoracic), the immune and lymphatic systems, muscular and skeletal system, and the general rate of metabolism. The ANS is the only system that influences both energy-matter transformation and information processing because it has three levels of function that affect both types of activities: initiation, calibration, and completion. The ANS has two general branches: parasympathetic (para, or, πΣ) and sympathetic (Fig. 3.5). The sympathetic branch has two subbranches: alpha-sympathetic (alpha, or αΣ) and beta-sympathetic (beta, or, βΣ).10 As discussed further, each branch has various points of origin and variable neurotransmitters based on its location of activity (i.e., central vs peripheral). Thus, it is not correct to equate the tenth CN, the vagus nerve with πΣ. The vagus is part of what comprises πΣ function, but is not the parasympathetic branch of the ANS. Thus, we refer to the various branches based on their general type of function. A summary of general function is that para represents initiation, alpha represents calibration, and beta represents completion. The particular expression of these relationships depends on the system with which the ANS acts upon (Table 3.1).

Concept of autacoids Autacoids, in the current model of physiology, are defined as locally produced and locally expressed factors that affect physiology. With this definition, there are numerous substances that meet this definition.11 We do not dispute this. However, in the context of integrative physiology according to the theory of Endobiogeny, we refer ANS autacoids

34  The Theory of Endobiogeny

FIG. 3.5  Autonomic nervous system (ANS) and its branches. The ANS has multiple origins. Para is derived primarily from the vagus cranial nerve, but also fibers arising from the spinal cord. Alpha arises from the locus ceruleus in the brain stem. Beta arises from the adrenal medulla in the periphery. (© 2014 Systems Biology Research Group.)

TABLE 3.1  General concept of parasympathetic, alpha- and beta sympathetic-like activity throughout the body Area

Para

Alpha

Beta

General

Initiate

Calibrate

Complete

Metabolism

Basal rate of metabolism

Calibration of duration or intensity of metabolism

Acceleration and completion of metabolism

Endocrine

Basal rate of secretion (production) of a hormone

Calibration of duration or intensity of secretion of a hormone

Excretion of a hormone from its gland

Sensory

Receipt of information

Alertness, contextualization of information

Relatedness of information

Motor

Conceptualization

Planning

Execution

Sensory

Threshold of sensation

Intensity of sensation

Propagation of information

Motor

Basal threshold of contraction

Calibration of timing and intensity of contraction

Contraction

ENS

Basal rate of motricity

Calibration of timing and intensity of motricity

Contraction

Emunctories

Basal rate of flow

Congestion

Decongestion

Basal rate of detoxification

Calibration of rate of detoxification

Excretion of toxins

CNS

PNS

­ ithout specification simply as “autacoids” because they w are so fundamental to the theory of how the neuroendocrine system regulates the terrain, and to the origin of numerous disorders. The ANS autacoids are serotonin, which regulates πΣ, and histamine, which regulates αΣ. These ­autacoids

regulate the ANS in three ways: (1) localization of action, (2) intensification of action, and (3) timing of progression of the ANS cycle. This only applies to the parasympathetic and alpha-sympathetic branches. The nature of βΣ is fugacious. Adrenaline is a neurohormone and cannot have

The autonomic nervous system Chapter | 3  35

an autacoid, functionally or conceptually. Otherwise, it could not remain intense and brief in its action.

Parasympathetic (πΣ) The parasympathetic system is abbreviated as πΣ, for the Greek letter pi: π for para- and capital sigma: Σ for -sympathetic.

Origin and composition The parasympathetic nervous system represents the null state of human existence: equilibrium, energy-matter transformation, and information relay. It represents the basal functioning of metabolism in the maintenance of structure and function. Because this is so foundational, πΣ is the most complex and diverse of the three branches of the ANS. Its preterminal neurotransmitter acetylcholine (ACh) is also the preterminal neurotransmitter of the alpha-sympathetic system. Thus, πΣ regulates the basal functioning of metabolism and of the sympathetic nervous system (Fig. 3.6).12 The peripheral fibers of the parasympathetic nerves are derived from two locations: central and peripheral. Central nerves are the CNs that arise in the brain stem. Most act centrally, originating as preganglionic CNs that synapse at various ganglia. The postganglionic fibers are composed of fibers from CN V, the trigeminal nerve. The vagus nerve is a CN that arises centrally but acts peripherally. The remainder of the peripheral nerves arises from the spinal cord (explained below).12 1. Central a. Preganglionic i. CN III: Oculomotor → Ciliary ganglion 1. Accommodation 2. Miosis ii. CN VII: Facial → Pterygo-palatine ganglion, submandibular 1. Lacrimation 2. Nasal secretions 3. Salivation a. Sublingual b. Submandibular 4. Mucous glands 5. Taste receptors iii. CN IX: Glossopharyngeal → Otic ganglion 1. Salivation: Parotid gland b. Postganglionic i. CN V1: Ophthalmic ii. CN V2: Maxillary iii. CN V3: Mandibular 2. Peripheral a. Vagus nerve i. Thoracic viscera ii. Abdominal viscera (except descending colon)

b. Splanchnic bed i. Thoracic: T12 ii. Lumbar: L1 iii. Sacral: S2–4 1. Descending colon 2. Pelvic basin a. Ureters, urinary bladder and sphincters b. Anal sphincter c. Glands d. Women i. Vagina: Secretions during sexual arousal ii. Uterus iii. Fallopian tubes e. Men i. Penis: Tumescence ii. Prostate

Neurotransmitter: Peripheral 1. Preterminal: Acetylcholine (ACh) (Fig. 3.6) 2. Terminal: ACh, precursor: Choline amino acid 3. Receptors12 a. Nicotinic (N) i. N1: Somatic muscular contraction ii. N2: Transmission of ANS impulses b. Muscarinic: M1, M2, and M3 4. Autacoid: Serotonin: delays the release of Noradrenaline (NA) from alpha-sympathetic receptors

Parasympathetic autacoid: Serotonin Serotonin plays a complex and pivotal role in the body. It engages in peripheral and central activity, is an autacoid, hormone and neurotransmitter, has an agonist-antagonistic relationship with insulin, and plays a key role in wakeful states and sleep.13

Peripheral activity The majority of serotonin (95%) is produced and used in the enteric tract.13 In this capacity, it plays two roles: the autacoid of πΣ, and an enteric hormone of the ENS. As an autacoid, it prolongs the general duration of πΣ activity by delaying the release of NA from sympathetic nerve fibers.14 As an enteric hormone, it regulates the motricity of the bowel, the rate of absorption of glucose from the small intestine, and delays the activity of insulin.13 This peripheral activity supports the central role of serotonin as an analogue of πΣ for the diffusion of glucose. This endocrine activity dovetails with that of its role as an autacoid. As an autacoid, it improves the local efficiency of parasympathetic activity to stimulate the rate of function of the annexal glands: (1) Exocrine pancreas: secretion of enzymes that break down carbohydrates, (2) Endocrine pancreas:

36  The Theory of Endobiogeny

(a) Glucagon: formation of glucose as glycogen, (b) Insulin: penetration of glucose into cells, (3) Liver: storage of glycogen.13 As a peripheral hormone, enteric serotonin has complimentary actions. Within the small intestines, it affects the rate of absorption of glucose and general motricity of the intestines.13, 15 Globally, it acts to delays the activity of insulin to favor central consumption of glucose, of which central serotonin facilitates its diffusion.13

Neurotransmitter: Peripheral

Central activity

Histamine is fundamental in the regulation of alpha-­ sympathetic neurons.21 Like serotonin, histamine has wideranging activity in both central and peripheral functions.13 Moreover, similar to serotonin, it is both autacoid and neurotransmitter,22 and also plays a role in calibrating wakeful and sleep states.23 If we only consider the peripheral effects of histamine both indirectly (as an autacoid) and directly, we observe the following types of activity:

Approximately 5% of total serotonin is produced in the brain. Leaving aside the neurotransmitter function of serotonin, its relationships to peripheral πΣ and anabolism is as the metabolic analogue of para. It augments the passive diffusion of glucose, acquired through its participation in peripheral digestion, into the brain. This central activity is enhanced by its peripheral antagonistic relationship to insulin noted above. It delays the activity of insulin in the periphery in order to allow the brain, as a vital organ, to have privileged access to glucose prior to that of the nonvital organs.

Alphasympathetic (αΣ) The alpha-sympathetic system is abbreviated using the Greek letter α for alpha and capital Σ for sympathetic.

Origin and composition In contrast to πΣ, αΣ activity is reactionary in nature. It both reacts to input stimuli and it stimulates other systems to react. The origin of alpha and NA is the locus ceruleus (or, coeruleus), literally the “blue place,” located in the pons, below the fourth ventricle.16 The rich concentration of melanin causes it to appear blue when a histological specimen is stained. Melanocyte-stimulating hormone (MSH), which is part of the corticotropic axis, stimulates melanin. MSH and its derivatives play a capital role in managing the balance between central alpha- and central beta activity (cf. Chapter  6).17–19 The peripheral activity of αΣ is transmitted down the sympathetic ganglionic chain on either side of the spinal cord.

1. Preterminal: ACh (Fig. 3.6) 2. Terminal: NA, metabolic precursor: dopamine (DA) 3. Receptors20: α1 and α2 4. Autacoid: Histamine: Prolongs activity of NA

Alpha-sympathetic autacoid: Histamine

1. ANS: prolongs effects of NA (αΣ)24, 25 2. Cardiovascular a. Heart: hyperdynamic response to stress24 b. Arteries: reduced integrity of vascular tight junctions i. Augmentation of cellular nutrition ii. Localization of immune response 3. Lungs: sensitizes pulmonary neural activity26 4. Stomach: secretion of stomach acid27 5. Immunity a. Inflammation b. Chemotaxis of leukocytes (neutrophils, eosinophils)28

Peripheral activity As an autacoid, histamine’s role is not analogous to that of serotonin. It does not delay the release of adrenaline (i.e., βΣ). Instead, histamine, excreted along with NA, prolongs and amplifies the activity of αΣ.29, 30 The logic of this is that the expression of βΣ is commensurate to both the rate of rise and duration of αΣ stimulation. Thus, the more prolonged the rise and the longer its duration of alpha-sympathetic activity is, the greater the resulting expression of adrenaline will be. A normal sequencing-activity graph is illustrated in Fig. 3.7.

FIG.  3.6  Summary of parasympathetic versus alpha-sympathetic activity. Para is within the preganglionic activity of para and alpha because both use acetylcholine as their neurotransmitter. In postganglionic fibers, para uses ACh but has different receptors (muscarinic). Alpha uses different neurotransmitters and receptors. αΣ, alpha-sympathetic; βΣ, beta-sympathetic; πΣ, parasympathetic; ACh, acetylcholine; Mu, muscarinic receptor; NE, norepinephrine; Nic, nicotinic receptor. (© 2018 Systems Biology Research Group.)

The autonomic nervous system Chapter | 3  37

2, Chapter  11), impairment of adaptation syndromes (cf. Chapter 12), congestion (Chapter 11), and alterations in the rate, chronology, intensity, and quality of buffering capacity.

Betasympathetic (βΣ) The beta-sympathetic system is abbreviated as βΣ using the Greek letter β for beta, and capital Σ for sympathetic. FIG.  3.7  Normal peripheral autonomic sequencing-activity graph. The sequence starts with parasympathetic (πΣ) and its autacoid serotonin, which delays alpha-sympathetic activity. In effect, serotonin prolongs para activity. With the onset of alpha (αΣ), activity increases then is sustained thanks to histamine, which prolongs alpha. The activity of beta (βΣ) brings a brief peak of activity, followed by a sudden drop below the baseline level. What follows is the recovery phase back to baseline. (© 2014 Systems Biology Research Group based on the work of the SIMEPI, based on the work of SFEM, based on the concepts of Christian Duraffourd.)

Origin and composition The βΣ system is fugacious and univocal. It represents action. Unlike the πΣ and αΣ branches of the ANS, βΣ is expressed in the periphery by the neurohormone adrenaline, which is a neurologically medicated chemical that circulates in the blood. Thus, the reach of βΣ is not by neuronal termination but by circulation. Sympathetic nerve fibers terminate in the adrenal medulla upon which adrenaline is released (there is also a small amount of NA produced in the adrenal medulla).

Neurohormone: Peripheral 1. Preterminal: not applicable 2. Terminal: not applicable 3. Metabolic precursor: NA 4. Neurohormone: adrenaline 5. Receptor20: β1, β2, and β3 6. Autacoid: none (neurohormone) FIG.  3.8  Abnormal peripheral autonomic sequencing-activity graph. The optimal activity remains in black with abnormal activity in red. In this case, para (πΣ) activity starts out in the optimal level and duration. However, there is excess histamine that both increases the intensity of action of alpha (αΣ) and prolongs its duration. Since beta (βΣ) should be proportional to the level of alpha, the beta response is also much greater and longer than in the optimal state. The recovery phase is also longer than in the optimal state. Finally, the new setpoint of para is also elevated. (© 2014 Systems Biology Research Group based on the work of the SIMEPI, based on the work of SFEM, based on the concepts of Christian Duraffourd.)

A pathologic state may occur when the solicitation of αΣ is prolonged and/or intense. The longer the duration and/ or the greater the demand for alpha, the more commensurate the rise of histamine as an autacoid tends to be. This augments the number of peripheral receptors. The greater the number of peripheral receptors, the greater the likelihood that histamine will begin to act on its own as intrinsic receptors and create secondary effects that were not solicited as part of the adaptation demand. The sequencing-activity graph demonstrates prolonged duration and increased total level of alpha activity with an exaggerated and intense βΣ response with delayed recovery time (Fig. 3.8). This notion is capital when it comes to several disorders: spasmophilia (cf. The Theory of Endobiogeny, Volume

The physiological, anatomical, and metabolic activities of the sympathetic nervous system are summarized below. Impulses from the sympathetic ganglion are conducted by ACh—parasympathetic inside alpha-sympathetic. Within chromaffin cells of the adrenal medulla, the stimulation of the terminal nerve (ACh) stimulates the release of NA (αΣ), which leads to the release of adrenaline (βΣ) and to a lesser degree, additional NA (Fig. 3.9). The greater the degree of histamine prolongation of alpha, the greater the release of adrenaline will be,31 although delayed in timing and exaggerated in response. This type of delayed (spasmophilia) and exaggerated response of adrenaline is related to commonly occurring symptoms such as arrhythmia, tachycardia, and panic attacks.

Central activity of the ANS The ANS plays a role in the initiation, calibration, and completion of CNS functions in two ways. The first is the expression of the neurotransmitter associated with that branch of the ANS. This only applies to πΣ and αΣ branches of the ANS. That is to say, both ACh and NA have intrinsic actions related to arousal, fear, memory, feeding, etc.12, 32, 33 The second is neurotransmitters that functions as ANS

38  The Theory of Endobiogeny

Central para: Serotonin

FIG.  3.9  Metabolism and excretion of adrenaline. αΣ, alpha-­ sympathetic; βΣ, beta-sympathetic; πΣ, parasympathetic. (© 2018 Systems Biology Research Group.)

analogues. These are neurotransmitters that, with respect to mental function, play the role of taking in or preparing (para), calibrating or refining (alpha), movement or imagination (beta). This applies to all three branches of the ANS (Fig. 3.10). What is more, the parasympathetic and alphasympathetic branches of the ANS proper stimulate their central analogues.

ACh is a central neurotransmitter used by CNs, as noted above. It also plays a direct and independent role in various CNS processes via muscarinic receptors M4 and M5.32 According to the theory of Endobiogeny, ACh as a neurotransmitter entrains a sequential series of neurotransmitter activity starting but directly stimulating serotonin: serotonin → DA → TRH → histamine → serotonin…This refers primarily to 5HT1 receptors,34 though other receptors play modulatory roles.33 This assures a proper central functioning of learning, memory, planning, etc. within the CNS. That is to say, the sequence of neurotransmitters that are ANS-like act in mental function in a fractal manner identical to that of the ANS on digestion (cf. Fig. 3.13). As para stimulates intake and retention of nutrients, serotonin augments the intake of impressions from the environment. As alpha stimulates the retention and refinement nutrients, DA refines the impressions brought by serotonin through rational evaluation and executive decisionmaking. As beta stimulates contraction of digestive glands or expulsion of juices, TRH and histamine play a role in creating the “movement” of ideas from planning to execution. A second significance of the para-serotonin relationship is that serotonin functions as the analogue of both πΣ and insulin. Serotonin augments the diffusion of glucose across the blood-brain barrier.35, 36 The general level of central metabolism is initiated by serotonin as a neurotransmitter during sleeping and waking states and in this logic, it also is able to assure the necessary diffusion of glucose to fuel the general level of metabolic activity.13 This dissociates the brain, as a noble organ, from the general peripheral metabolic consumption of glucose regulated by πΣ and insulin sensitivity/insulin resistance. Where there are insulin receptors in the brain, insulin functions as an intracellular growth factor and does not diffuse glucose into brain cells.35

Central alpha: Dopamine

FIG. 3.10  Central analogues of autonomic nervous system (ANS). The ANS directly affects the key neurotransmitters serotonin, dopamine and TRH. In addition, each of these three neurotransmitters has an ANS-like activity: Serotonin is central para, dopamine is central alpha, TRH is central beta. (© 2014 Systems Biology Research Group.)

The role of the CNS is to manage information and maintain a certain degree of vigilance against the exterior world. DA plays a key role. NA (αΣ) assists this function in two ways: (1) maintaining physiologic vigilance in the brain stem, (2) relaunching dopamine for cognitive vigilance. The general role of central alpha is to regulate the level of alertness and awareness of the organism in relationship to central and peripheral activities, interior and exterior activities, and with respect to physiologic, mental, and emotional evaluations (cf. Chapter  12).15, 16 It has direct projections of neurons throughout the brain33: (1) Cortex: current state of alertness, (2) Subcortex: integration of general sympathetic tone vis-àvis external data, and (3) Lateral hypothalamus: regulation of orexigenesis. It has diffuse outputs that stimulate multiple areas of central activity in addition to its ­peripheral function: (1) Limbic area: memory, (2) Cerebellum: movement,

The autonomic nervous system Chapter | 3  39

(3) Thalamus: movement, (4) Cortex: arousal, behavior, and (5) Hypothalamus: adaptation syndromes and adaptability.16 Alpha (αΣ) and DA have complementary roles that are both additive and antagonistic. DA is the metabolic precursor of NA, the postganglionic neurotransmitter of alpha. DA precedes NA in metabolism but follows it in action, with respect to central activity. DA drives the highly complex cognitive processing of the cortex such as executive ­planning37–39 and anticipation of reward (Fig.  3.13).40–42 The additive role is expressed in two ways. First, NA’s actions calibrate CNS activity in a manner that makes the activity of DA more efficient. Second, NA directly stimulates DA release from the substantia nigra and other areas where DA is stored. In the terminology of Endobiogeny, the term “central alpha” refers to the ensemble of additive NA-DA activity. It is possible to differentiate the relative predominance of NA in relationship to DA from information in the history, physical examination, and biology of functions, but without this differentiation, one should not be categorical in concluding whether it is αΣ, DA, or both that are most implicated in central alpha activity. The NA calibrates the intensity of hypothalamic activity, which calibrates pituitary and then peripheral endocrine activity. The competitive role between αΣ and DA is expressed in DA’s inhibition of most central endocrine hormones (Fig.  3.11).43–48 In summary, the locus coeruleus irrespective of whether central or peripheral activity plays a key role in the integration of endocrine and nervous system function.

Central beta: TRH TRH is generally known for its role as the hypothalamic hormone of the thyrotropic axis. However, in our opinion, this is a later evolutionary assignment. Its primary role is as a neuromodulator with neurotransmitter activity. It synapses with the limbic area where it influences the intensity of emotions, the tangential and emotional quality of cognition and creativity, especially when colocated with histamine.22 The locus coeruleus (i.e., αΣ, i.e., NA) stimulates TRH release16 (solid red arrow), as noted in the triadic relationship mentioned in the discussion of central alpha (Fig.  3.12). Alpha-sympathetic from the locus coeruleus

FIG.  3.11  Relationship of alpha, dopamine, and hypothalamus. Alpha stimulates the hypothalamus, to increase release of hormones (solid red arrow). It also stimulates dopamine, which slows down hypothalamic action (solid blue arrow). The hypothalamus makes an appeal to dopamine (broken red arrow) on its own. (© 2015 Systems Biology Research Group.)

FIG.  3.12  Dopamine’s role in central adaptation. Dopamine has many roles in affecting central adaptation response. While it has a generally inhibitory effects on the hypothalamus, one exception is the hypothalamic thyrotropic hormone TRH, which it stimulates. Cf. the text for a full discussion. Red arrow, stimulates; blue arrow, inhibits; red broken arrow, accelerates. (© 2015 Systems Biology Research Group.)

relaunches TRH activity, referred to in Endobiogeny as thyroid relaunching. Both alpha and TRH have activity in the limbic area, which plays important roles in emotional states and memory. Alpha, synapses from the limbic area stimulate DA. DA also relaunches TRH and TRH acts as a neuromodulator (broken red arrow) accelerating the effects of DA. As DA rises, it starts to inhibit pituitary and hypothalamic endocrine releasing factors (CRH, GnRH, GHRH, and TRH) and alpha-sympathetic, preventing an endless positive feedback loop of central sympathetic activity. Central activity is dependent on peripheral organs to furnish energy for both basal and augmented central metabolism. The greater the rate of central metabolism, the greater the demand for glucose will be. There are three ways in which TRH acts as a central analogue of βΣ (i.e., adrenaline). The first is its sequential relationship to αΣ. As adrenaline is stimulated by peripheral alpha, TRH is directly stimulated by central alpha. The second is its relationship to movement. Thought is a movement of ideas. As adrenaline drives the fugacity of motor activity, so does TRH with respect to cognitive and emotional activity. The third, discussed in detail in this chapter, is TRH’s peripheral activity. Like adrenaline, TRH stimulates glucagon from the endocrine pancreas in order to rapidly release glucose from the liver.49 This allows TRH to ensure the appropriate amount and timing of glucose to support the intense augmentation of central metabolism that it entrains, with the assistance of central serotonin to augment its diffusion. Central serotonin, as the para-analog, acts to diffuse the glucose liberated indirectly by TRH into the brain, as mentioned earlier. The relationship between central and peripheral αΣ, βΣ, and πΣ, its effects on general thought patterns, and peripheral endocrine activity are shown in Fig. 3.13.

40  The Theory of Endobiogeny

FIG. 3.13  Autonomic nervous system and its central analogues in thought and adaptation. See text for discussion. (© 2015 Systems Biology Research Group.)

CNS-ANS-endocrine integration

ANS-endocrine-emunctory integration

The central and ANSs are imbricate in a permanent relationship that is both structural and functional in nature. The CNS structurally gives rise to the parasympathetic and alpha-sympathetic branches of the ANS. The CNS functionally stimulates the ANS based on perceptions of hierarchical and existential needs for the adaptation of the internal equilibrium. In this way, the CNS is to the ANS as to what the ANS is to the endocrine system: the initiator of the initiator of adaptation via the limbic area. As Duraffourd, Lapraz and Valnet noted:

The ANS has two types of direct relationships with the endocrine system, and a third relationship with respect to the emunctories and other organs that the endocrine system acts upon. First, hormones are an organo-metabolic product of the metabolism of endocrine glands (Chapter  4), meaning ANS regulates the general rate of production and excretion of these hormones under the general plan installed by trophin hormones that stimulate corresponding downstream glands. Second, the various adaptation syndromes (Chapter  12) are initiated by the ANS. Each endocrine axis has a relationship with a particular emunctory (Chapters 2 and 11). The ANS regulates blood flow to and from these organs as well as the general metabolic capabilities of these organs to increase detoxification capabilities.

The autonomic and endocrine systems] form a closed circuit. This design is such that the smallest amount of information received by one apparatus is instantly relayed unto the other. Regulators, they are themselves regulated by the actions of the central nervous system, which caps and governs them. It is the CNS that opens the door of relationships between the conscious and adjacent structures. Thus, the organism obligatorily responds with a mobilization of these three systems in various times and degrees based on the intensity of an aggression. But this reaction is necessary in order to maintain the integrity of the organism. Ref. 50

The ANS functionally regulates the CNS through n­ eurotransmitters/neuro-hormones that have central and peripheral activity. Finally, ANS functionality influences the structural plasticity of CNS structure.

Conclusions The nervous system is responsible for information processing. The ANS is unique among the branches of the nervous system because its role is to calibrate this process, thus its activity is both central and peripheral. In this way, it affects the rate of function, intensity, amplitude, duration and quality of processing of information including the various states of consciousness, learning, memory, etc. The ANS also calibrates the endocrine system. In this function, the ANS influences the management of the

The autonomic nervous system Chapter | 3  41

Alpha

Alpha

Planning

Para Conceptualization

Calibration of secretion

Beta Neurotransmitter entrainment

Para

Execution

Beta

Rate of secretion

Hormone production

Excretion

Learning

Adaptation syndromes

Alertness

Endocrine

CNS

Behavior

General adaptation syndrome

Sleep-wake cycle Motricity

Congestion

Adaptability

ANS

ENS

Emunctories

Function

Function Para

Beta

Rate of secretion

Beta

Para

Excretion

Rate of secretion

Excretion

Alpha

Alpha

Calibration of secretion

Calibration of secretion

Alpha

Alpha

Calibration of contraction

Calibration of responsiveness

Beta

Para

Para

Conduction of response

Threshold of responsiveness

Sensory

Congestion

Beta

Threshold of contraction

PNS

Conduction

Motor

FIG. 3.14  Alpha sympathetic relaunches the hypothalamic, pituitary and peripheral adrenal cortex within the corticotropic axis, as well as adrenaline within the adrenal medulla. αΣ, alpha; βΣ, beta; ACTH, adrenocorticotropic hormone; ANS, autonomic nervous system; CRH, corticotrophin releasing hormone. (© 2015 Systems Biology Research Group.)

­ anager. Through its metabolic and motor activity, the m ANS affects every organ and system in the body and thus also influences the qualitative and quantitative aspects of the adaptation syndromes and adaptability. The neurotransmitters and autacoids of the ANS have multiple roles in the central and peripheral physiology including those that are independent of their intrinsic function within the ANS, but always interdependent. Dysfunction of the ANS can be local, regional, or systemic in nature, affecting central and/or peripheral physiology. A proper understanding of the ANS and its physiologic and pathophysiologic activity offers key insights into the origins or propagators of various disorders as well as novel therapeutic approaches to symptomatic and etiologic treatments. The global perspective of ANS activity, central and peripheral, in relationship to the CNS, PNS, ENS, endocrine system, and emunctories is summarized in Fig. 3.14.

References 1. Miller JG. Living Systems. New York: McGraw-Hill; 1978. 2. Haines  DE. Central nervous systems, overview. In: Aminoff  MJ, Daroff  RB, eds. Encyclopedia of the Neurological Sciences. Academic Press; 2014. 3. Qosa H, Miller DS, Pasinelli P, Trotti D. Regulation of ABC efflux transporters at blood-brain barrier in health and neurological disorders. Brain Res. 2015;1628(Pt B):298–316. 4. WIllis  MA, Haines  DE. The limbic system. In: Haines  DE, Mihailoff GA, eds. Fundamental Neuroscience for Basic and Clinical Applications. 5th ed.Elsevier; 2018:457–467. e451 [chapter 31]. 5. Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008;29(1):117–124. 6. Pollak  TA, Drndarski  S, Stone  JM, David  AS, McGuire  P, Abbott NJ. The blood-brain barrier in psychosis. Lancet Psychiatry. 2018;5(1):79–92.

42  The Theory of Endobiogeny

7. Yehuda  R. Post-traumatic stress disorder. N Engl J Med. 2002;346(2):108–114. 8. Møller  AR. Anatomy and physiology of sensory organs. In: Møller  AR, ed. Sensory Systems. Academic Press; 2003:33–74. [Chapter 2]. 9. Furness JB. Enteric nervous system: structure, relationships and functions. In: Reference Module in Biomedical Sciences. Elsevier; 2015. 10. Biaggioni  I, Kaufmann  H. Autonomic nervous system; overview. In: Aminoff MJ, Daroff RB, eds. Encyclopedia of the Neurological Sciences. 2nd ed.Elsevier; 2014:352–354. 11. Barral  J-P, Croibier  A. Homeostasis of the cardiovascular system. In: Barral  J-P, Croibier  A, eds. Visceral Vascular Manipulations. Elsevier; 2011:46–60. [chapter 3]. 12. Benarroch EE. Parasympathetic system; overview. In: Aminoff MJ, Daroff  RB, eds. Encyclopedia of the Neurological Sciences. Academic Press; 2014:805–808. 13. Donovan MH, Tecott LH. Serotonin and the regulation of mammalian energy balance. Front Neurosci. 2013;7:36. 14. Schliker  E, Glaser  T, Lümmen  G, Neise  A, Göthert  M. Serotonin and histamine receptor-mediated inhibition of serotonin and noradrenaline release in rat brain cortex under nimodipine treatment. Neurochem Int. 1991;19(4):437–444. 15. Neuhuber  W, Worl  J. Monoamines in the enteric nervous system. Histochem Cell Biol. 2018;150(6):703–709. 16. Waterhouse  BD, Navarra  RL. The locus coeruleus-norepinephrine system and sensory signal processing: a historical review and current perspectives. Brain Res. 2018, 1–5;. 17. Ellacott KL, Cone RD. The central melanocortin system and the integration of short- and long-term regulators of energy homeostasis. Recent Prog Horm Res. 2004;59:395–408. 18. Brzoska  T, Luger  TA, Maaser  C, Abels  C, Bohm  M. Alphamelanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases. Endocr Rev. 2008;29(5):581–602. 19. Guillemin  R, Vargo  T, Rossier  J, et  al. Beta-endorphin and adrenocorticotropin are selected concomitantly by the pituitary gland. Science. 1977;197(4311):1367–1369. 20. Ciccarelli  M, Sorriento  D, Coscioni  E, Iaccarino  G, Santulli  G. Adrenergic receptors. In: Endocrinology of the Heart in Health and Disease: Integrated, Cellular and Molecular Endocrinology of the Heart. 2017:285–315, Academic Press, New York. [chapter 11]. 21. Murakami M, Yoshikawa T, Nakamura T, et al. Involvement of the histamine H1 receptor in the regulation of sympathetic nerve activity. Biochem Biophys Res Commun. 2015;458(3):584–589. 22. Leurs R, Hough LB, Blandina P, Haas HL. Histamine. In: Brady ST, Siegel  GJ, Albers  RW, Price  DL, eds. Basic Neurochemistry. 8th ed.Elsevier; 2012:323–341. [chapter 16]. 23. Monti  JM. Involvement of histamine in the control of the waking state. Life Sci. 1993;53(17):1331–1338. 24. Neugebauer  E, Lorenz  W, Rixen  D, Stinner  B, Sauer  S, Dietz  W. Histamine release in sepsis: a prospective, controlled, clinical study. Crit Care Med. 1996;24(10):1670–1677. 25. Tarnoky  K, Tutsek  L, Nagy  S. The role of histamine in the increased cardiac output in hyperdynamic endotoxemia. Shock. 1994;1(2):153–157.

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Fedin  AN, Kryukova  EN, Nekrasova  EA. Interaction of histamine and glucocorticoids with neural structures of the respiratory tract. Neurosci Behav Physiol. 2003;33(3):289–294. 27. Hunyady  B, Zolyomi  A, Czimmer  J, et  al. Expanded parietal cell pool in transgenic mice unable to synthesize histamine. Scand J Gastroenterol. 2003;38(2):133–140. 28. Xu  X, Zhang  D, Zhang  H, et  al. Neutrophil histamine contributes to inflammation in mycoplasma pneumonia. J Exp Med. 2006;203(13):2907–2917. 29. Li M, Hu J, Chen Z, et al. Evidence for histamine as a neurotransmitter in the cardiac sympathetic nervous system. Am J Physiol Heart Circ Physiol. 2006;291(1):H45–H51. 30. Li M, Luo X, Chen L, Zhang J, Hu J, Lu B. Co-localization of histamine and dopamine-beta-hydroxylase in sympathetic ganglion and release of histamine from cardiac sympathetic terminals of guineapig. Auton Autacoid Pharmacol. 2003;23(5–6):327–333. 31. Marley PD. Mechanisms in histamine-mediated secretion from adrenal chromaffin cells. Pharmacol Ther. 2003;98(1):1–34. 32. Whitehouse  PJ. Acetylcholine. In: Aminoff  MJ, Daroff  RB, eds. Encyclopedia of the Neurological Sciences. 2nd ed.Elsevier; 2014:352–354. 33. Robert  PH, Benoit  M. Neurochemistry of cognition: serotonergic and adrenergic mechanisms. In: Goldenberg  G, Miller  BL, eds. Handbook of Clinical Neurology. Elsevier; 2008:31–40. [chapter 2]. 3 4. Pauwels  PJ. 5-HT 1B/D receptor antagonists. Gen Pharmacol. 1997;29(3):293–303. 3 5. Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012;136(1):82–93. 3 6. Jurcovicova  J. Glucose transport in brain—effect of inflammation. Endocr Regul. 2014;48(1):35–48. 37. Tombeau Cost  K, Unternaehrer  E, Plamondon  A, et  al. Thinking and doing: the effects of dopamine and oxytocin genes and executive function on mothering behaviours. Genes Brain Behav. 2017;16(2):285–295. 3 8. Mitaki  S, Isomura  M, Maniwa  K, et  al. Impact of five SNPs in dopamine-related genes on executive function. Acta Neurol Scand. 2013;127(1):70–76. 3 9. Han DH, Yoon SJ, Sung YH, et al. A preliminary study: novelty seeking, frontal executive function, and dopamine receptor (D2) TaqI A gene polymorphism in patients with methamphetamine dependence. Compr Psychiatry. 2008;49(4):387–392. 4 0. Glimcher PW. Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis. Proc Natl Acad Sci U S A. 2011;108(suppl 3):15647–15654. 4 1. Bodi  N, Keri  S, Nagy  H, et  al. Reward-learning and the noveltyseeking personality: a between- and within-subjects study of the effects of dopamine agonists on young Parkinson's patients. Brain. 2009;132(Pt 9):2385–2395. 4 2. Berridge KC, Robinson TE. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev. 1998;28(3):309–369. 4 3. Cheung  CY, Kuhn  RW, Weiner  RI. Increased responsiveness of the dopamine-mediated inhibition of prolactin synthesis after destruction of the medial basal hypothalamus. Endocrinology. 1981;108(3):747–751.

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Cheung CY, Weiner RI. Supersensitivity of anterior pituitary dopamine receptors involved in the inhibition of prolactin secretion following destruction of the medial basal hypothalamus. Endocrinology. 1976;99(3):914–917. Galzin AM, Dubocovich ML, Langer SZ. Presynaptic inhibition by dopamine receptor agonists of noradrenergic neurotransmission in the rabbit hypothalamus. J Pharmacol Exp Ther. 1982;221(2):461–471. Borgundvaag  B, George  SR. Dopamine inhibition of anterior pituitary adenylate cyclase is mediated through the high-affinity state of the D2 receptor. Life Sci. 1985;37(4):379–386. Foord  SM, Peters  JR, Dieguez  C, Scanlon  MF, Hall  R. Dopamine receptors on intact anterior pituitary cells in culture: function­

al association with the inhibition of prolactin and thyrotropin. Endocrinology. 1983;112(5):1567–1577. 48. Onali  P, Schwartz  JP, Costa  E. Inhibition of VIP-sensitive adenylate cyclase by dopamine in rat anterior pituitary. Adv Biochem Psychopharmacol. 1983;36:199–207. 4 9. Zhang  Z, Machado  F, Zhao  L, et  al. Administration of ­thyrotropin-releasing hormone in the hypothalamic paraventricular nucleus of male rats mimics the metabolic cold defense response. Neuroendocrinology. 2018;107(3):267–279. 5 0. Duraffourd C, Lapraz JC, Valnet J. ABC de Phytothérapie dans les maladies infectieuses. Paris: Editions J. Grancher; 1998. 

Chapter 4

A clinical introduction to the endocrine system according to the theory of Endobiogeny For the species, the most important role of the hormones is ­reproduction, but for the individual it is differentiation and adaptation. It becomes increasingly more obvious, furthermore, that the principal medical application of endocrinology is not the treatment of the primary but secondary diseases of the endocrines. [Primary endocrinopathies] are rare diseases in comparison with the hormonal derangements resulting from maladaptation to stress. Hans Selye1

Introduction There are standard resources that adequately and even exhaustively describe the endocrine actions of hormones. “What is a hormone?” is not the subject of this chapter or this book. Endocrinology arose as a study of endocrinopathies. This approach limited an appreciation of the role of the endocrine system across all systems. There is growing awareness by endocrinologists of the effects of the environment on the endocrine system and the endocrine system on disorders in various other systems. However, the line of research remains largely unifactorial, and increasingly genetic or molecular in nature. If systems are integrated in their function and allow for the interrelated activity of its parts, the manager of the system—the endocrine system—must ipso facto work in a similar way. The question we should be asking is, “How are hormones organized in function?” The more comprehensive our conceptual framework is, the greater our ability to see patterns and relationships previously undetected. Hormones are a chemical messenger system that coordinate, attune, and harmonize the various levels of metabolic demands and responses. In this way, it assures the coherence of how Life expresses itself in an organized manner. As the manager of the terrain, a study of the endocrine systems is essential in Endobiogeny. What we propose is a theory of integrative physiology based on the management of metabolism by the endocrine system, calibrated by the autonomic nervous system, and supported by digestive and emunctory organs. The theory of Endobiogeny p­ resents a The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00004-5 © 2019 Elsevier Inc. All rights reserved.

number of novel ­concepts with respect to endocrine function that conceptualize how a complex, integrated, and interrelated system such as the human organism can function in permanent dynamism. This regulated dynamism ensures the formation and maintenance of structure, the function of structure, adaptation of structure, and the adaptation of the global system, from aggression to restitutio ad integrum. There are five core concepts with regard to endocrine function according to the theory of Endobiogeny. They are summarized below, and elaborated on throughout the chapter. 1. One manager: The endocrine system is the manager of the terrain (cf. Chapter 2) 2. Two lines of metabolic activity: Metabolism is composed of catabolic and anabolic activity. Endocrine activity will be conceptually arranged based on their net catabolic or anabolic activity. 3. Four axes of function: Endocrine activity occurs along four axes in alternating turns of catabolic and anabolic effects. 4. Two loops of endocrine activity: The four endocrine axes proceed in a sequence then repeat themselves in a second loop with effects complementary to the first. What is initiated at the beginning of the first axis of the first loop is completed with the end of the fourth axis of the second loop. 5. Seven types of endocrine activities: Based on its effects on metabolism there are seven types of endocrine activities: (1) cellular, (2) tissular, (3) endocrine, (4) endocrinometabolic, (5) endocrinotissular, (6) organometabolic, and (7) organotissular.

Concept of management of the endocrine system One of the capital properties of the endocrine system is its ability to manage itself through feed-forward, feedthrough, and feedback mechanisms. This guarantees the rate and 45

46  The Theory of Endobiogeny

d­ uration of secretion (production) of a hormone and its threshold and timing of excretion (release of the hormone from its site of production). A standard approach to endocrinology primarily considers this vertical activity, i.e., topbottom (hypothalamic-pituitary-end organ) and bottom-top (end organ-pituitary-hypothalamic). This works well when assessing endocrinopathies of the endocrine glands themselves, such as a prolactinoma or congenital adrenal hyperplasia. Beyond this, the endocrine system manages a complex and dynamic system. What is implicated in complexity is that multiple types of activity occur at multiple levels of function which may be additive or competitive or both. To ensure this, we must study five qualities of endocrine management: (1) sequencing (that which precedes the necessary is itself necessary), (2) timing, (3) rhythmicity, (4) periodicity, and (5) duration, to be discussed later in this chapter. In essence, the endocrine system has one goal and two principles. The goal: regulation of metabolism to assure the integrity and survival of the organism. The principles are two. First, self-interest: each endocrine axis acts according to its own needs. Second, cooperation: each unit of endocrine activity must prepare the activity of that which proceeds it and diminish the activity of that which preceded it.

Classical definitions of hormone activity In discussing the activity of hormones, we distinguish the uniqueness of the endocrine system from other systems. The nervous system has a defined, anatomical tract. For example, the vagus nerve originates in the brain stem and travels as a physical nerve fiber to multiple locations in the periphery. Its field of activity is anatomically defined. Where it touches, it affects. In contrast, a hormone travels. The notion of an endocrine axis is a concept, not an anatomical system with physically connecting parts. The timescale of neurons is milliseconds. The timescale of hormones is seconds to days. The ANS is digital in its action. Constantly switching on and off. Endocrine action is analog, constantly on but variable in intensity and duration. It ceaselessly

s­ ynergizes with hundreds of local cellular local and global hormonal, neurotransmitter, and immune factors. There are five types of endocrine activity from a standard endocrinology perspective (Table 4.1): Endocrine: Acts on distant targets for general demands. They have global, regional, and local effects on the general metabolic activity of the cell. This is the primary level of hormonal assessment in Endobiogeny because it is upstream and global in its ability to coordinate the activity of interrelated physiologic activity throughout the body. Example: In adaptation, cortisol’s actions on liver, muscle, stomach, thymus, and central nervous systems. Intracrine: Acts on distant targets for local demands. Example: DHEA enters into a cell and is converted to an estrogen or gonadal androgen depending on the requirements of the cell. Paracrine: Acts on local targets for local demands. Cells excrete paracrine factors to induce coupled physiologic activity among local cells. Examples: Fibroblastic growth factor, tyrosine kinase. Autocrine: Acts on self as target. Autocrine factors regulate the structural and structuro-functional activity of the cell that excreted the information molecule. They can promote or diminish their own activity. Example: Interleukins act as autocrine factors on immune cells. Pheromones: Acts on nonself-target at a distance. Pheromones are hormones that are transmitted through nonhematogenous spread outside an organism to affect the physiology of another organism. Example: Androstenedione affects mood, cooperation, and other interpersonal activities.2–7

A functional approach to hormone activity: Levels of metabolism The theory of Endobiogeny also characterizes hormones based on their effects on metabolism. There are seven levels of action, three basic and four combinatorial: (1) cellular, (2) tissular, (3) endocrine, (4) endocrinometabolic, (5) endocrinotissular, (6) organometabolic, and (7) organotissular (Table 4.2).

TABLE 4.1  Summary of classical hormonal activity based on distance from site of action Type

Region

Site

Example

Endocrine

Distant cells

Membrane receptors

Cortisol in adaptation

Intracrine

Within the cell

Cytoplasm, nucleus

DHEA

Paracrine

Adjacent cells

Membrane receptors

Fibroblast growth factors

Autocrine

Excreting cell

Membrane receptors

Interleukine-1

Pheromone

Other organisms

Alloreceptors

Androstenedione

A clinical introduction to the endocrine system according to the theory of Endobiogeny Chapter | 4  47

TABLE 4.2  Hormone classification based on metabolic action Activity

Description

Example

Cellular

Cellular metabolism for its own benefit based on cellular demands

Production of mitochondria in a myocyte

Tissular

Tissular metabolism for its own benefit based on tissular demands

Healing of muscle fiber injury Muscle metabolism during muscle growth postexercise

Endocrine

Hormonal stimulation of excretion of second hormone

ACTH stimulation of cortisol excretion Negative feedback of cortisol on ACTH

Endocrinometabolic

Hormonal regulation of cellular metabolism based demands greater than that of the cell

FSH upregulation of estrogen receptors within the thyroid Alteration of myocyte glucose metabolism due to programmatic onset of puberty

Endocrinotissular

Hormonal regulation of tissular metabolism based on demands greater than the tissue

Programmatic increase in muscle tissue density and strength during puberty estrogens + androgens

Organometabolic

Hormonal regulation of organ metabolic activity as a whole based on demands greater than the cell

ACTH stimulation of adrenal cortex to produce (secrete) cortisol by uptake and metabolism of cholesterol Increase in myocyte ATP production during exercise

Organotissular

Hormonal regulation of organ tissular activity based on demands greater than the cell

FSH and LH regulation of gonad size and activity form fetogenesis through gonadopause Upregulation of muscle fiber contraction and recovery during exercise

Cellular metabolism Cellular metabolism is the intrinsic metabolism of the cell for itself. It is the creation, organization and management of material structure, and the functioning of that structure. The cell regulates itself by internal mechanisms regulated by communication between the membrane and the mitochondria. We theorize that mitochondria serve an endocrine-like managerial function within the cell, from the time before the existence of an endocrine system.8–10 Examples: 1. Production of mitochondria in a myocyte 2. Cell membrane expansion due to intrinsic cell growth

Tissular metabolism Tissular metabolism is the metabolic activity of tissues for its own benefit based on local demands. It is the coordinated activity of many cells in their structure or function as tissue. Examples: 1. Structure: Growth of the thumb in infancy 2. Function: a. Muscle metabolism during muscle growth postexercise b. Osteoclast and osteoblast activity in bone density regulation c. Healing dermal abrasion

Endocrine metabolism This is the classical conception of endocrine activity: feed-forward and feedback activities on endocrine glands.

Endocrine metabolism represents the vertical, horizontal, and radial regulating actions of hormones. Endocrine metabolism runs the endocrine loops. Examples: 1. ACTH feed-forward stimulation of cortisol during adaptation 2. Cortisol’s negative feedback on ACTH to downregulate its activity 3. Prolactin relaunching CRH to start the second loop of the general adaptation syndrome

Endocrinometabolic Endocrinometabolic activity is hormonal adjustment of cell metabolism based on demands beyond the intrinsic cellular function. Each cell regulates itself for its own benefit based on its own requirements. However, the cell lives within a community consisting of all other cells. It must also regulate its own intrinsic function in relationship to the needs of others. This regulation can be local (i.e., autocrine and paracrine) or distant (i.e., endocrine). Regardless, the goal is to influence cell metabolism for the benefit of other cells, tissues, or larger systems within the organism. It is a way of coordinating the coherence of function starting at the cellular level. For example, as a child grows and the level of physical activity increases. Glucagon, insulin, and insulin-like growth factors exert endocrinometabolic effects on capabilities of the liver in storing and releasing glucose. When endocrinometabolic activity affects the number of hormone receptors, it determines the threshold of sensitivity of

48  The Theory of Endobiogeny

r­ esponse of cells to hormone. It does not affect the vertical or horizontal endocrine loops. It creates the demand and the immediate regulation of the general endocrine activity, which does affect the loops. Examples:

Organotissular

1. FSH upregulation of estrogen receptors in the thyroid: This improves the coupling of catabolic thyroid activity relative to the anabolic activity by estrogens. 2. Estrogens: Rate of protein metabolism in cells.

1. FSH’s role in the formation, maintenance, maturation, and de-maturation of the gonads throughout the various phases of life from fetogenesis to gonadopause. 2. Upregulation of muscle fiber contraction and recovery during exercise.

Endocrinotissular

In summary, there are seven levels of metabolism. The endocrine system regulates five of them in order to harmonize local activity relative to regional or global demands.

Endocrinotissular activity is the hormonal regulation of tissular metabolism in order for the tissue’s output to benefit regional or global demands. Examples: 1. Programmatic increase in muscle fiber density and architecture during adolescence by estrogens + androgens. 2. Hepatic lobule repair after viral injury during acute hepatitis.

Organometabolic It refers to the hormonal regulation of organ metabolic activity as a whole based on demands greater than the cells within the organ. Examples: 1. ACTH stimulation of cortisol production through cholesterol metabolism. 2. Estrogen’s influence on the rate of production of T4 within the thyroid thanks to the endocrinometabolic activity of FSH to upregulate the number of estrogen receptors on the thyroid. 3. Increase in myocyte ATP production during exercise.

It is the hormonal regulation of organ tissular activity based on demands greater than the tissue. Examples:

Endocrine calibration In order for the endocrine system to efficiently and logically regulate metabolism, it must itself be calibrated and ­ regulated based on information received from the ANS, emunctories and other hormones (Table  4.3). See Chapters 3 (ANS), 10 (endocrine-endocrine coupling), and 11 (­endocrine-emunctories) for details.

Concept of endocrine axes Metabolism is a singular concept: ceaseless maintenance of life. Life is an alchemical process in which some substances are transformed into another. From the singularity of metabolism arises the duality of catabolism and anabolism. Catabolism releases energy inherent in chemical bonds. Anabolism uses that energy to produce or assemble. When we unfold the unicity of metabolism into the quadratic secular activity of life itself we see the necessity of organizing endocrine action according to catabolic and anabolic effects (Fig. 4.1).

TABLE 4.3  Calibration of the endocrine system by the ANS, hormones or emunctories Regulation

Example

Logic

Application

ANS-endocrine

Alpha → general Adaptation syndrome

Calibrates intensity and duration of endocrine activity

Address ANS in treatment when seeking to modulate insufficient or excessive endocrine activity

Endocrine-endocrine coupling

FSH calibrates TRH production

As FSH stimulates anabolic estrogens, FSH calibrates the intensity of TRH action in stimulating a commensurate catabolic response

In reducing sugar cravings due to elevated TRH in premenstrual syndrome, evaluate FSH-estrogens and peripheral thyroid activity as well

Endocrineemunctories

Aldosterone → kidney

Aldosterone regulates tissular and cellular hydroelectric activity, so it modulates the kidney’s role in water and electrolyte

With tissue edema, to improve renal diuretic function, address adrenal cortex production of aldosterone

A clinical introduction to the endocrine system according to the theory of Endobiogeny Chapter | 4  49

a­ pproaches to endocrine organization. The HPA axis only includes the hormones directly implicated in stimulation of adrenal cortex hormones. The nomenclature “Corticotropic axis” also includes other organs implicated in the regulation of fluid and electrolytes as well as emunctory function related to the axis.

Geometric axis

Nomenclature: -tropic vs hypothalamicpituitary [end organ] The preferred nomenclature in Endobiogeny for an endocrine axis is with the suffix “-tropic.” This is in contrast to the classical nomenclature of “hypothalamic-pituitary [HP][end organ] axis. Use of the term “-tropic” is more inclusive and functional, reflecting the notion of integrated and interrelated systems. It includes associated glands and organs that are implicated in the very functioning of the primary endocrine activity. Table  4.4 demonstrates the different TABLE 4.4  HPA vs corticotropic axis Level

HPA (standard)

Corticotropic (endobiogeny)

Hypothalamic

CRH

CRH

Pituitary

ACTH

ACTH, POMC, MSH, vasopressin, oxytocin, endorphins

End organ

Adrenal cortex: cortisol, DHEA, aldosterone, etc.

Adrenal cortex: cortisol, DHEA, aldosterone, etc.

Associated

Eq

ua

Ax is

FIG. 4.1  Arrangement of endocrine function by alternating catabolic and anabolic axes. Within each outlined red or blue box, the top line is the hypothalamic hormone, the middle pituitary and bottom peripheral glands containing various hormones. Corticotropic: CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropin hormone; adrenals=adrenal cortex. Gonadotropic: LHRH=GnRH: gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH: luteinizing hormone; gonads=ovaries/ testicles. Thyrotropic: TRH, thyrotropin-releasing hormone; TSH, thyroidstimulating hormone. Somatotropic: GHRH, growth hormone-releasing hormone; GH, growth hormone; PL, prolactin. Pancreas: endocrine pancreas: insulin and glucagon. (© 2014 Systems Biology Research Group.)

The word “axis” in geometry refers to an imaginary line around which something rotates (Fig.  4.2). The first concept is that the line is imaginary—it is purely conceptual— but efficient for organizing ideas based on function. For example, there is no anatomical articulation between the hormones in a given endocrine axis as one finds with the joints of the skeletal system. One may argue that the various glands are linked by their sequential actions on each other, as we have demonstrated with classical vertical information loops. This is neither untrue, nor is it completely true. As we will demonstrate, there are other axes of function that are horizontal and radial in nature. The second concept is rotation: a rhythmic movement that unfolds over time. The concepts of rhythmicity, of pulsation, and of variability of release of hormones are key concepts in endocrinology. For example, it is not the total daily release of growth hormone (GH) that informs the body with respect to growth activity, but the amplitude, phase, and frequency of release that is key. Consider circadian measurement of three hormones in three situations: normal (gray), acute critical (dark black) and convalescent (thin black line) physiology for three hormones: GH, thyroid stimulating hormone (TSH), and prolactin (PRL).11 Considering just GH, we note that healthy adults (gray line) have two peak excretions during the evening. In acute illness, amplitude, phase, and frequency of release are all suppressed. In chronic illness, phase and frequency are partially restored, but amplitude is not. The area under the curve is approximately the same for healthy and chronically ill adults, but the inappropriate rhythmicity means that the efficiency of GH is impaired (Fig. 4.3).

tor Ecliptic

Kidney: renin Liver-kidney-lungs: angiotensin CV: atrial natriuretic factor, nitric oxide Emunctories: kidney, liver, skin, intestine FIG. 4.2  Illustration of a geometric axis.

50  The Theory of Endobiogeny

FIG. 4.3  Rhythmicity of endocrine excretion in various physiologic states. The gray lines illustrate optimal patterns of rhythmic excretion. Nocturnal serum concentration profiles of growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin (PRL) illustrated in acute critical illness (thin black line) and chronic critical illness (thick black line) in the intensive care unit. (Reproduced from Van den Berghe G, de Zegher F, Bouillon R. Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab. 1998;83(6):1827–1834. doi:https://doi.org/10.1210/ jcem.83.6.4763.)

FIG. 4.4  Phase shifts in hormone excretion.

Part of the rhythmicity of the endocrine system is the chronologic timing of endocrine function. Fig. 4.3 demonstrates the dysfunction of three pituitary hormones during nocturnal phase of activity. During chronic illness, each hormone has some restored rhythmicity, but they are phase shifted. In other words, even when it does peak, it is not at the optimal time. So, for a single hormone, the phase shifting can be graphically represented as shown in Fig.  4.4, where the red line is the timing of excretion during health, and the blue line during illness. If we superimpose the activity of all three hormones from Fig. 4.3 (TSH, GH, PRL), we note that the additive effects

of their individual nocturnal rhythms have been transformed from in-phase (Fig. 4.5) to out-of-phase waves (Fig. 4.6). If we dip our toe into the ocean of molecular biology and quantum biophysics for just a moment, we should consider that every element of matter is composed of atoms and subatomic particles that vibrate at signature frequencies. Hormones are no exception. Thus, to graph the simultaneous activity of endocrine function in a given moment across space and time would really look more like the fractal in Fig. 4.7 than in Figs. 4.4–4.6. In a sense, a hormone is a quantum of information. Hormones—or any matter—never touch their receptors as represented in a “lock and key” model. They engage in various levels of electromagnetic and electrochemical vibrations and interactions in order to achieve resonance and entrainment. At every level of consideration, quantum, molecular, and chemical endocrine functions are a story of rhythm, harmony, and entrainment. The fractal harmony of neuroendocrine regulation could be mapped out in quantum cartography perhaps like in Fig. 4.8. However, for the pedagogic purposes, the endocrine system will be shown in somewhat static fashion so as to match our Newtonian view of the gross material world.

FIG. 4.5  Phase linked function of multiple hormone.ART: Replace with attached Fig. 4.5

FIG. 4.6  Phase shifted function of multiple hormone.ART: Replace with attached Fig. 4.6

A clinical introduction to the endocrine system according to the theory of Endobiogeny Chapter | 4  51

various hormonal activities in order to accomplish together what each could not do on its own (Chapter 10).

Concept of endocrine cycles Endocrine function occurs in a cycle of alternating catabolic and anabolic activity in order to assure a proper state of metabolic regulation. One observes the following: 1. The anabolic axes have two pituitary hormones 2. The catabolic axes have one pituitary hormone 3. The primary end-organ of each axis has three unique hormones

FIG. 4.7  Visualization of multiendocrine function across space and time. Each color represents a different endocrine axis and the actions of peripheral glands. The center point represents an organizing goal of action. The movement across linear time is from left to right. The thickness of a line represents the intensity of endocrine function at the moment of time. (From Wikimedia Commons by Jonathan Zander I. [CC-BY-SA-3.0].)

There is a logic to the variation in activity of a single hormone that stimulates multiple hormones. There is also a logic to the timing of the secretion and excretion of endorgan hormones. Otherwise, a simple release of all the endorgan hormones from all the glands all at once would favor chaos rather than order. The concept of the endocrine loops presents a theoretical construct in how endocrine function pivots at both pituitary and end organ levels. It also introduces the notion of complementarity of function through competitive and additive function (discussed later in this chapter and Chapters 6–11). The basic concept of the endocrine loops is that the end of the first loop is the middle of the entire cycle, for it stimulates and progresses the second loop. The purpose of the first loop of endocrine activity is to mobilize material (catabolism) and initiate construction (anabolism). The purpose of the second loop is to finalize catabolism and complete anabolism. The two loops are schematically shown in Fig. 4.9. Four conclusions can be drawn about the general pattern of the loops with respect to the anabolic axes and the uniqueness of the somatotropic axis in particular: 1. Anabolic hormones have two pituitary hormones because anabolism is more complex than catabolism. 2. The somatotropic axis has two hypothalamic and two pituitary hormones. 3. The somatotropic axis’ pituitary hormone prolactin (PL) is a pivot around which the two loops turn. 4. Somatotropic insulin ends pro-anabolism in second loop.

FIG.  4.8  Quantum fracticality of endocrine function. The interior of the structure represents the global endocrine regulation of the terrain. The branching, clustered features represent specific acts of regulation. (From Wikimedia Commons by Prokofiev [CC BY-SA 3.0].)

Political axis There is another meaning of axis that is used in politics: an alliance between two or more entities that forms the nidus for a larger grouping of entities working for a greater purpose. This second sense of axis or alliance is used in the theory of Endobiogeny to refer to functional associations of

Endocrine-endocrine regulation There are three levels of endocrine-endocrine regulation across the axes: vertical, horizontal, and radial.

Vertical regulation Vertical regulation is the classical notion of top-bottom and bottom-top regulations. The three principles of vertical regulation are feed-forward, feedthrough, and feedback (Fig. 4.10).

52  The Theory of Endobiogeny

FIG. 4.9  Schematic of first and second loop endocrine activity. In the second loop, prolactin (PL) is shown by the red arrows stimulating both the corticotropic and gonadotropic axes. Somatostatin has local and peripheral locations of production. In the bottom-right corner of the second loop figure, it is shown being released from organs within the GI system. Corticotropic: CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone. Gonadotropic: GNRH, luteinizing hormone releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone. Thyrotropic: TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. Somatotropic: GHRH, growth hormone-releasing hormone; SS, somatostatin; GH, growth hormone; PL, prolactin; IGF, insulin-like growth factor. (© 2014 Systems Biology Research Group.)

FIG.  4.10  Feed-forward and feedback loop to regulate hypoglycemia. (From Wikimedia Commons by Rosenbach D. [CC BY 3.0].)

Feed-forward: The downfacing arrows on the right half of Fig.  4.10 represent a cascade of activity. The stimulus (level 1) gives information to a sensor (level 2) to produce something. The product of the sensor stimulates a control mechanism (level 3). Level 3’s product has the ultimate effect on the target of action (effector). Feedthrough: What happens inside each box is the feedthrough mechanism. It is the specific way inside each unit of action that the product is ultimately made, e.g., how ACTH stimulates production and excretion of cortisol. Feedback: The dark, ascending arrow from effector (level 3) to stimulus is the feedback mechanism. It ensures the discontinuation or reduction in feed-forward information to calibrate the quality of the effect relative to its own

axis of activity. Each previous level that receives feed-­ forward information also provides feedback information for the level above it. Applying these concepts of vertical control to the endocrine system, and specifically the corticotropic axis, we see the following type of schematic (Fig. 4.10). A change in serum concentration of glucose is a stimulus. The sensor is the hypothalamus. Its feed-forward response is to excrete CRH, which stimulates the control: the pituitary gland. The pituitary releases ACTH as its response to stimulation. The ACTH stimulates the effector gland, the adrenal cortex. The adrenal cortex excretes the effector: glucocorticoids that alter the level of glucose. As blood sugar levels rise, cortisol inhibits CRH so that its own production and activity are regulated to avoid hyperglycemia. The ultimate goal of vertical regulation is the modification of endocrine production and activity within its own axis of function. This is a valid and crucial level of management to understand. However, endocrine activity does not occur in isolation or without any consequence for other lines of endocrine activity. Because of the complexity of both the organism and the management of the organism by the endocrine system, other types of regulation also exist to ensure proper management of the manager of the terrain (i.e., the endocrine system).

Horizontal regulation Horizontal regulation refers to the regulation of endocrine activity across endocrine axes be it within the same gland (i.e., pituitary: TSH stimulates GH). The necessity of horizontal regulation arises from the need to regulate both what has come before and what is to come. Horizontal regulation assures both a good quality of function as well as the proper

A clinical introduction to the endocrine system according to the theory of Endobiogeny Chapter | 4  53

duration of function of hormones as an ensemble, and is a form of feed-forward and feedback regulation. Continuing our consideration of the corticotropic axis, we can combine vertical regulation within the axis, and horizontal regulation within the pituitary to see how the organism installs a higher order of regulation. ACTH, rising levels: 1. Vertical regulation ● Negative feedback on CRH in the hypothalamus. ● Positive feed-forward of adrenal cortex to produce cortisol. 2. Horizontal regulation ● First loop: Calibrates FSH secretion to harmonize estrogen production relative to cortisol. ● Second loop: Calibrates LH secretion harmonize androgen production relative to aldosterone.

Radial regulation Radial regulation is a type of endocrine regulation that encapsulates both vertical and horizontal regulation. Radial regulation goes across axes and can move across central and peripheral glands. The logic here is that vertical regulation informs an axis properly about the quality of its production and activity in and of itself. Horizontal regulation informs another axis at the same level of the quality of activity of one factor relative to another. Radial regulation provides both types of information simultaneously. To go back to our prior discussion of cortico-­ gonadotropic regulation, ACTH stimulates the secretion of cortisol and also FSH. Moreover, cortisol, a peripheral corticotropic hormone, goes across endocrine axes of function (corticotropic → gonadotropic) and levels of regulation (peripheral → central) to regulate FSH. The ACTH’s horizontal stimulation of FSH indicates how much cortisol it is anticipated to make. In this way, FSH can calibrate itself to stimulate a proportional amount of estrogens. The radial information from cortisol is about what was actually achieved by cortisol. This information is about accomplishment, not possibility. The notion of radial endocrine management is crucial to understanding why diseases occur with a clustering of physiologic anomalies and a syndromic presentation of symptoms (Chapter 10). This concept forms the basis of disease management discussed in The theory of Endobiogeny Volumes 1 and 2 (Fig. 4.11).

Conclusions The endocrine system regulates the complexity of the Life expressing itself in an organized fashion. The endocrine system’s regulation of itself and its calibration by other factors is similarly complex. This ensures a high degree of responsiveness and attunement of metabolic demands to the

FIG.  4.11  Vertical, horizontal, and radial endocrine regulation. The example demonstrates vertical, horizontal, and radial regulation in the coupling of the corticotropic and gonadotropic axes. Vertical: ACTH stimulates (red arrow) cortisol. Cortisol has a catabolic action. Horizontal: ACTH prepares FSH to calibrate the anabolic estrogen response to match the catabolic activity of cortisol. ACTH stimulates the production of FSH within the pituitary. Radial: Cortisol influences the amount of FSH produced (secreted) and released (excreted). Rising levels of cortisol calibrate and assist the production of FSH (top diagonal solid purple line). Peak levels block its release (middle diagonal broken green line). This is to prevent a premature action by estrogens before cortisol has completed its actions. As cortisol levels fall (lower diagonal line, solid green), FSH is excreted to increase the excretion of estrogens, and to produce additional estrogens. Not shown: Negative feedback loop by cortisol on ACTH to slow down its own production. (© 2015 Systems Biology Research Group.)

requirements of the organism. In addition to the classical definition of hormones by location of origin and distance of action, we presented the Endobiogenic notion of hormone function by type of metabolism regulated. A new system of classification of hormones based on both the geometric and political notions of axis were presented, allowing for an expansion of classification of hormones based on complementarity of action rather than vertical control mechanisms. With this notion of association arises the notion of endocrine axial associations, and new concepts of regulation: horizontal and radial. The organization of the endocrine system in this fashion, while conceptual provides a sense of coherence to the notion of how the terrain is managed. For the clinician, it forms the basis of explaining the origins of disorders and dysfunctions, and will provide the foundation for the selection of a rational selection of therapeutic interventions.(Courtesy of Florida Center for Instructional Technology.)

References 1. Selye  H. Stress and the general adaptation syndrome. Br Med J. 1950;1(4667):1383–1392. 2. Benton D. The influence of androstenol—a putative human pheromone—on mood throughout the menstrual cycle. Biol Psychol. 1982;15(3–4):249–256. 3. Grosser  BI, Monti-Bloch  L, Jennings-White  C, Berliner  DL. Behavioral and electrophysiological effects of androstadienone, a human pheromone. Psychoneuroendocrinology. 2000;25(3):289–299. 4. Hummer  TA, McClintock  MK. Putative human pheromone androstadienone attunes the mind specifically to emotional information. Horm Behav. 2009;55(4):548–559.

54  The Theory of Endobiogeny

5. Huoviala  P, Rantala  MJ. A putative human pheromone, androstadienone, increases cooperation between men. PLoS One. 2013;8(5):e62499. 6. Lundstrom JN, Goncalves M, Esteves F, Olsson MJ. Psychological effects of subthreshold exposure to the putative human pheromone 4,16-androstadien-3-one. Horm Behav. 2003;44(5):395–401. 7. Samaras N, Samaras D, Frangos E, Forster A, Philippe J. A review of age-related dehydroepiandrosterone decline and its association with well-known geriatric syndromes: is treatment beneficial? Rejuvenation Res. 2013;16(4):285–294. 8. Schrader M, Godinho LF, Costello JL, Islinger M. The different facets of organelle interplay-an overview of organelle interactions. Front Cell Dev Biol. 2015;3:56.

9. Wacquier  B, Combettes  L, Van Nhieu  GT, Dupont  G. Interplay between intracellular Ca2+ oscillations and Ca2+ -stimulated mitochondrial metabolism. Nat Sci Rep. 2016;6:19316. www.nature.com/ scientificreports. 10. Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82(1):47–95. 11. Van den Berghe G, de Zegher F, Bouillon R. Clinical review 95: acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab. 1998;83(6):1827–1834.

Chapter 5

The pineal axel From time to time we feel the urge to reorganize our classifications in medicine, even if nothing really new is added—just as we rearrange the contents of our desk drawers. It gives us a chance to eliminate the useless objects and to put the most useful ones into accessible positions. It may even call to our attention some long-forgotten item that we banished into obscurity at a time when we failed to realize its now so obvious utility. Hans Selye.1

Introduction to the pineal axel The pineal gland has been a source of medical, philosophical, theological, and spiritual inquiry since antiquity.2 No less a mind than Renée Descartes considered it to be the “seat of the soul.” Our interest will be limited to its physiologic purpose, which is no less grand in our opinion. The pineal gland is also referred to as epiphysis cerebri and conarium, for the gland appears in gross examination like a pine (pineal) cone (conarium). The organism has within itself intrinsic rhythms. These rhythms respond to demands placed on it by the external world that arise from the conditions of time and space: day and night, seasons, solar flares, geomagnetic fluctuations, etc. The pineal gland harmonizes internal rhythms to external ones. It attunes our microcosm to the macrocosm by adjusting metabolism and adaptation capabilities to the reality of our existence on a rotating, slightly oblong object that revolves around its star, the sun. The pineal gland is literally the third eye because it is the internal eye of the body. It reacts to the duration of light perceived by the two physical eyes and converts this information into electrochemical information in the form of melatonin and other hormones (not discussed here) that influence the four endocrine axes. Thus, in our classification system, the pineal gland is not an endocrine axis, but a supra-axial epiendocrine gland with supracontrol function. In other word, it is the axel around which all other axes unfold with respect to their chronobiologic functioning.

Location The pineal gland is located in the very center of the brain, at the midline between the two hemispheres, in the e­ pithalamic The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00005-7 © 2019 Elsevier Inc. All rights reserved.

body where the two thalamic bodies meet (Fig. 5.1). Its anatomical location creates a privileged position by which it can efficiently monitor all external and internal states, central and peripheral, by means of electromagnetic (photonic) or electrochemical (hormones, neurotransmitters, and electrolytes) information. It is bathed in cerebral spinal fluid yet the blood-brain barrier does not sequester it. It receives the second highest rate of blood flow per gram of weight second only to the kidney.

Hormone: Melatonin Hormone: Melatonin, aka N-acetyl-5-methoxy-tryptamine. Metabolism: Tryptophan → Serotonin → Melatonin, through a rate-limiting methylation process. Regulation (Fig. 5.2) ●

●

●

Stimulation ⚫ Secretion: αΣ ⚫ Excretion: πΣ Inhibition ⚫ ACTH ⚫ Cortisol Regulation: Oxytocin (cf. Oxytocin) Periodicity: Nocturnal > diurnal.

Melatonin’s purpose: Rhythmicity The pineal gland has a singular purpose accomplished through several ends: the global rhythmicity of the organism through its integration into cosmobiologic phenomenon. This includes circadian, seasonal, and circannual rhythms. Diurnal rhythms are regulated based on the varying duration of light produced by the rotation of the earth around its axis and its revolution around the sun. Nocturnal rhythms are installed by the duration of darkness with superimposition of photonic and electromagnetic effects of lunar cycles in its reflection of solar luminosity. Nocturnal physiology is not merely the “opposite” or lack of diurnal physiology, but it has its own specific chronobiologic priorities and orientations with increased cerebral metabolism and diminished muscular movement. In addition, the pineal gland helps regulate seasonal changes. The changes in duration of light more than temperature solicits variable levels 55

56  The Theory of Endobiogeny

FIG. 5.1  Location of pineal gland in the brain. On coronal view (right), the pineal gland (red circle) is located at the exact center of the brain and brain stem. On lateral view, it is at the crossroads of an anterior-posterior line that runs through the pituitary and hypothalamus, and, a cephalad-caudal line that runs from the crown through the cerebellum. (Modified by Systems Biology Research Group from an image by Life Science Database (LSDB) [CC BY-SA 2.1] via Wikimedia Commons.)

of metabolism of glucose. This is accomplished through the regulation of the intensity of action of the two catabolic axes: corticotropic and thyrotropic (Fig. 5.3). The implications of the pineal gland’s entrainment of light variation (cosmobiology) and its implications in human physiology (chronobiology) have not been fully delineated but appear to affect many aspects of the human life cycle and general behavioral: ●

FIG. 5.2  Regulation of melatonin. See text for details. Red arrow, stimulates; blue arrow, inhibits; green broken arrow, regulates; purple broken arrow, converts to. (©2015 Systems Biology Research Group.)

●

Reproduction: Menstrual phase locking, fertility, and rates of parturition3–8 Health: Myocardial accidents,9–12 strokes, gastric bleeding,13 and death from cancer12

Pineal gland

Melatonin

POMC

βMSH

αMSH

Seasonal adaptability

General adaptation Nocturnal endocrinology

Thyroid gland

Adrenal cortec

Pituitary relauching

FIG.  5.3  Overview of melatonin activity. The direct mechanism of pineal regulation of diurnal, seasonal, and general adaptability is through proopiomelanocortin (POMC) hormone. The POMC is split into beta and alpha melanocyte-stimulating hormones (MSH), which then influence these three types of adaptation responses. See Chapter 6 for a full discussion. (© 2015 Systems Biology Research Group.)

The pineal axel Chapter | 5  57

●

●

Intraspecies aggression: War,14 homicide,15–17 suicidal tendencies,18 and motor vehicle accidents12, 19 Interspecies aggression: Incidence of animals biting humans20

Melatonin physiology A certain degree of cyclicity is nearly as characteristic of life as adaptability itself, and the lack of periodicity, or rigidity, is almost equivalent to death. The female sexual cycle, the pulse, the sleep rhythm with all the concomitant diurnal variations, the interchange between activity and rest, between work and play, the periodic renewal of cells in various organs are all indispensable for the maintenance of normal life. Stressors tend to disrupt this periodicity in many ways. It would be interesting to examine the possible relations between the diseases of adaptation due to stress and what might be called the “diseases of periodicity.”

TABLE 5.1  Melatonin and psychiatric illnesses Melatonin Disorder

Serum-AM

Urine-PM

Anorexia

↑

–

Bulimia

↑

↑

Mania

–

↑

Schizophrenia

–

Blunted peak

Depression

–

↓

Seizures

–

↓

Aging

–

↓

Alzheimer’s

–

↓

(Based on Verster GC. Melatonin and its agonists, circadian rhythms and psychiatry. Afr J Psychiatry. 2009;12(1):42–46.)

Hans Selye.1

Nocturnal activity: The direct effects of melatonin during the nighttime can be considered as generally restorative and regenerative in nature: antiinflammatory, antioxidant, inhibition of insulin, stimulation of proteolytic pancreatic enzymes, and neuronal reorganization.21 Suppression of nocturnal melatonin surges can be deleterious in a precritical terrain. It can increase the risk of oncogenesis22, 23 and weight gain.24, 25 Diurnal activity: The chief and perhaps most ancient activity of melatonin is production of melanin (hence the origin of the name “melatonin” to protect the skin from ultraviolet light). Melatonin also plays a role in cardiac and gastric motricity.21 Melatonin plays an important role in dysthymia and other types of psychiatric maladies.26 The greater the activity of melatonin is the greater the tendency toward diseases of mania. The lower the activity of melatonin is the greater the tendency toward diseases of psychomotor retardation. As we noted in the discussion of rhythmicity of hormones, amplitude and duration of release are also important to the efficacy of melatonin, viz., its suspected role in schizophrenia. The association of melatonin in various psychiatric disorders is summarized in Table 5.1. The relationship between melatonin and mental states is complex and has not been fully elucidated. However, some general relationships have been established. It is melatonin’s direct and indirect relationship with alpha-­ sympathetic, dopamine, prolactin, and TRH (Fig.  5.4, Chapter  8, and Section “Activity: Memory recall, qualification of global adaptation response”). The pineal gland influences the terrain through its modulation of adaptability and mental and emotional states. It regulates rhythmicity, chronology, and amplitude of these various factors. The duration of sustain of melatonin ­release

FIG. 5.4  Melatonin, neurotransmitter, and neuroendocrine influences on adaptability and mental states. Alpha plays the key role. In the adaptation response, it stimulates (red arrow) dopamine, which aids in the perception of an aggression and sequential planning of actions. Alpha also stimulates TRH, which plays a role in neuromodulation, memory, mood, and the emotional quality of the association of the current aggression to past ones. Alpha stimulates prolactin, which turns the endocrine loops by initiating the second loop of activity. Thus, it plays a role in adaptability. The TRH stimulates prolactin as its hypothalamic hormone. Prolactin stimulates dopamine to aid in its role. However, dopamine inhibits prolactin to prevent an excessive adaptation response. Alpha stimulates melatonin excretion from the pineal gland. Melatonin in turn affects the activity of TRH and prolactin. In a simplified and schematic fashion, this is how the pineal gland plays a role in one’s mental health. (© 2017 Systems Biology Research Group.)

varies based on the time of year (longer sustain in the winter, shorter sustain in the summer). This alters prolactin release patterns, and this is key to adaptability, given a particular level of function of alpha, TRH, and dopamine. Thus, we can start to understand the periodicity of certain types of psychiatric conditions or events. For example, there are higher rates of depression in the spring and fall,27 but the

58  The Theory of Endobiogeny

Antiinflammatory

UV protection

Antioxidant

Vasomotricity Diurnal Gastric motility Regulates enteric pacemarkers

Melatonin

Nocturnal

Cognitive function

Antitumoral Pancreas Exocrine, endocrine

Neurons

Immunity

Synapsing. repair

Splenohumoral

FIG. 5.5  Summary of melatonin activity. (© 2014 Systems Biology Research Group.)

highest rates of suicide are in the summer. There is also an association between season of birth and suicide risk.28, 29 So far, these remain correlations and require further investigation to parse out cause, effect, and mechanism.

11.

Conclusions

13.

The pineal gland, via its primary hormone melatonin, acts as an epiendocrine gland that regulates all the axes. Melatonin has a restorative and regenerative role at night and a protecting and motoric role during the day. It plays a key role through its response to amount and duration of light in numerous adaptation syndromes (Fig. 5.5).

12.

14.

15. 16.

References

17.

1. Selye  H. Stress and the general adaptation syndrome. Br Med J. 1950;1(4667):1383–1392. 2. Lopez-Munoz F, Rubio G, Molina JD, Alamo C. The pineal gland as physical tool of the soul faculties: a persistent historical connection. Neurologia. 2012;27(3):161–168. 3. Criss  TB, Marcum  JP. A lunar effect on fertility. Soc Biol. 1981;28(1–2):75–80. 4. Cutler  WB. Lunar and menstrual phase locking. Am J Obstet Gynecol. 1980;137(7):834–839. 5. Cutler  WB, Schleidt  WM, Friedmann  E, Preti  G, Stine  R. Lunar influences on the reproductive cycle in women. Hum Biol. 1987;59(6):959–972. 6. Guillon P, Guillon D, Lansac J, Soutoul JH, Bertrand P, Hornecker JP. Births, fertility, rhythms and lunar cycle. A statistical study of 5,927,978 births. J Gynecol Obstet Biol Reprod. 1986;15(3):265–271. 7. Guillon  P, Guillon  D, Pierre  F, Soutoul  JH. Seasonal, weekly and lunar cycles of birth. Statistical study of 12,035,680 births. Rev Fr Gynecol Obstet. 1988;83(11):703–708. 8. Law SP. The regulation of menstrual cycle and its relationship to the moon. Acta Obstet Gynecol Scand. 1986;65(1):45–48. 9. Sitar J. The causality of lunar changes on cardiovascular mortality. Cas Lek Cesk. 1990;129(45):1425–1430. 10. Sitar J. The effect of solar activity on lunar changes in cardiovascular mortality. Cas Lek Cesk. 1989;128(14):425–428.

18.

19.

20.

21.

22.

23.

24.

Sitar J. Does the lunar phase have an effect on sudden cardiac and vascular deaths? Cas Lek Cesk. 1988;127(21):651–654. Stoupel  E, Kalediene  R, Petrauskiene  J. Clinical cosmobiology: distribution of deaths during 180  months and cosmophysical activity. The Lithuanian study, 1990–2004. The role of cosmic rays. Medicina. 2007;43(10):824–831. Roman EM, Soriano G, Fuentes M, Galvez ML, Fernandez C. The influence of the full moon on the number of admissions related to gastrointestinal bleeding. Int J Nurs Pract. 2004;10(6):292–296. Persinger  MA. Wars and increased solar-geomagnetic activity: aggression or change in intraspecies dominance? Percept Mot Skills. 1999;88(3 Pt 2):1351–1355. Thakur  CP, Thakur  B, Singh  S, Kumar  B. Relation between full moon & medicolegal deaths. Indian J Med Res. 1987;85:316–320. Thakur  CP, Sharma  D. Full moon and crime. Br Med J. 1984;289(6460):1789–1791. Thakur  CP, Sharma  RN, Akhtar  HS. Full moon and poisoning. Br Med J. 1980;281(6256):1684. Kollerstrom  N, Steffert  B. Sex difference in response to stress by lunar month: a pilot study of four years' crisis-call frequency. BMC psychiatry. 2003;3:20. Alonso Y. Geophysical variables and behavior: LXXII. Barometric pressure, lunar cycle, and traffic accidents. Percept Mot Skills. 1993;77(2):371–376. Bhattacharjee  C, Bradley  P, Smith  M, Scally  AJ, Wilson  BJ. Do animals bite more during a full moon? Retrospective observational analysis. BMJ. 2000;321(7276):1559–1561. Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese  J. International union of basic and clinical pharmacology. LXXV. nomenclature, classification, and pharmacology of G proteincoupled melatonin receptors. Pharmacol Rev. 2010;62(3):343–380. Schernhammer  ES, Rosner  B, Willett  WC, Laden  F, Colditz  GA, Hankinson  SE. Epidemiology of urinary melatonin in women and its relation to other hormones and night work. Cancer Epidemiol Biomarkers Prev. 2004;13(6):936–943. Lin  X, Chen  W, Wei  F, Ying  M, Wei  W, Xie  X. Night-shift work increases morbidity of breast cancer and all-cause mortality: a meta-analysis of 16 prospective cohort studies. Sleep Med. 2015;16(11):1381–1387. Peplonska B, Bukowska A, Sobala W. Association of rotating night shift work with BMI and abdominal obesity among nurses and midwives. PLoS One. 2015;10(7):e0133761.

The pineal axel Chapter | 5  59

25. 26. 27.

Ko SB. Night shift work, sleep quality, and obesity. J Lifestyle Med. 2013;3(2):110–116. Verster GC. Melatonin and its agonists, circadian rhythms and psychiatry. Afr J Psychiatry. 2009;12(1):42–46. Sher  L, Oquendo  MA, Galfalvy  HC, Zalsman  G, Cooper  TB, Mann  JJ. Higher cortisol levels in spring and fall in patients with major depression. Prog Neuro-Psychopharmacol Biol Psychiatry. 2005;29(4):529–534.

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Antonsen  JH, Gonda  X, Dome  P, Rihmer  Z. Associations between season of birth and suicide: a brief review. Neuropsychopharmacol Hung. 2012;14(3):177–187. Kalediene R, Starkuviene S, Petrauskiene J. Seasonal patterns of suicides over the period of socio-economic transition in Lithuania. BMC Public Health. 2006;6:40.

Chapter 6

Corticotropic axis A brief discussion of the hypothalamus and pituitary glands The hypothalamus contains the master regulating hormones of the endocrine system. In the classical endocrine consideration, hypothalamic hormones stimulate pituitary hormones in a vertical feed forward action and are inhibited in turn by these hormones through feedback. While this is certainly true, the role of the hypothalamus is more complex. It is itself subjected to regulation by the pineal gland.1 It is the origin of classical hormones which are in turn neurotransmitters (TRH, histamine),2 regulators of the global energy economy (pro-opiomelanocortin, αMSH),3 consolidators of dreams and memory (growth hormone releasing hormone),4, 5 and many other divergent tasks. Thus, we find that a more complete consideration of hypothalamic hormones must include these various activities. The pituitary gland consists of three lobes: anterior, intermediate, and posterior. The anterior lobe contains the majority of pituitary hormones and includes all those that regulate the four endocrine axes: corticotropic (POMC, ATCH, β-lipotropin), gonadotropic (FSH, LH), thyrotropic (TSH), and somatotropic (GH).6 The intermediate lobe is exclusively dedicated to POMC derivatives of the corticotropic axis (MSH family, endorphins, γ-lipotropin, ACTH).7 The posterior pituitary contains two key and unique hormones: vasopressin and oxytocin.8 According to the theory of Endobiogeny, pituitary hormones have direct inter- and intra-axial peripheral activities that complement the activity of its peripheral glands. This is where the notion of the axial arrangement of hormones in alternating catabolic and anabolic functions (Chapter 4) reveals a logic that allows us to develop a coherence theory of complex systems regulation. For example, catabolic ACTH stimulates the “adjacent” axial hormone anabolic FSH, and anabolic FSH stimulates its “adjacent” axial hormone TSH, etc. (Chapter 10). What is more, pituitary hormones have extra-axial activity on other endocrine glands and nonendocrine glands. In the assessment of clinical disorders of adaptation, it is important to evaluate the role of central factors, peripheral factors, and central-peripheral interactions, both within each axis and across axes as they relate to one another in a coherent and logical manner. The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00006-9 © 2019 Elsevier Inc. All rights reserved.

The relationship of the hypothalamus to the pituitary is functional in nature. The hypothalamus is not adjoining the pituitary. Its hormones are discharged by nerve terminals into the hypophyseal portal drainage system that baths the anterior pituitary cells. Thus, all hypothalamic hormones are neurohormones. An overview of the general relationship reveals a few interesting observations:6 (1) prolactin is the only pituitary hormone not regulated by a hypothalamic hormone within its own axis. It is regulated by the hormone TRH9 and the neurotransmitter dopamine,10 (2) the cells that produce growth hormone take up about 50% of the anterior pituitary,11 and (3) approximately two-thirds of the total volume of the anterior pituitary is dedicated exclusively to somatotropic hormones, indicating their crucial role in global functioning (Table 6.1).11

Introduction to the corticotropic axis The general function of the corticotropic axis is to ensure the survival of the organism through the management of the internal energy economy, and, the mobilization and distribution of metabolites, electrolytes, and fluids. The net effect of the corticotropic axis is catabolic, but it is also antianabolic, and, in the second loop, pro-anabolic (Fig. 6.1).

Introduction to its hypothalamic hormones When we refer to hypothalamic corticotropic hormones, we are referring to hormones that originate and are stored in the hypothalamus and whose most prominent actions are central in nature. In this respect, there are two hormones: ­ corticotropin-releasing hormone (CRH) and pro-­ opiomelanocortin (POMC). The hypothalamic hormones are made of polypeptide amino acids.3 The posterior pituitary hormones vasopressin and oxytocin are made in the hypothalamus and primarily stored in the posterior pituitary, though they have central projections from the hypothalamus.12 For this reason, we classify them as pituitary hormones.

Corticotropin-releasing hormone (CRH) Location: Hypothalamus, parvaventricular nucleus. Composition: Polypeptide Regulation (Fig. 6.2) 61

62  The Theory of Endobiogeny

TABLE 6.1  Pituitary volume by cell type Cell type

Hormone

% Pituitary cell population

Hypothalamic hormone

Corticotroph

ACTH

15–20

CRH (+), vasopressin (+)

Gonadotroph

FSH, LH

10–15

GnRH (+)

Thyrotroph

TSH

3–5

TRH (+), somatostatin (−)

Somatotroph

GH

40–50

GHRH (+), somatostatin (−)

Lactotroph

Prolactin

10–25

TRH (+), dopamine (−)

(+): stimulates, (−): inhibits. GH: growth hormone. Modified from Nussey S, Whitehead S. The pituitary gland. In: Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001 [chapter 7]; Copyright © 2001.

Corticotropic

Gonadotropic

Thyrotropic

Mobilization

Initiation

Energy

of metabolites

Lipids Carbohydrates

of metabolites

Somatotropic

Lipids

Proteins

Proteins

Mobilization

from metabolites

of metabolism

Carbohydrates

Carbohydrates

Cell interior Aminos, carbs, lipids, electrolytes

Delivery of metabolites

Energy Completion of metabolism

Cell exterior FIG. 6.1  Summary of metabolic activity by endocrine axis. The relationship of each axis to metabolites and metabolism is presented. The corticotropic axis mobilizes lipids, proteins, and carbohydrates. The proteins mobilized are then incorporated into anabolism by the gonadotropic axis in the cell’s interior. The thyrotropic axis (viz., TRH) also catabolizes proteins, which the gonadotropic axis can use. The thyrotropic axis both liberates and demands the use of carbohydrates through its regulation of ATP production. Like the corticotropic axis it also liberates lipids (TRH) which help repair or form the cell membrane, its exterior. The somatotropic axis is the great designer of structure and ensures the appropriate proportion of nutrients to each cell and tissue. (© 2014 Systems Biology Research Group.) ●

●

Stimulation ● αΣ ● Prolactin Inhibition ● Dopamine ● ACTH ● Glucocorticoids

Function: CRH regulates the general functioning of pituitary management of the adrenal cortex. The CRH stimulates the secretion and excretion of all the anterior pituitary hormones from pituitary POMC (ACTH, MSH, lipotropins, endorphin, and enkephalin).13 Mechanism: Stimulates the cleavage of pituitary POMC as a precursor to these hormones.13

Corticotropic axis Chapter | 6  63

FIG.  6.2  CRH regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits. (© 2014 Systems Biology Research Group.)

Pro-opiomelanocortin (POMC) NB: Both the hypothalamic and pituitary roles of POMC are discussed here. Location: Hypothalamus, arcuate nucleus: Hormone3 Composition: Polypeptide Hypothalamic function: The POMC is a regulator of the energy economy of the organism. It plays both central and peripheral roles, direct and indirect. It links the CNS and endocrine systems. Through its relationship with pineal melatonin, links the interior rhythms and priorities to the exterior rhythms and demands (Fig. 6.3).14 The POMC is produced within the arcuate nucleus of the hypothalamus. This location is positioned at the crossroads of cerebral, cerebrospinal fluid, and blood circulation, where it receives extensive information about circulating levels of metabolites and other related information. It has extensive projections into the CNS where it integrates into a larger family of hormones such as leptin and ghrelin. In this role, it monitors and respond to insulin activity, and the distribution and storage of both carbohydrates and lipids.3 Hypothalamic POMC projects into the brain stem—including the locus ceruleus.3 It also has receptors on the skin and hair where it influences pigmentation and adaptation. Pituitary function: It ensures the general regulation of the corticotropic axis as well as the privileged utilization of lipids for steroidogenesis within the adrenal cortex. Pituitary POMC is the precursor to all the corticotropic hormones of the anterior pituitary.7 There are two classes of products derived from POMC based on the receptors on which they act: melanocortins (ACTH, alpha-MSH, beta-MSH) and endorphins (beta-lipotropin, gamma-lipotropin, beta-­ endorphin and enkephalins) (Fig.  6.3). The cleaved segments of POMC are subsequently modified through glycosylation, phosphorylation, etc. to form various hormones. Both of these families of POMC derivatives play important roles in economizing and optimizing corticotropic adaptation during basal and functional demands, adaptation syndromes, and adaptability states such as the change of seasons.

In general, the melanocortins, ACTH, α-MSH, and βMSH, favor the augmentation of corticotropic activity (discussed further). Endorphins stabilize corticotropic activity and moderate the intensity of adaptation demands.15 The lipotropins while classified as endorphins, play a dual role. They have endorphin activity and also economize lipid utilization by favoring steroidogenesis within the adrenal cortex, thus making ACTH activity more efficient.7 While various adaptation syndromes and the general regulation of endocrine function utilize alpha-sympathetic (αΣ) discharge, the role of α-MSH is to calibrate the adaptation response during the “long route” of adaptation across the pituitary (Fig. 6.4). It does this in three ways: 1. Regulates energy homeostasis and stimulates secretion of ACTH independent of αΣ, CRH, and other factors, essentially adapting the ACTH response to adaptation.16 2. Augments cortisol release from the adrenal cortex by upregulating the number of ACTH receptors and the efficiency of adrenal cortex response to ACTH 3. Compliments and balances effects of the adaptation syndromes through its antipyretic, antiinflammatory, cicatrizing, and anorexigenic activity.17 The β-MSH/β-endorphin route is considered the “short loop” because it directly stimulates the corticotropic axis (and cortisol inhibits β-MSH).18 The two β-hormones have an agonist-antagonist relationship. β-MSH’s general role is to optimize the general catabolic activity of the organism in an immediate and direct fashion. It stimulates cortisol release without the aid of ACTH and entrains thyroid activity outside the vertical feedback information of TRH and TSH. Cortisol diminishes production of ACTH and β-endorphin, limiting the duration of the loop.19 β-endorphin acts as a stabilizing element in the adaptation responses (Fig.  6.5). It stimulates ACTH excretion from the pituitary. This can stimulate the secretion of both cortisol and aldosterone.20, 21 However, β-endorphin inhibits cortisol (dotted line) allowing for a predominance of aldosterone and a completion of second loop physiology.22 β-endorphin blocks the consumption of calcium, allowing for stable or elevated serum levels. β-endorphin also reduces serum potassium by increasing intracellular flux, which helps stabilize cell membranes.15 Aldosterone also reduces serum potassium by increasing its urinary excretion.23 Dysfunction of POMC activity is related to ponderal disorders and red pigmentation of the hair.24

Introduction to anterior pituitary hormones related to corticotropic activity The anterior pituitary hormones are directly responsible for managing the primary corticotropic activity. The hormones are two: ACTH and γ-lipotropin. Only ACTH will

64  The Theory of Endobiogeny

CRH

POMC

ACTH

b-lipotropin

g-lipotropin

Enkephalins

b-MSH

b-endorphin

a-MSH

Pituitary Adaptation syndromes

Horizontal stimulation

ACTH efficiency

Short adaptation

Amplifies within adrenal cortex

ACTH receptors Upregulation on Adrenal cortex

Adrenal cortex

Stimulation of thyroid

FIG. 6.3  The central and peripheral effects of both hypothalamic and pituitary POMC. (© 2014 Systems Biology Research Group.)

Rise in serum K Glutamate

a-MSH

Reduced serum Ca

Adaptation syndromes ACTH

FSH

TSH

GH, PL

Adrenals

Gonads

Thyroid

Pancreas

FIG. 6.4  Role of alpha-MSH in the long root of adaptation. (© 2014 Systems Biology Research Group.)

Elevated serum Ca

b-endorphin

Reduced serum K: intercellular flux ACTH Reduced serum K: urinary excretion

Aldosterone

Cortisol

FIG. 6.5  Beta-endorphin reduces cortisol and helps ACTH transition to second loop stimulation of aldosterone. At the same time, it favors intracellular activity. (© 2014 Systems Biology Research Group.)

Corticotropic axis Chapter | 6  65

be discussed here. The intermediate lobe contains the majority of POMC derivatives, divided into two classes: melanocortins (ACTH, α-MSH, and β-MSH) and endorphins (lipotropins, endorphins, and enkephalins).7 They serve complimentary roles in augmenting (e.g., α-MSH, β-MSH) or diminishing (e.g., β-endorphin) corticotropic activity.

Adrenocorticotropic hormone (ACTH) Location: Anterior pituitary Composition: Polypeptide, derived from POMC Regulation (Fig. 6.6) ●

●

Stimulation ● αΣ ● CRH ● α-MSH ● Vasopressin ● Prolactin Inhibition ● Glucocorticoids

Function: ACTH has two general functions: regulation of peripheral corticotropic activity and adaptation of immunity. The regulation of peripheral corticotropic activity can be divided into two categories: adrenal cortex and skin. The effects of ACTH on the adrenal cortex are the primary function. There are two mechanisms of action of ACTH: genomic and nongenomic. The genomic effects of ACTH take hours to days. The ACTH stimulates the transcription of the enzymes that process low-density lipoprotein (LDL) cholesterol into various steroid compounds.25 Recall that ACTH is part of the melanocortin family of POMC derivatives. What we refer to as the “ACTH receptor” is actually melanocortin receptor 2R (MC2R). From the perspective of integrative physiology according to the theory of Endobiogeny, this is suggestive of an etiologic and teleological relationship between ACTH, melatonin, and MCR2 with melanin in the regulation of internal and external equilibrium against aggressions faced on the envelop (viz., skin), exterior, and interior of the organism.

The nongenomic effects of ACTH occur within seconds to hours. The immediate effects are to stimulate the excretion of stored adrenal cortex hormones especially when colocated with other factors such as lipotropin and α-MSH.25 The slightly delayed effects are to increase the uptake and utilization of lipids into the adrenal cortex to make additional hormones on demand. The ACTH’s effects on immunity are two. It stimulates the production of T-lymphocytes within the thymus. This is counterbalanced by ACTH’s stimulation of cortisol, which diminishes circulating lymphocytes.26–29 According to the theory of Endobiogeny, in its physiologic action (e.g., not experimental pharmacologic actions), the ACTH upregulates the number of peripheral histamine receptors to enhance chemotaxis of leukocytes once histamine has participated in vascular permeability. Cortisol diminishes histamines in turn.30 In summary, conceptually, one can say that that which ACTH stimulates in a first time of adaptation will be downregulated in a second time from its release of cortisol.

Melanocyte stimulating hormone (MSH) endorphins MSH derivatives and endorphins are produced within the anterior and intermediate pituitary along with ACTH. Their role in the corticotropic axis was discussed above.

Introduction to posterior pituitary hormones The general role of the posterior pituitary hormones is to calibrate the central and peripheral effects of corticotropic activity vis-à-vis the CNS, pineal and periphery within the internal and external milieus. It contains two hormones, both polypeptides are formed in the hypothalamus but primarily stored in the posterior pituitary: vasopressin and oxytocin.31 They have complimentary functions that are at times agonistic and antagonistic.

Arginine vasopressin Location: Posterior pituitary. It is produced in the hypothalamus and stored in the posterior pituitary. Composition: Polypeptide Regulation (Fig. 6.7) ●

●

FIG. 6.6  ACTH regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits; purple broken arrow, converts to. (© 2014 Systems Biology Research Group.)

Stimulation ● Osmoreceptors: Increased plasma osmolarity: hypothalamus ● Baroreceptors: Reduced plasma volume: carotid sinus, veins, cardiac atria ● Angiotensin II ● Melatonin Inhibition ● Atrial natriuretic peptide ● Oxytocin ● Glucocorticoids

66  The Theory of Endobiogeny

FIG. 6.7  Vasopressin regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits. (© 2014 Systems Biology Research Group.)

Function: Arginine vasopressin (AVP), or simply vasopressin, calibrates the central and peripheral adaptation responses of the organism during diurnal states. It does this in two ways: peripheral adrenal relaunching and optimization of hemodynamics.12, 31, 32 Proper hemodynamics aids in central processing and consciousness, and central and peripheral distribution of nutrients. When secreted through the hypophyseal portal system in conjunction with CRH, vasopressin stimulates the release of ACTH from the anterior pituitary to ensure sufficient stimulation of the adrenal cortex.13, 33 Through its direct release from the posterior pituitary, it augments retention of fluid by acting as an antidiuretic hormone in the kidneys, hence its alternate name, antidiuretic hormone (ADH). It increases peripheral vascular resistance, which along with the retention of water improves the perfusion pressure and delivery of nutrients, hence, the name, vasopressin. Thus, AVP participates with aldosterone, angiotensin, and rennin in electrochemical and hydrodynamic preservation.34 The AVP aids in the regulation of internal rhythms based on the imposition from and interaction with the external environment as a metarhythmic modality of hierarchical

integration of terrestrial organisms into celestial activities.31 Pineal melatonin stimulates the release of vasopressin from the posterior pituitary.35 Vasopressin then participates in the general adaptation syndrome by stimulating and colocating with CRH to stimulate ACTH, and colocating with ACTH and MSH to stimulate the adrenal cortex and cortisol.31 Vasopressin liberates oxytocin. Oxytocin inhibits dopamine’s inhibition of central hormones, allowing for adaptation to continue (Fig. 6.8).31 AVP has an emerging role in lifecycles and socialization that compliments that of oxytocin,36 and its impairment is associated with disruptions in mood and learning.37, 38 Through direct projections into the CNS, it influences bonding, sexual activity, and other types of behavior.36, 39 It also synapses within the locus ceruleus where it influences alphasympathetic activity.

Oxytocin Location: Posterior pituitary. Like vasopressin, it is synthesized in the hypothalamus. Most oxytocin is stored in the posterior pituitary and released into the periphery.31 Also, like vasopressin, there are central projections from the hypothalamus throughout the CNS to regulate central behavior (cf. below). Composition: Polypeptide Regulation (Fig. 6.9) ●

●

Stimulation ● Vasopressin ● Estrogen Inhibition ● Progesterone (peripheral oxytocin activity)

Purpose: The purpose of oxytocin is to aid in the preservation and propagation of the organism. Oxytocin has a

FIG. 6.8  Pineal-anterior and posterior pituitary relationship in adaptation. The pineal hormone melatonin is closely linked to posterior pituitary activity and adaptation. Melatonin stimulates vasopressin, which has various effects. It stimulates oxytocin to inhibit dopamine (DA), releasing DA’s inhibition of prolactin (PL). Vasopressin co-stimulates ACTH along with CRH and directly supporting adrenal cortex participation in the adaptation responses. It also stimulates MSH, which has roles in stimulating cortisol excretion and the thyroid gland. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

Corticotropic axis Chapter | 6  67

integration to mate selection.8 Where vasopressin integrates the individual’s internal rhythms to that of the external milieu, oxytocin integrates the individual’s life rhythms to that of other members of the same species. FIG. 6.9  Oxytocin regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

series of additive and competitive activities vis-à-vis serotonin, dopamine, vasopressin, and the general functioning of the corticotropic axis.12, 31 Oxytocin has anxiolytic properties, counteracting the adverse effects of dysregulated cortisol in the central nervous system (CNS).37, 40 Thus, oxytocin enhances diurnal consciousness and decision-making.37, 41 Oxytocin and serotonin are produced in the same region of the hypothalamus.42 We theorize that oxytocin stimulates serotonin with the goal of favoring a more refined perception of light and sound, thus augmenting sociability. In other words, it is not a univocal effect of oxytocin to improve socialization. It requires the proper functioning of other neurotransmitters, neurohormones, etc. Proper oxytocin function allows for the intensity of serotonergic perception of stimuli to be dampened, allowing for a pleasant state of awareness. Oxytocin receptors are densely concentrated in areas where dopamine also functions (substantia nigra, globus pallidus, and preoptic area), where it helps regulate the entrainment of central neuroendocrine function between serotonin and dopamine, thus regulating the balance between awareness and processing of stimuli. Vasopressin stimulates oxytocin, but oxytocin inhibits vasopressin (Figs. 6.8 and 6.9) and ACTH.43 However, oxytocin, possibly when colocated with endorphins or enkephalins, inhibits dopamine’s inhibition of central endocrine functioning, acting as a turnkey between the demands for augmented and restrained adaptation.44, 45 The net effect of the triadic relationship of oxytocin, vasopressin, and serotonin is central and peripheral stimulation during diurnal consciousness. Thus, activity of vasopressin and associated factors during the day results in the predominance of alertness factors, allowing oxytocin to re-orient serotonin toward increased perception and not sleep. According to the theory of Endobiogeny, oxytocin plays a complex and variable role in regulating circadian rhythms and the corresponding states of consciousness and awareness. Oxytocin opposes and amplifies melatonin activity. It opposes melatonin’s inhibition of reproduction by increasing feelings of love and affection, and by facilitating parturition.8 In the absence of vasopressin, oxytocin amplifies melatonin’s soporific effects at night by inhibiting antimelatonin factors such as ACTH and cortisol, enhancing a nondiurnal state of consciousness at night. In summary, oxytocin plays key roles in various aspects of the lifecycle, from fertility to parturition, from lactation to parenting, from social

Introduction to peripheral hormones The notion of peripheral hormones in the corticotropic rubric extend well beyond the adrenal cortex. This is a reflection of the continued complexity of the corticotropic axis and its crucial role in both reproduction (cf. oxytocin) and survival. A brief overview of the glands and their hormones are as follows.. 1. Adrenal cortex a. Glucocorticoids, i.e., cortisol b. Mineralocorticoids, i.e., aldosterone c. Androgens, i.e., DHEA d. Progestogens, i.e., progesterone e. Estrogens, i.e., estradiol 2. Liver, lungs, kidney, and blood: Angiotensin production and conversion to Angiotensin II 3. Kidney: Renin

Introduction to the adrenal cortex The adrenal gland is located atop (ad-) the kidney (renalis), hence the nomenclature “supra-renal” or “adrenal.” It is a retroperitoneal organ located lateral to the spinal column, between the 10th and 12th ribs in the adult human.46 The adrenal gland has two parts: the medulla and the cortex. The medulla, the inner part, produces mainly adrenaline (80%) and some noradrenalin (20%).47 The cortex is further divided into three zones, from inner to outer most layers (Fig. 6.10). The zona reticularis produces adrenal androgens, zona fasiculata cortisol, and zona glomerulosa aldosterone.48 Central corticotropic hormones and neurotransmitters of the ANS (including adrenaline) are polypeptides produced within a lipid (viz., the brain). In contrast, hormones of the adrenal cortex are lipid-derived steroids produced within a proteinaceous gland. Both gonadal and adrenal hormones share these same metabolic precursors, though they are produced in different proportions in the two glands.25 Metabolically, we can classify the steroids as belonging to three families based on the number of carbons (C) they contain: 1. C21 steroids: Pregane a. Progesterone b. Cortisol c. Aldosterone 2. C19 steroids: Androstane a. DHEA b. Testosterone c. Dihydrotestosterone

68  The Theory of Endobiogeny

FIG. 6.10  Adrenal cortex histology. (Source: Jpogi [CC0 1.0], from Wikimedia Commons.)

3. C18 steroids: Estrane a. Estradiol b. Estrone c. Estriol The remainder of the discussion will focus on the most important hormones representative of their class and zone of production rather than a detailed discussion of each metabolic intermediate, summarized in Fig. 6.11. The adrenal cortex is unique among endocrine glands because it assures both the two essential aspects of life: survival and reproduction. It is also the only gland that is both the foundation of structure and a manager of function. Thus, the adrenal cortex contains within itself the potentiality of both the corticotropic and gonadotropic axes. Looking at the hormones it produces, we observe the following types of activities (Table 6.2). From an integrative physiologic approach, there are three levels of assessment of adrenal cortex function: absolute global output, permissive activity, and adaptive activity. Absolute global output refers to the quantitative rate of secretion (production) and excretion (release) of adrenal cortex hormones. This witnesses the relative distribution of organometabolic activity1 of the adrenal cortex. The general competency of the adrenal cortex affects the general metabolism, ANS, and cardiovascular function. Despite the catabolic actions of cortisol, which can be substantial, the net action of the adrenal cortex

is anabolic. This comes from the role of aldosterone, adrenal androgens, and adrenal estrogens. The impact of adrenal cortex anabolic hormones needs to be evaluated in relationship to cortisol and thyroid metabolic activities. According to the theory of Endobiogeny, “catabolism nourishes anabolism.” Catabolism is a series of actions in which simpler material is derived from the partial or complete breakdown, disassembly, or destruction of more complex material. The time of catabolism is the time of preanabolism (cf. Chapter 9), the time of the gathering of all necessary material prior to the onset of anabolism. Anabolism is the assemblage, build up or metaarrangement of less complex material into more complex associations. It is a type of promise or potential of achievement, which depends on the proper material being present. The time of anabolism is the time of work, which means that the cell is “closed” to additional material so that it may work with that which has already been gathered for assembly. According to the theory of Endobiogeny, if the anabolic impetus of the adrenal cortex exceeds or precedes the catabolic actions of peripheral thyroid hormones, it can actually diminish metabolism. To illustrate this point, Table 6.3 reviews the effects of increased adrenal cortex activity, where it is relative greater than cortisol and thyroid metabolic activities. The inverse is true when adrenal cortex activity is insufficient or diminished in relationship to cortisol and thyroid metabolic activities.

1. We define the term “organometabolic” as the hormonal regulation of organ metabolic activity as a whole based on demands greater than that of the cell (cf. Chapter 4).

Corticotropic axis Chapter | 6  69

FIG. 6.11  Diagram of the pathways of human steroidogenesis. (By David Richfield (User:Slashme) and Mikael Häggström. Derived from the previous version by Hoffmeier and Settersr (2014). WikiJ Med 2014;1(1). doi:10.15347/wjm/2014.005. [CC-BY-SA-3.0] Via Wikimedia Commons.)

TABLE 6.2  General actions of adrenal cortex hormones Action

Cortisol

Structure

Adrenal androgens

Estrogens

Progesterone

✓

Foundation of initial fetal structure

Initiation of regulation of structure

Regulation of structure

Aldosterone

Function of structure

✓

✓

✓

✓

✓

Function

✓

✓

✓

✓

✓

Permissivity

✓

Adaptation

✓

✓

✓

✓

✓

✓

✓

Reproduction

✓ ✓

70  The Theory of Endobiogeny

TABLE 6.3  Effects of increased adrenal cortex actions on cellular metabolism and global function Function

Effect of elevated global adrenal cortex activity

Catabolism

Diminished effective catabolism to initiate metabolism

Anabolism

Depends on the relative anabolic predominance (catabolism/anabolism index)

General rate of metabolism

The global rate of metabolic is diminished by global adrenal gland activity, which indicates that an attempt to initiate anabolism exceeded and may proceed catabolism, which nourishes anabolism and must occur first

Passive cellular permeability

Can delay or diminish passive flow of electrolytes and fluids into the cell if cortisol is not sufficiently elevated to delay the time of anabolism

Histamine

Diminishes histamine

Necrosis

Diminishes necrosis and extends cell life even beyond its optimal efficiency of function

Inflammation

Diminishes inflammation. Evaluate relative to thyroid function and the rate of necrosis

The permissive activity of the adrenal cortex refers to the way in which its hormones create an environment favorable to actions of other hormones, physiologic, and metabolic functions. Table 6.4 demonstrates the effects of permissive actions are greater than that of adaptive actions. The more the adrenal cortex is dedicated to the production of adrenal androgens and estrogens, the greater its permissive function but the less its adaptive capabilities, according to our definition. The less efficient the gonads are in producing estrogens and androgens, the greater the appeal to the adrenal cortex will be because it can also produce adrenal androgens, estrogens, and progesterone. This tends to occur at the expense of metabolic activity dedicated to the production of glucocorticoids. The adaptive capabilities of the adrenal cortex refer to three types of activities. The first is the intrinsic organo-­ metabolic activity of adrenal cortex in the production of cortisol relative to its other products. This is implicated because of the relative importance of cortisol in the adaptation process in relationship to that of the other adrenal hormones. To wit, the total serum concentration of cortisol is 1000 times that of aldosterone, but 96% of cortisol is bound vs. 60% of aldosterone due to the necessity of having significant amounts of cortisol in reserve (Chapter 10).49 The second is its effects on cellular nutrition. The third is the general adaptive processes of vigilance and memory.50 Based on Miller’s

TABLE 6.4  Permissive activity of adrenal cortex Function Adrenal metabolic

Cellular nutrition

Comment Androgens

Favors production of adrenal androgens from cholesterol and its subsequent activity

Estrogens

Favors production of adrenal estrogens from cholesterol and its subsequent activity

Active membrane permeability

Favors the dynamic flux of nutrients into the cell for structural purposes relative to functional ones

Active intracellular osmolar gradient

Favors the dynamic flux of electrolytes and water into the cell for structural purposes relative to functional ones

theory of living systems this encompasses four of the nine functions of information management within a ­living ­system: external input transduction, internal input transduction, channeling, and memory (Chapter 2).51 The adaptive role of the global adrenal cortex is most favored when its activity is diminished relative to cortisol output (Table 6.5). A favorable level of adaptive adrenal cortex activity relative to its permissive function allows for an optimal degree of vigilance, memory, recall and cellular permeability of nutrients.40, 52–54 We consider an elevated level of adrenal cortex activity relative to cortisol as potentially protective mechanism against excessive central adaptation activity which can intensify memories of traumatic events (noradrenaline, dopamine, TRH, histamine, etc.).2, 40, 53, 55–59

Cortisol: Glucocorticoids Glucocorticoids are called such because they are derived from the adrenal cortex (-corticoid) and have effects on circulating glucose (gluco-). However, as one early researcher observed, calling them glucocorticoids is like “describing an elephant by the shape of its tail.”60 In other words, the effects of glucocorticoids are far broader than its effects on carbohydrates. Location: Zona fasciculata (primary) and Zona reticularis of the adrenal cortex. Composition: Cholesterol-derived steroid. There are four glucocorticoids all derived from progesterone: 11-­ deoxycortisol, deoxycorticosterone, corticosterone, and cortisol. Cortisol is the active glucocorticoid. Corticosterone is metabolically convertible with cortisol and represents a posttranslational reservoir material within the general b­ uffering

Corticotropic axis Chapter | 6  71

TABLE 6.5  Effects of optimal adaptive role of the adrenal cortex Function

Comment

Passive cellular membrane permeability

Increased passive membrane permeability, allowing metabolites to enter into cells with the greatest metabolic demand

Vigilance

Increased vigilance by not dampening the effects of histamine

Memory recall52

Heightened memory recall. The greater the activity of the adrenal cortex, the greater the risk of suppressing recall of events. This may be a protective phenomenon to protect the brain from shutting down due to shortcircuiting of metabolic pathways. Evaluate relative to thyroid and MSH activity

capacity of the organism for additional cortisol.48 “Cortisol” will be used interchangeably with the term “glucocorticoid” and will refer to the general activity of these products. Regulation (Fig. 6.12) ●

●

Stimulation ● α-sympathetic ● CRH ● ACTH ● α-MSH ● β-MSH Inhibition ● Endorphins (favor aldosterone over cortisol, preserves calcium) ● Cortisol ● Estrogen (reduces serum levels via corticoid binding globulin)

Purpose: The purpose of cortisol is to ensure the adaptability of the organism at every moment in time, to every type of aggression. This is accomplished by mobilizing metabolites, fluids, and electrolytes, and, augmenting physiologic activity related to defense: consciousness, movement, and immunity. Cortisol is a “first loop,” catabolic hormone, though it also is expressed briefly in the second loop to regulate estrogens (Chapter  10). Among the two catabolic axes, the corticotropic has the broadest influences on all metabolites and processes in the body. Within the corticotropic axis, the adrenal cortex has the broadest influence on physiology, and within the cortex, cortisol as the broadest influence on physiology. When we say that the goal of the corticotropic axis is to assure the survival of the organism, it is cortisol that plays the most direct and constitutive role, though by no means does it act alone. Cortisol has two general roles: permissive and adaptive. The concept is not unique to Endobiogeny but reflects a

FIG. 6.12  Regulation of cortisol. See text for details. Red arrow, stimulates; blue arrow, inhibits; purple broken arrow, converts to; broken teal arrow, reduces serum levels. (© 2015 Systems Biology Research Group.)

classical physiologic approach to glucocorticoid activity.30 What Dr. Duraffourd did was to create a formula based on biomarkers that model the tissular permissive and adaptive activities of cortisol.61 Permissive activity of cortisol refers to its role in potentiating the activity of other physiologic processes in the body.30 Examples of cortisol’s permissive role include efficiency of binding of all other hormones to their receptors, receptiveness to catecholamines and rate of glycogenolysis. NB: The permissiveness of the adrenal cortex in its global function is different from the specific permissive activity of cortisol though it encompasses and implies the efficacy of cortisol activity. Adaptive activity refers to cortisol’s role in adaptation. In the syndromes of adaptation (cf. Chapter  12), cortisol plays a role in immediate adaptation, chronic adaptation, and the general adaptation syndrome, including chronobiologic variations.62 Thus, it is valuable to consider that cortisol has a particular circadian rhythm and within this pattern lays another pattern, both of which are crucial to its permissive and adaptive roles (Fig. 6.13).62 As with all other hormones, the circadian pattern becomes less synchronized with age. Like a fractal, there are numerous iterations of the rise and fall of cortisol throughout the day with particular amplitudes and frequencies that reveal more accurately the activity of cortisol. Broadly speaking, we can divide them into diurnal and nocturnal patterns. Diurnal fluctuations are low-amplitude, high-frequency variation. This indicates the greater adaptive role of cortisol during the day. Very fine and frequent excretions of cortisol are required to constantly adjust the internal equilibrium throughout the waking hours. The nocturnal pattern is high-amplitude, low-frequency variation. This favors a predominance of the permissive role of cortisol and the preparation of the corticotropic axis for subsequent waking the following morning.

Mechanism of action The actions of cortisol like many hormones can be categorized in two general ways: nongenomic and genomic. Nongenomic effects occur within minutes, genomic effects within hours (typically 6–24 h), which represent the time it takes to produce and express a new cellular

72  The Theory of Endobiogeny

Plasma cortisol (nmol/L)

Young men Old men

400

200

0 08

12

16

20

00

04

08

Clock time FIG.  6.13  Circadian variations of cortisol in young and older men. In young men (purple line) serum levels of cortisol peak at 0800, reach their nadir at 0000 to ensure adequate sleep. The rise from then to their peak. However, within this general pattern, there are peaks and troughs throughout the day, crucial for proper regulation of alertness, metabolism, etc. Older men (red line) show the same general trend, however there is a slight time lag, and altered peaks. (Reproduced from Copinschi G, Caufriez A. Hormonal circadian rhythms and sleep in aging. In: Encyclopedia of Endocrine Diseases. 2nd ed. Academic Press; 2019: 675–689. © 2019 Elsevier Inc.)

product.63 Genomic effects regulate transcription of genes. Nongenomic effects do not. With respect to cortisol specifically, three types of nongenomic effects have been discovered.54 The first is cortisol-membrane interaction. This was alluded to in the discussion of adrenal cortex function and membrane permeability. The second is cortisol to membrane-bound cortisol receptor activity. The third is translocation of cortisol to cytosolic cortisol receptors. The latter two involve alteration of signal transduction pathways.64 Many of the permissive functions of cortisol operate by nongenomic mechanisms. Specifically, mobilization and sequestration of immune elements, cardiac function, intracellular communication, neural proliferation and neuroendocrine interaction, memory, and the quality of the central management of adaptation occur by this mechanism.52, 54, 64 The genomic effects of cortisol are complex. The general sequence of events is as follows: cortisol translocates into the cytoplasm, where it binds to one of two glucocorticoid receptor (GR): alpha (α) and beta (β). The majority of the classical actions of cortisol are regulated by GRα. GRβ serves to inhibit the actions of GRα, and also has its own intrinsic activity. One of the actions of GRβ is to downregulate the production of GRs (cf. Fig. 6.12). The cortisol-GR complex (C-GR) translocates into the nucleus. There are four types of events that can occur, which result in the upor downregulation of certain genes: (1) intrinsic activity,

(2) coupling with response elements, (3) tethering, and (4) composite activity with transcription factors. The end result is the solicitation of proteins for the formation of various enzymes that are subsequently modified and then expressed. For example, C-GR downregulates transcription of interleukin 1β (IL-1β),54 which reduces fever, inflammation, cell proliferation, and lymphocyte activation. C-GR also downregulates the transcription of osteocalcin,54, 65 which diminishes the sensitivity of the cell to estrogens, to mitochondrial proliferation, and to insulin sensitivity.66–73 Conversely, cortisol upregulates NF-κB,54 which plays a role in the catabolism of muscle, and downregulates IGF-1,54, 74 which in turn reduces anabolism of muscle. These are examples of how the antiinflammatory, catabolic and antianabolic effects of cortisol are executed. To add to the complexity of cortisol activity, there are eight isoforms of each of the two GR receptors, variable distribution of the isoforms in different parts of the body and interperson variation, variable response elements, and posttranslational modifications by phosphorylation and acetylation which alter the degree of cortisol efficiency.54 The clinical implications are that it is not the quantitative output of a hormone but its downstream effects on metabolism indicate its final functional activity.61 This helps explain why glucocorticoid dosing is so variable, and its effects somewhat unpredictable. There are 12 effects of cortisol on metabolism and physiology (cf. Fig. 6.14 for summary): (1) autonomic nervous system, (2) endocrine system, (3) central nervous system, (4) blood elements, (5) metabolites, (6) liver, (7) gastrointestinal (GI) tract, (8) kidney, (9) electrolytes, (10) bone, (11) cardiovascular system, and (12) immune system. The generalities of the nonendocrine, non-ANS activities are summarized below, and then discussed in detail subsequently.

Autonomic nervous system Cortisol affects the ANS directly and indirectly. Directly, it upregulates the number of βΣ-receptors,75 augmenting adrenaline’s actions in adaptation. Indirectly, through its other activities noted below, such as utilization of calcium, sodium/potassium balance, and membrane permeability, it can upregulate the general rate of functioning of the ANS.

Endocrine system It has classical negative feedback on its stimulating hormones.63 The general permissive activity of cortisol helps regulate the functioning of central endocrine activity by inhibiting its overexpression and by regulating the duration of secretion and timing of excretion of various hormones across the axes. In embryonic development, cortisol plays a role in the development of the corticotropic axis as well as various organs such as the lungs and thymus.54 Cortisol

Corticotropic axis Chapter | 6  73

Gluconeogenesis

Glucose

Glycogenlysis

Calcium loss

RBC

Blocked absorption

Platelets

Gastric acidity

Gluose

Blocked hepatic consumption

WBC

Gastric mucosa Reduced volume

Lipids Blocked lipogenesis

Liver

Lipids

GI tract

Increased

Increased absorption

Lymphocytes

Increased FFA

Glucose

Blood elements

Reduced uptake

Amino acids

Metabolites

Myolysis

Decreased

Eosinophiils Basophils

Cortisol Cardiovascular

AntiInflammatory

Neutrophils

Lipids

Chronotropy

Other

Immunologic

Inotropy

Delayed wound healing

Dromotropy

AntiAllergic

Lymphoid

Circulation/perfusion –

+

PO4 , K & H+ loss

Thymus Reduced volume

Lymph nodes Reduced volume

Kidney

Bone

Electrolytes

CNS

Sodium gain

Water retention

Calcium loss Calciuria

Calcium gain Resorptoin

Calcium consumption

α waves Increase

FIG. 6.14  Summary of the 12 areas of cortisol activity. (© 2015 Systems Biology Research Group.)

diminishes anabolic activity of hormones such as FSH, LH, estrogens, somatostatin, prolactin, and inhibits insulin resistance. Cortisol augments proliferation and growth.75

Central nervous system Cortisol receptors are widely represented throughout all areas of the brain, including the limbic area, reticular activating system, and subcortical and cortical areas. It augments a number of complex conscious and unconscious functions related to cognition, emotions, memory, and learning52 and favor a state of calm alertness, and focus when well adapted to central cognitive requirements. This is expressed as an increase in α-brain wave activity when cortisol is permissive and well-regulated.76 Cortisol also favors a more extroverted state, although other factors need to be present simultaneously. Within these general observations are implications for various types of neuropsychiatric disorders such as depression, anxiety, seizures, schizophrenia, and substance addiction (cf. Chapter 8, “TRH” section).

Blood elements Cortisol mobilizes various marrow-derived products that play a role in the adaptation response. It augments the gen-

eral levels of three major marrow-derived cellular elements in blood: erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (platelets). White blood cells are a family of five types of cells that arise from a common hematopoietic precursor. White cells differentiate into neutrophils, monocytes, eosinophils, basophils, and lymphocytes. With respect to leukocytes, it specifically favors the mobilization and proliferation of neutrophils. This activity is protective against a dysregulated immune and inflammatory response. The mobilization of white blood cells favors the general adaptive capacity of the organism. In adults, the plurality or majority of leukocytes are neutrophils. The general role of neutrophils is immune regulation and anabolism of tissue. Neutrophils participate in the immunologic response through inflammation77 and phagocytosis of microbes and cellular debris.78 Neutrophils exhibit a short half-life of 3–6 h, requiring a constant production by bone marrow to maintain normal circulating levels. Cortisol increases the sequestration and/or apoptosis of lymphocytes, eosinophils, and basophils.26–29, 79, 80 Lymphocytes are white blood cells that are key mediators of immunity. There are three types. B cells are matured in the bone. T cells are matured in the thymus. They are part of the adaptive, or, specific immune system. Natural kill

74  The Theory of Endobiogeny

(NK) cells are a third type of lymphocyte that is part of innate, or, nonspecific immunity. In general, lymphocytes, especially T-lymphocytes and NK cells play important roles in surveillance and destruction of viruses and tumors. T cells immunoregulation the adaptive immune system by stimulating production of antigen-specific antibodies from B-lymphocytes. Cortisol at permissive levels, compliments ACTH, and other upstream regulators of immunity. As a protective and regulatory measure, at higher levels cortisol downregulates all aspects of leukocyte function except neutrophils. Eosinophils are a subpopulation of white blood cells. The ACTH causes an acute and proportional rise in circulating eosinophils.81, 82 Eosinophils have direct antimicrobial effects through the production of RNase enzymes83–92 and the generation of reactive oxygen species. They are also immunomodulatory through antigen presentation to T-cells.93–99 Indirectly, they are a secondary source of histamine, which modulates the immune system.100, 101 Thus they have a cortisol-like activity. Thus, eosinophils, like lymphocytes, are expressed as a “hedge” against a possible delay or insufficiency in cortisol expression. A sufficient expression of cortisol, as with lymphocytes, corrects this response to ACTH thus reducing circulating eosinophils in three ways: (1) suppression of eosinophil maturation, recruitment, and survival,102 (2) sequestration of mature eosinophils in lymphoid organs,103 and (3) stimulation of eosinophil apoptosis through transcriptional upregulation.104 Basophils are the least populous of all white cells. The ACTH augments circulating basophils proportional to intensity of its appeal for more glucocorticoids. Basophils play a role in innate immunity particularly against allergens105 and parasites.106 Basophils share receptors similar to eosinophils, such as eotaxin, and may serve as a tertiary method of adapting the adrenal response to aggressors in the face of inadequate cortisol response and insufficient eosinophil response. Cortisol diminishes circulating basophile levels. The sum effect of all leukocytes is to participate in immunity, tissue healing, and inflammatory processes, especially during the acute phase of infections. Cortisol in the presence of erythropoietin stimulates hematopoiesis, the formation of red blood cells (RBC), or, erythrocytes.107 RBC’s contain hemoglobin, which carries oxygen to individual cells. Thus, this relationship between cortisol and RBC’s improves the quality of adaptation but

improving oxygen-carrying capacity, thus aiding aerobic metabolism of ATP, vasodilation of microcirculation, and reduction of vascular resistance. Platelets arise from megakaryocytes in the bone marrow. They have four primary functions. The first is hemostasis. In immediate adaptation, this is necessary in the event of exsanguination. The second, related in part to the first, is adsorption of serum factors such as clotting factors and calcium, which allows them to participate in immediate hemostatic activity.108 The third is repair and growth of connective tissue via platelet-derived growth factors such as ­insulin-like growth factor 1 (IGF-1), fibroblast growth factor, and others.109, 110 Platelets are also the primary transporter of serotonin, which can augment the uptake of enteric glucose during the adaptation response.111 Finally, platelets participate in pro-inflammatory activity, adapting innate and adaptive immune mechanisms through the expression of chemokines and cytokines, and receptor-receptor interaction with leukocytes.112 Platelets also contain histamine, which is secreted before aggregation occurs.113 From the experimental evidence, the effects of cortisol are contradictory. For example, very high dose pharmacologic dosing induces thrombocytopenia through bone marrow suppression. However, glucocorticoids are also recommended for thrombocytopenia for in-hospital patients.114 However, clinically, conditions associated with insufficient cortisol (eosinophilic conditions and inflammatory disorders) are associated with thrombocytosis.115–117 When one considers the sum of action of platelets, it favors recovery states more than adaptation states. In our opinion, acute, physiologic, and adaptive cortisol during adaptation syndromes diminishes circulating platelets but improves thrombocyte formation in the bone marrow in a permissive way through its antiinflammatory action. Since about one-third of mature platelets are sequestered in the spleen, acute thrombocytosis in the face of elevated cortisol activity will be considered to have been the result of platelet mobilization by adrenaline from the spleen (cf. Chapter 15 and Theory of Endobiogeny, Volume 2, Chapter 1).118

Metabolites Cortisol mobilizes all three energetic and nutritive elements in the body: carbohydrates, proteins, and lipids (Table 6.6). With respect to carbohydrates—glucose specifically—cortisol

TABLE 6.6  Summary of cortisol’s effects on metabolites by location Gluconeogenesis

Mobilization of stores

Blocked uptake

Liver

Liver

Systemic

Amino acids

Skeletal muscle

Skeletal muscle

Lipids

Adipocytes

Liver

Glucose

Increased uptake

Small intestines

Corticotropic axis Chapter | 6  75

increases serum levels in multiple ways, mainly through the liver. This highlights the liver’s importance as an element of the buffering capacity and the syndromes of adaptation. Cortisol increases gluconeogenesis from amino acids and lipids, emphasizing the interdependence of the various nutrient stores, most likely in the presence of growth hormone and other growth factors.119 It augments the liberation of stored glucose via glycogenolysis. Finally, cortisol diminishes the uptake of glucose by nonvital organs.120 Cortisol augments proteolysis of skeletal muscles and blocks anabolism of skeletal muscle, with a regulatory role played by insulin.121–123 In this way, it augments the availability of amino acids for the immediate and short-term use by critical systems in the body for critical purposes such as neurotransmitters, immunoglobulins, and catalytic enzymes. Finally, cortisol augments the circulating concentration of lipids in three ways. It increases lipolysis of adipocytes, increasing the availability of free fatty acids.124–126 It blocks lipogenesis in the liver and increases absorption of fats from the small intestine.127, 128

Liver Cortisol and the liver have a permanent and close relationship in basal states of metabolism, adaptation syndromes, and adaptability. As noted above, cortisol places demands on the liver to generate glucose from noncarbohydrate substance as well as glycogenolysis. The mobilization of amino acids also allows the liver to metabolize carrier proteins for hormones.

GI tract We have noted the augmentation of lipid absorption from the GI tract. In addition to this, cortisol increases the production of hydrochloric acid in the stomach and reduces volume of the gastric mucosa.30 This serves as a defense against external pathogens that would enter the organism through the oral cavity. Cortisol opposes intestinal actions of Vitamin D by diminishing absorption of calcium.129

Kidney and electrolytes Cortisol has a permissive effect on glomerular filtration.130 The primary electrolyte changes are a loss of calcium and phosphate by blocking reabsorption in the distal tubules.75 Cortisol has 1:1 binding affinity with the aldosterone receptor in the kidney,130 thus it also plays a role in the retention of sodium (and chloride) and thus water. In this exchange, potassium and protons are excreted to preserve serum charge neutrality. Prolonged action on the mineralocorticoid receptor (MR) can reduce serum pH.131, 132 This mineralocorticoid activity of cortisol is generally well regulated by the kidney because the MR is coupled with the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-OHSD), which converts cortisol to its inactive form,6,

132

allowing aldosterone activity to predominate. During states of intense, acute expression of cortisol, or chronically elevated cortisol, the activity of this enzyme can become insufficient, resulting in a greater mineralocorticoid activity by cortisol regardless of the expression of aldosterone. Glycyrrhiza glabra (Licorice) blocks the activity of this enzyme, favoring mineralocorticoid activity of cortisol within the kidney, which is why chronic consumption of this plant medicinally or gastronomically can result in hypertension.6 In summary, cortisol affects the retention or loss of the following electrolytes and fluids within the kidney (Table 6.7). There is a logic related to the retention of certain electrolytes and the loss of others. The most complex relationship is that of calcium. Cortisol augments the serum levels of calcium via osteoclasty.133 However, the net effect of cortisol is diminished serum calcium. It stimulates the consumption of calcium for various cellular processes. This is crucial for immediate adaptation and ultimately for various forms of adaptation and basal function. However, to limit this stimulatory effect, cortisol blocks absorption of calcium from the intestines as well as stimulates its excretion from the kidney, as discussed earlier. The maintenance of adequate intravascular volume and hence perfusion pressure is essential for survival. It ensures sufficient cerebral perfusion for consciousness, as well as the perfusion of nutrients into cells in the periphery (and the brain). This is accomplished through the retention of sodium (and chloride), which then attracts water. Potassium and hydrogen ion loss help preserve charge neutrality from the retention of sodium. Potassium is the primary intracellular cation and helps maintain membrane stability by elevating the electro-physiologic threshold of response. The loss of potassium then serves a dual purpose because it diminishes the availability of potassium to resist the activation of cellular activity imposed by calcium.

Bone The bones contain the vast majority of calcium stored within the body. Calcium acts as the great accelerator of activity within the body. It is an essential cofactor in numerous enzymes, lowers the threshold of excitability of cell

TABLE 6.7  Cortisol’s actions on renal electrolyte regulation Retention

Loss +

Sodium (Na )

Potassium (K+)

Chloride (Cl−)

Hydrogen (H+)

Water (H2O)

Calcium (Ca2+) Phosphate (PO43− )

76  The Theory of Endobiogeny

membranes, particularly neurons, and augments cardiac and skeletal muscular contractions. Cortisol augments the rate of osteoclasty,133 liberating calcium into the serum, as bone is 70% calcium bound to inorganic salts, and contains >99% of global calcium stores.132 It also blocks the incorporation of calcium into bones.

Cardiovascular system Cortisol has diverse effects within the heart as well as the vasculature. Within the heart, it sensibilizes sinoatrial conduction, improving dromotropy.134 It increases the sensitivity of catecholamines through the upregulation of βΣ-adrenergic receptors. It improves through βΣ effects inotropy and chronotropy. With respect to the myocardium, it reduces—in physiologic doses—myocardial inflammation, improving lusitropy (myocardial relaxation).134 Within the vasculature, in conjunction with its mineralocorticoid activity, it inhibits endothelial production of vasodilators such as prostaglandins and nitric oxide.54

Immunologic system Cortisol is antiinflammatory through mechanisms discussed above. It is also antiallergic through its reduction of the number of mast cells, and stabilization of mast cell membrane, inhibiting release of histamine.135 Cortisol does not affect the activity of histamine already in circulation. We hypothesize that through its negative feedback on ACTH, cortisol can diminish the proliferation of histamine receptors. In adaptative levels, cortisol diminishes the volume of the thymus and reduces the size of lymph nodes. Cortisol’s effects on T-lymphocytes were discussed earlier. An adapted expression of cortisol aids in the regulation of the immune system by limiting the intensity of ongoing immune activity as well as its duration. However, cortisol also inhibits or delays wound healing,54 which allows for the immune activity within the extravascular spaces to continue without premature discontinuation. Of course, prolonged or dysregulated cortisol activity will adversely affect this process through immune suppression and improperly delayed anabolism of tissue.

Dihydroepiandrosterone (DHEA) Adrenal androgens Composition: A C19 cholesterol-derived steroid in the Androstane family. Location: Adrenal cortex, Zona reticularis Regulation ● ●

Stimulation: ACTH Inhibition: Gonadal androgens and estrogens

Purpose: Foundation of structure and evolution of structure. Foundation of structure is expressed in fetogen-

esis, and again with development of secondary sexual characteristics. The DHEA provides a reservoir of preandrogen and preestrogen material that can be converted within specific tissue by process called intracrinology. There are two main adrenal androgens produced in the zona reticularis: DHEA and its derivative Δ4-androstenadione. The remainder of the discussion will focus on DHEA as a representation of the products of this innermost section of the adrenal cortex. Quantitatively, DHEA is the most-produced adrenal cortex hormone, however, it is not the most used hormone in circulation.6 While it has intrinsic effects (discussed later), it serves primarily as a reservoir for regionalized anabolism. The DHEA is co-released with cortisol during the first loop of corticotropic activity when stimulated by ACTH. The DHEA compliments the activity of cortisol. Where cortisol is catabolic and mobilizes nutrients, DHEA as its inactive sulfated variant DHEAS circulates in anticipation of anabolic activity to follow the effects of cortisol. Unlike cortisol, DHEA is not bound to corticosteroid binding globulin (CBG), and unlike androgens and estrogens, very weakly bound to sex hormone-binding globulin (SHBG). Inactive DHEAS circulates in the blood and enters target tissues where it is converted cell by cell to specific androstane or estrane family hormones by intracrinology.136, 137 Once DHEAS has entered a cell, it is converted back into DHEA then further converted into various androgens or estrogens as per the needs of each cell. The hormones produced within the cell act only within that cell, then are excreted in an inactivated form. Thus, DHEA helps achieve a regionally specific modification of gonadotropic activity, reducing the risk of systemic exposure to increased levels of androgens and estrogens.136–138

Grand phases of development There are three grand phases: 1. Fetogenesis a. Foundation of structure b. Sex determination 2. Puberty a. Fertility: Foundation of self-propagation b. Sexual dimorphism 3. Gonadopause a. Deinstallation of structure b. Deinstallation of fertility

Phase 1: Fetogenesis By day 33 of gestation, the primordial adrenal cortex form from mesodermal tissue. By 8 weeks both aspects of the adrenal gland function. A rudimentary fetal adrenal medulla with chromaffin cells produces adrenaline. Within the adrenal cortex three distinct histological and functional zones

Corticotropic axis Chapter | 6  77

are active. The outer distinct zone (DZ) produces mineralocorticoids and becomes the zona glomerulosa of the mature adrenal cortex. The medial transitional zone (TZ) produces glucocorticoids and becomes the zona fasciculata. The inner fetal zone (FZ) produces adrenal androgens and becomes the zona reticularis.46 The FZ is the largest portion of the fetal adrenal unit, which produces adrenal androgens, comprising 75% of the fetal adrenal complex (Fig. 6.15).139 The DHEA plays an important role in the fetal-placental unit not only by stimulating the growth of the fetus through

various genomic mechanism, but also through intracrinologic activity in the placenta where DHEA is converted into estrogens.46 The increase in the weight of the fetal adrenal gland parallels the increasing fetal DHEA production. In the third trimester, maternal DHEA peaks and fetal DHEA synthesis declines.139 In contrast, the fetus remains more under the influence of materno-placental cortisol for the first two trimesters, with fetal adrenal cortisol production markedly increasing in the third trimester, in part to participate in parturition (Fig. 6.16). There are numerous factors that play a role in fetal and postfetal growth, most notably the somatotropic hormones (growth hormone), insulin-like growth factors and insulin. What is important to distinguish is that within the general schematic of Endocrino-tissular activity of the anabolic axes, there is mass, length, and width. The DHEA and thus the gonadotropic hormones influence mass. Somatotropic factors influence length and width: growth hormone and IGF’s length, prolactin width. The story of growth is mainly hidden in the “threefold veils” of uterine life. It is a story of mass. Length and width are like notes in the margin of this story.6 In prenatal life, mass increases 875,000,000-fold (from 0.004 mg to 3.5 kg). In postnatal life, the organism gains only 20 times its weight (from 3.5 to 70 kg). Prenatal length increases 5000-fold (0.01–50 cm) and only 3.5-fold in postnatal life (50–175 cm). The story of the fetus is written by DHEA. With respect to sexual dimorphism, the null state of the human being is female. Every male will develop female genitalia if not for two factors: anti-Müllerian

FIG. 6.15  Adrenal cortex during fetogenesis. See text for discussion and abbreviations. (Reproduced from Ishimoto H, Jaffe RB. Development and function of the human fetal adrenal cortex: a key component in the fetoplacental unit. Endocr Rev 2011;32(3):317-355. doi:10.1210/er.20100001, Oxford University Press.)

4.0

Fetal cortex Adult cortex Medulla

Volume (mL)

3.0

2.0

1.0 .6 .2 1

2

3

Prenatal trimesters

0

2

4

6

8

10 12 2

Postnatal months

4

6

8

10 12 14 16 18

Childhood years

FIG. 6.16  Degonadicization of adrenal cortex. Left: Fetal cortex peaks in volume (mass) at birth. Right: It rapidly declines in volume within the first 3 months of life because the need for it to function as a gonad is now resolved, hence “degonadicization.” It is not until the onset of puberty, though, that the fetal qualities of the adrenal cortex are full resorbed (middle box, far right). (Reproduced from Chen LX, Carr BR. The Human Fetal Adrenal Gland—A Review of Its Function and Development. In: Skinner MK, ed. Encyclopedia of Reproduction. 2nd ed. vol. 3: Academic Press; 2018:399-405. © 2018 Elsevier Inc.)

78  The Theory of Endobiogeny

hormone and the sex-determining region on the Y chromosome (SRY).6 We hypothesize that in male fetuses variable factors including those mentioned and human chorionic gonadotropin hormone (hCG) affect the intracrinologic conversion of DHEA to androgens in local tissues to influence the development of male genitalia prior to the stage in which the fetal gonads can produce gonadal androgens. The hCG has luteinizing hormone-like activity139 and may open up receptors and stimulate the transcription of the enzymes required to convert DHEA to testosterone and dihydrotestosterone in the fetus, both of which play distinct roles in the development of male genitalia. Serum DHEA levels reach their peak at birth then decline over the first year of life, a process referred to in Endobiogeny as “fetal degonadicization.” It is initiated between weeks 3 and 12 of postnatal life by the reduction in adrenal androgens,140 (cf. Chapter 13) noted on histology by the involution of the fetal cortex and the reduction in prominence of the zona reticularis (Fig. 6.16).48, 141

Phase 2: Puberty: Foundation of sexual dimorphism and fertility The second grand phase of sexuality is puberty. The first phase of puberty is referred to as adrenarche because it is initiated by a change in adrenal cortex activity. Cortisol precedes DHEA by augmenting the general metabolic functioning of cells. Around 10–12 years of age (cf. Chapter 13), DHEA levels rise again to increase tissue mass and function through the mechanism described above. The second and final peak of DHEA occurs in the second decade of life and declines thereafter.142 700

Phase 2.5: Pregnancy: A special consequence of fertility In women, fertility is a discrete event that occurs during puberty and ends abruptly with gonadopause (phase 3). This is not the case with men where gonadopause represents a gradual decades-long decline rather than an abrupt end. Returning to women, the elements of fertility are established during puberty and pregnancy is an occasional consequence of this fertility, in which DHEA plays a key role. Thus, we refer to it as phase 2.5. While there are a panoply of hormones that play a role in pregnancy, as the pregnancy progresses, maternal DHEA plays an increasingly important role as a source of gonadal hormones for the maternal-placental-fetal triad.139 Maternal DHEAS levels are relatively steady for 22 weeks, then increase nearly threefold before birth.

Phase 3: Gonadopause Men express more quantitative production of DHEA throughout life as it favors initially the formation of gonadal androgens. They also continue to produce gonadal androgens, though at reduced rates as they age, and have a reduction in bioavailability of the androgens that they do produce.143 Gonadopause for men tends to be more subtle, gradual, and relative in nature. In contrast, menopause for women can be more dramatic and results in a complete loss of production of gonadal hormones from the ovaries (Fig.  6.17).143 However women continue to require about 30%–50% of the premenopausal levels of gonadal hormone production for basic anabolic requirements. Thus, in women DHEA can play a more crucial role in the recovery of gonadal hormone production without requiring a proliferation of adipocytes as a “third ovary.”

DHEA levels in males and females of different ages (mean±sem)

600 500

400 M 20–39years M 40–60years

300

F 20–39years F 40–60years

200 100 0 8:00 a.m. 10:00 a.m. 12 noon 14.00 p.m. 16.00 p.m. 18.00 p.m.

FIG. 6.17  Circadian and age-based DHEA levels in males and females. (Reproduced from Al-Turk W, Al-Dujaili EA. Effect of age, gender and exercise on salivary dehydroepiandrosterone circadian rhythm profile in human volunteers. Steroids 2016;106:19-25. doi:10.1016/j.steroids.2015.12.001. © 2016 Published by Elsevier Inc.)

Corticotropic axis Chapter | 6  79

General effects of DHEA The DHEA plays a role in sexual dimorphism, particularly the development of pubic hair from light, sparse, and soft to dark, coarse, and dense.144, 145 It also stimulates the development of hair growth in the low-sacral region of the back and the distal extremities. The DHEA plays a role in libido as well. The DHEA has activity in the brain where it appears to play a role in creativity.146 It can also destabilize neuronal membrane stability and favors neuronal irritability and the characteristic of being irritable. It plays a role in muscle mass and bone density as well as in immunity.138 According to clinical trials, the DHEA to cortisol ratio appears to play a positive role in resilience and adaptation to stress, whereas DHEA alone does not predict this type of behavior, and DHEA supplementation alone in posttraumatic stress disorders may have adverse consequences.40 This supports the discussion above regarding the quantitative and qualitative output of the adrenal cortex.

Aldosterone: Mineralocorticoids Location: Outermost adrenal cortex: zona glomerulosa. Composition: It is a C21 cholesterol-derived steroid in the Pregane family. Regulation (Fig. 6.18) ●

●

Stimulation ● ACTH ● Endorphins ● Elevated serum potassium (K) ● Elevated serum sodium (Na) ● Angiotensin II ● Prostaglandin E’s Inhibition ● Atrial natriuretic peptide (ANP) ● Dopamine (peripheral: direct, central: indirect via ACTH reduction) ● Progesterone (antagonizes its actions)

Purpose: The purpose of aldosterone is to assure the hydroelectric integrity of the organism. To this end, it has a structural and functional role. The structural role of aldosterone relates to the intracellular osmotic pressure and

FIG.  6.18  Regulation of aldosterone. See text for details. Red arrow, stimulates; blue arrow, inhibits; blue broken arrow, antagonizes. (© 2015 Systems Biology Research Group.)

electrolyte balance. The adaptive, functional role assures adequate intravascular volume and perfusion pressure for the delivery of nutrients. Hence, there is an adaptive increase in aldosterone in pregnancy.

Mechanism of action As with other steroid hormones aldosterone has nongenomic and genomic effects.147 However, what is unique is that the mineralocorticoid receptor (MR) has 1:1 affinity for both cortisol and aldosterone. As mentioned earlier, in most peripheral areas where the MR receptor is expressed, it is coupled with an enzyme that inactivates cortisol. In this way, despite having a serum concentration several log below that of cortisol, it is aldosterone that has the principle mineral corticoid role in the retention of sodium and water, and the excretion of potassium and hydrogen ions. The ACTH stimulates all three layers of the adrenal cortex. Secondary factors determine which zone is stimulated. For example, according to the theory of Endobiogeny, αMSH augments both the number of ACTH receptors on the zona fasciculata for cortisol production, and the intracellular response to the production and excretion of cortisol, but not DHEA or aldosterone. With respect to aldosterone there are four direct factors that regulate the secretion and excretion of aldosterone both independently and in concert with ACTH: (1) Angiotensin II, (2) elevated serum potassium levels,147 (3) serum sodium (osmolar and barometric pressure sensors), and (4) prostaglandin E-series.148, 149 Their activity involves three types of mechanisms within the zona glomerulosa. The first is an increase in the conversion of cholesterol to pregnenolone. The second is a potassiumlinked cytosolic release of calcium stored within specific organelles. This signals intracellular cascades that stimulate the transcription of the DNA encoding the synthesis of aldosterone (and not cortisol or DHEA). The third is the excretion of aldosterone into circulation. The structural activity of aldosterone is nutritive in nature and constant in its activity. It follows sequentially the first loop activity of estrogens in the initiation of metabolism. In the second loop, it precedes growth hormone in the completion of anabolism. It assures sufficient entry of water and electrolytes to maintain intrinsically optimized, dynamic tonicity, turgor, and tensegrity of the cell as a three-dimensional fluidfilled membrane-bound structure relative to the neighboring cells and vis-à-vis the osmolarity of the ground matrix. Water movement expands the size of the cell and allows for sufficient hydrostatic pressure to resist crushing by neighboring cells that are undergoing similar expansion. Tensegrity refers to the tensile integrity of the cell: its ability to retain its integrity in the face of sheering forces, compression and distortion. The functional, adaptive activity of aldosterone is integrated into a series of baro-osmotic and chemo-osmotic sensors that regulate perfusion pressure. The heart (atrial natriuretic peptide), kidney (renin), and vasculature (baro- and

80  The Theory of Endobiogeny

chemoreceptors) serve as the primary sensing stations of systemic integrity of intravascular status and perfusion pressure.6 A drop in renal perfusion pressure stimulates the release of renin from the kidney. Angiotensin is produced by the liver and is converted by renin to Angiotensin I. Angiotensin I is converted in the lungs (or kidneys) to Angiotensin II, discussed further later in this chapter.150 Pathologic states that alter these factors, such as congestive heart failure, dehydration, hemorrhage, nephrotic syndrome, and hepatic cirrhosis trigger aldosterone release.6 Prolonged expression of aldosterone favors metabolic alkalosis, but also fixates calcium to glutamic acid, reducing ionized calcium and favoring spasmophilia.

not cardiac output, vascular resistance, or blood pressure per se, but perfusion pressure, which is the net effect of these factors. Perfusion pressure is the pressure that allows for transcapillary delivery of nutrients to cells. With respect to the CNS, it also participates in maintenance of the diurnal consciousness required for the integration of information and decision-making, and the direction of motor movement. It is quite logical then to group the liver, lungs, and kidneys in their endocrine function are part of the corticotropic axis. As discussed above (mineralocorticoid activity), they are integrated into a network of hormones that regulate various aspects of intravascular dynamics beyond water retention.

Locations of action

Renin: Kidney

The retention of sodium and water is a classic genomic action. In the kidneys, it occurs at the level of the epithelial surface of the distal collecting tubal, the final point of sodium and water salvage. The specific genomic action of aldosterone involves regulation of transcription of the luminal Na-K transporter where it takes up sodium and excretes potassium into the lumen to be excreted in the urine. It also regulates transcription of proteins related to the Na-K ATPase pump. Aldosterone’s actions are found in numerous epithelial tissues6:

Renin is a renal hormone. It is stimulated by a reduction in renal perfusion pressure, an increase in renal sympathetic activity or hyponatremia, as detected within the kidney.6 Thus, the role of renin is to preserve the integrity of the kidney first and that of the organism second. It converts angiotensin into Angiotensin I.

● ● ● ● ●

Kidney Distal colon Sweat glands Salivary glands Gastric juices

According to the theory of Endobiogeny there are ACTH receptors in the distal colon that signal this activity when the hydroelectric demand is functional in nature and not strictly structural and nutritional. Within the CNS and skeletal muscle, aldosterone has an inverse effect: it increases serum potassium and diminishes serum sodium. Within the CNS, as with GRs, the MR is diffusely expressed, especially in the brainstem and limbic area, where it plays a role in the central regulation of the adaptation responses.52 As noted in the discussion of the anterior pituitary, endorphins favor the production of aldosterone relative to cortisol, and favor the preservation of central calcium, both stimulating and complimenting the role of aldosterone. The final functional effect of central aldosterone activity is to reduce central adaptation response by increasing intracellular potassium, which raises the response threshold.151

Associated locations, glands, organs and hormones: Liver, lungs, kidney, heart, vasculature posterior pituitary, and CNS There are myriad factors involved in regulation of intravascular dynamics. What ensures survival of the organism is

Angiotensin: Liver-kidney-lungs Angiotensin is a hormone that has constitutive effects throughout the body that serve the global system. Angiotensin is produced within the liver and excreted into the blood in its inactive form. Renin converts hepatic angiotensin to Angiotensin I. Angiotensin I is converted in the lungs to Angiotensin II.152 Of all corticotropic hormones, Angiotensin II plays the most constitutive and comprehensive role in directly and indirectly regulating the hemodynamic cycle (Fig.  6.19). Its direct effects include an augmentation of sympathetic activity, which improves cardiac output. It vasoconstricts, improving perfusion pressure. It augments tubular reabsorption of sodium, chloride, and water and the excretion of potassium, which improves intravascular volume. Within the CNS, it stimulates thirst and a craving for salt. It also augments lipogenesis.152, 153 Its indirect effects complement its direct effects. It stimulates the excretion of aldosterone,154 whose effects have already been discussed. It stimulates vasopressin, which has three roles: increased vascular tone, antidiuresis (prevents the loss of free water), and relaunching of the adrenal cortex activity by stimulating ACTH in the presence of CRH. Together with vasopressin, angiotensin aids in myocardiac repair.155 The counterbalancing hormones, also within the corticotropic axis, include the following (cf. Tables 6.8 and 6.9): ●

Heart: Atrial natriuretic factor (ANF). It inhibits aldosterone and renin, and has the opposite effects: excretion of sodium and water.156–158

Corticotropic axis Chapter | 6  81

Renin-angiotensin-aldosterone system +

Surface of pulmonary and renal endothelium: ACE

+

Angiotensin I

Tubular Na+ Cl– reabsorption and K+ excretion. H2O retention Adrenal gland: cortex

+ Angiotensinogen

+ Na+

Kidney

Lungs Liver

+

Angiotensin II

+

K+ Cl– H2O

+

– Kidney

Arteriolar vasoconstriction, increase in blood pressure

+

Stimulatory signal Inhibitory signal Reaction Active transport

Water and salt retention. Effective circulating volume increases. Perfusion of the juxtaglomerular apparatus increases

Renin

+

–

Secretion from an organ

Passive transport

Aldosterone secretion

+ Decrease in renal perfusion (juxt aglomerular apparatus)

Legend

Sympathetic activity

Arteriole

ADH secretion Pituitary gland: posterior lobe

+

Collecting duct: H2O reabsorption

H2O

FIG. 6.19  Renin-angiotensin-aldosterone system. (By Soupvector [CC BY-SA 4.0], from Wikimedia Commons.)

TABLE 6.8  Summary of agonistic hydroelectric activity

●

Location

Factor

Effect

Liver

Angiotensin (AT), AT I

Precursor to AT I and II

Kidney

Renin

Converts AT → AT I

Lung

Angiotensin II

Regulates entire hemodynamic profile: • Direct: Sympathetic sensibilization (hemodynamics), vasoconstriction (vascular tone), water and sodium retention • Indirect: Vasopressin (water retention and vasoconstriction), aldosterone (water and sodium retention)

Adrenal cortex

Aldosterone

Sodium and water retention, potassium and hydrogen loss, central adaptation response

Posterior pituitary

Vasopressin

Water retention (no electrolytes), increased vascular tone, adrenal cortex relaunching

Locus ceruleus

Noradrenalin

Hemodynamics, vascular tone

Adrenal medulla

Adrenaline

Hemodynamics, vascular tone

Vasculature: Nitric oxide (NO) and prostaglandins are constitutive molecules and as such are not strictly corticotropic hormones. They are mentioned here because they vasodilate through paracrine effects and as such antagonize the effects of the above-mentioned hormones,

●

and in fact trigger their release beyond a certain point of reduced intravascular pressure.159, 160 CNS: Dopamine’s peripheral activity on the kidneys is one of vasodilation, increased production of urine, and increased excretion of sodium.161, 162

82  The Theory of Endobiogeny

First loop (Fig. 6.20)

TABLE 6.9  Summary of antagonistic hydroelectric activity ●

Location

Factor

Effect

CNS

Dopamine

Vasodilates renal arteries, increases sodium and water loss

Heart

Atrial natriuretic peptide

Inhibits rennin, aldosterone: stimulates excretion of water and sodium

●

Prostaglandins Nitric oxide

Vasodilates

●

Vasculature

●

Integration of corticotropic function For the clinical endobiogenist, there are three general ways of considering the functioning of each axis within its own intrinsic function (but always in relationship to the ANS), illustrated by a discussion of the corticotropic axis. 1. Interaxial: Intrinsic function of only the hormones in the “hypothalamic-pituitary-adrenal cortex” axis 2. Corticotropic: Intrinsic function of all the hormones with the corticotropic axis, including those produced in the liver, lungs, kidney, and heart. 3. Intra-axial coupling: The linking of functional relationships of hormones across axes as it relates to physiologic relationships and pathophysiologic conditions, that is, diseases (Chapter 10). The first approach, interaxial, is discussed first, followed by an illustration (Fig. 6.20).

ANS: αΣ stimulates the excretion of all three levels of corticotropic activity: ● Hypothalamus: CRH ● Pituitary: ACTH ● Adrenal cortex: Cortisol, DHEA Hypothalamus: CRH stimulates ACTH Pituitary: ACTH stimulates the secretion and excretion of cortisol and DHEA Adrenal cortex: ● Cortisol is a catabolic and an antianabolic hormone that mobilizes all major metabolites, electrolytes and water. ● DHEA is a preanabolic hormone that prepares the body to utilize what cortisol has mobilized at a later time by being locally converted to anabolic gonadal hormones. Second loop:

● ●

●

●

ANS: αΣ continues its stimulation of the corticotropic axis Hypothalamus: CRH is also stimulated by prolactin (not shown in the diagram in Fig.  6.20—cf. somatocorticotropic axis) Pituitary: ACTH + CRH + vasopressin and/or endorphins stimulates aldosterone. Adrenal cortex: ● Aldosterone mobilizes electrolytes and water for the nutritional and adaptation demands of the organism. Aldosterone is a pro-anabolic hormone as it favors anabolism by providing secondary material that refines the quality of structural integrity and nutritional quality.

FIG. 6.20  Simplified first and second loop corticotropic activity. (© 2015 Systems Biology Research Group.)

Corticotropic axis Chapter | 6  83

FIG. 6.21  Elaborated first and second loop corticotropic activity. (© 2015 Systems Biology Research Group.)

A more detailed presentation can be discussed with an expanded list of hormones and elaborating the specific activity of the hormones within the axis. First loop (Fig. 6.21) ●

●

●

ANS: αΣ stimulates the excretion of all three levels of corticotropic activity: ● Hypothalamus: CRH ● Pituitary: ACTH ● Adrenal cortex: Cortisol, DHEA Hypothalamus: ● CRH stimulates pituitary POMC to produce ACTH ● CRH stimulates pituitary POMC to produce αMSH Pituitary: ● αMSH - Stimulates ACTH and general pituitary functioning - Increases the number of ACTH receptors on the adrenal cortex - Augments the intensity of cortisol release from the adrenal cortex

ACTH stimulates the secretion and excretion of cortisol and DHEA. Adrenal cortex: ● Cortisol mobilizes glucose, proteins, lipids, electrolytes, and water ● DHEA prepares the body to utilize what cortisol has mobilized at a later time by being locally converted to anabolic gonadal hormones ●

●

Second loop: ●

●

ANS: αΣ continues its stimulation of the corticotropic axis Hypothalamus: CRH is also stimulated by prolactin (not shown)

●

●

●

Anterior pituitary: ACTH favors the secretion and excretion of aldosterone. Posterior pituitary: Vasopressin ● Stimulates the release of ACTH ● Stimulates aldosterone excretion Adrenal cortex: ● Aldosterone mobilizes electrolytes and water for the nutritional and adaptation demands of the organism ● Vasopressin blocks renal water loss and increases vascular tone, complimenting the actions of aldosterone

Conclusions The corticotropic axis plays diverse roles in the protection and propagation of the individual organism. Due to its role in various adaptation syndromes, it has a direct or indirect impact on the other three endocrine axes, emunctories, and all tissues. It plays a key role in the global energy economy of the organism, including the general rate of metabolism and the state of cellular permeability. It also plays an important role in cognitive and emotional states, altering the ability to perceive and hierarchize internal and external threats and priorities. Over half a century ago, the surgeon and experimental physiologist Hans Selye anticipated that understanding “diseases of adaptation” would be key to addressing a host of disorders not classically considered to be endocrinopathies: everything from asthma to alcoholism (Chapter 12).163 The theory of Endobiogeny confirms this and expands on it by enlarging the concept of what is a corticotropic hormone, and evaluating how it is integrated and interconnected with hormones from the other three axes and various emunctories.

84  The Theory of Endobiogeny

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Chapter 7

Gonadotropic axis Introduction to the axis The gonadotropic axis is an anabolic axis with two general purposes: maintenance and propagation of life. It is the initiatory axis of metabolism. It manages protein anabolism especially in the interior of the cell. To assure associated adequate energy for this anabolic endeavor, it solicits lipids and carbohydrates for oxidation for ATP. Thus, the thyrotropic (lipolysis) and somatotropic (glucose) axes are yoked in a chain of compensatory responses (Fig. 7.1). The gonadotropic axis regulates tissues arising from the embryonic mesoderm. These tissues are protein-rich and/or are directly stimulated by gonadotropic hormones. For example, gonadal androgens stimulate the formation and excretion of red blood cells, which are of mesodermal origin.1–7 Other structures of mesodermal origin are connective tissues, bone, cartilage, synovial membranes, and serous linings of body cavities.8 According to the theory of Endobiogeny, the gonadotropic axis initiates de novo construction, reconstruction, and restoration of tissues in general, and mesodermal tissue in particular. While the female is the null sex state of the human (Chapter 6), LH and androgens are the null activity within the gonadotropic axis, as will be demonstrated later. There are nine major hormones of the gonadotropic axis common to men and women throughout life1: 1. Hypothalamic: GnRH: Gonadotropic-releasing hormone 2. Pituitary a. FSH: Follicle-stimulating hormone b. LH: Luteinizing hormone 3. Gonad a. Estrogens: Estradiol, estriol, estrone b. Progesterone c. Gonadal androgens: Testosterone, dihydrotestosterone (DHT) Schematically and functionally there are three key differences between the corticotropic and gonadotropic axes. The gonadotropic axis (Table 7.1): 1. Is anabolic in nature, which is enhanced by the agonist-antagonist, competitive-additive relationships ­ of its peripheral hormones. The corticotropic axis is

predominantly catabolic, with the seeds of anabolism within it (from its anabolic steroids and aldosterone). 2. Has two pituitary hormones (FSH, LH) owing to the nature of anabolism and sexual dimorphism. In contrast, the corticotropic axis has multiple pituitary hormones: ACTH, POMC derivatives, vasopressin, and oxytocin. Fig. 7.1 shows only ACTH for simplicity since it is the primary pituitary hormone of adrenal cortex stimulation. 3. Releases one hormone in the first loop (estrogen) and two in the second loop (progesterone, androgens). The corticotropic axis releases two in the first loop (cortisol, DHEA) and one in the second loop (aldosterone).

Hypothalamus: Gonadotropin-releasing hormone (GnRH) Location: Hypothalamus Composition: Polypeptide Regulation (Fig. 7.2) ●

●

●

Stimulation ● FSH decline (cortisol delays excretion) ● Activin ● Estrogen decline ● LH decline (cortisol delays excretion) ● Progesterone decline ● Androgens ● TRH ● Leptin Inhibition ● ACTH (delays excretion) ● FSH rise ● Inhibin ● Estrogens rise ● LH rise Regulation ● Endorphins

Purpose: The purpose of GnRH is to stimulate secretion and excretion of FSH and LH to ensure general competency of the structural maintenance and reproductive capabilities. Mechanism: While GnRH is the sole hypothalamic gonadotropic hormone, it regulates the expression of two pituitary

1. Gonadotropic hormones such as activin, inhibin and human choriogonadotropin (hCG) will not be discussed here. The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00007-0 © 2019 Elsevier Inc. All rights reserved.

89

90  The Theory of Endobiogeny

Corticotropic

Gonadotropic

Thyrotropic

Mobilization of metabolites

Initiation of metabolism

Energy from metabolites

Lipids

Proteins

Somatotropic

Lipids

Proteins

Carbohydrates

Mobilization of metabolites

Carbohydrates

Carbohydrates

Cell interior Aminos, carbs, lipids, electrolytes

Delivery of metabolites

Energy Completion of metabolism Cell exterior

FIG. 7.1  Gonadotropic regulation of protein metabolism. The axis solicits proteins for the cell’s interior. DNA, enzymes, etc. are proteinaceous. The thyrotropic and gonadotropic axes follow in turn to complete metabolism. (© 2014 Systems Biology Research Group.)

TABLE 7.1  Comparison of key differences in the corticotropic and gonadotropic axes First loop

Corticotropic

Gonadotropic

Hypothalamic

CRH

GNRH

Anterior pituitary

ACTH

FSH

End-organ Hormone

Cortisol

Second loop

Corticotropic

Gonadotropic

Hypothalamic

CRH

GNRH

Anterior pituitary

ACTH

LH

End-organ Hormone

Aldosterone

Progesterone

DHEA

hormones. The indication for the release of FSH vs LH is the amplitude and frequency of GnRH release. GnRH is released as a neurohormone and destroyed by autolysis within minutes, allowing for the rhythm of its release to be frequently varied. Throughout life GnRH exhibits a pulsatile release pattern. Chronology of release of GnRH also communicates information to the pituitary separate from its amplitude and frequency.9 In general, a low-frequency, high-amplitude pulse favors FSH and a high-frequency low-amplitude pulse favors LH (Fig. 7.3).10 The other three axes also influence the release of GnRH by blocking, delaying, or stimulating it, or by influencing pituitary responsiveness to GnRH (cf. Chapter 10), most notably prolactin.11–13 The default GnRH release pattern in adults favors the stimulation of LH.14, 15 In our opinion, this is an evolutionary approach that conserves energy in the organism. If FSH

Estrogens

Androgens

was favored as the default pituitary hormone, there would be an endless loop of initiation of metabolism via estrogens. As it stands, a rise in peripheral androgen activity solicits GnRH pulsatility to slow down so as to favor a compensatory production of estrogens. Similarly, prolactin as a somatotropic hormone favors LH production over FSH to facilitate the end of metabolism. The relationship between estrogens and GnRH is more complicated. Estrogens maintain a biphasic relationship. A decline in estrogens in the presence of central opioids reestablishes low-frequency GnRH output that favors FSH to relaunch estrogens.9 Within the pituitary, hormones inhibin and activin further calibrate FSH activity.16 As estrogen levels rise, they favor the transcription of LH.9 TRH, the hypothalamic thyrotropic hormone also favors low-frequency GnRH output to relaunch estrogen activity. According to an

Gonadotropic axis Chapter | 7  91

ovarian syndrome) or insufficiency (delayed puberty, amenorrhea, and infertility) (Fig. 7.5). Because of the complex nature of the menstrual cycle in anticipation of fertility each month, GnRH in women is subjected to constant and periodic variation in frequency and amplitude both by intra-axial factors as well as radial and horizontal factors. Thus, from our 40  years of clinical practice, we have observed that women appear to be more susceptible to desynchronization disorders of gonadotropic origin throughout life from adaptative states that are installed as a result of these chronic, varying demands. These disorders may be spontaneous, due to menstrual cycles or peri-pregnancy physiology or iatrogenic from oral contraceptives and other hormone replacement therapies. Examples include hyperestrogenism participating in the onset of autoimmune and allergic disorders, hyperandrogenism and their role in uterine fibroids, as well as disorders of over- and undersolicitation of the adrenal cortex such as metrorrhagia and depression. In addition, the local, regional, and systemic installation of congestion that it solicits helps explain the increased frequency of cellulite, pelvic congestion with neuro-vegetative dissociation (feet and hands having discrepant temperatures and circulation) and lymphato-venous disorders in women as compared to men.

FIG.  7.2  Regulation of GnRH. See text for details. Red arrow, stimulates; blue arrow, inhibits; green broken arrow, regulates; brown broken arrow, delays. (© 2014 Systems Biology Research Group.)

integrative physiologic reflection, the logic of this is that it favors an anabolic environment that can manage the metabolites mobilized both by its own actions (viz., TRH) and those of the other hormones within the thyrotropic axis (i.e., thyroxin). Across the phases of life, and considering sexual dimorphisms, there are additional variations in amplitude, frequency, and peripheral response. To note, fetogenesis, infancy and gonadopause are times of a relative predominance of FSH in relationship to LH with quantitatively diminished peripheral endocrinometabolic activity of estrogens and androgens. The period of fertility is exemplified by—in women—a high degree of monthly variation of LH greater than FSH, again supporting our hypothesis that the luteal line is the default of the gonadotropic axis in mature fertile adult humans (Fig. 7.4)15 Desynchronization of GnRH within the general functioning of the endocrine system can lead to various disorders of gonadotropic excess (precocious puberty and polycystic

1 GnRH pulse/3 h

50

LH (ng/mL)

Location: Anterior pituitary gonadotrophs Composition: Two-unit glycoprotein consisting of αand β-units. Unlike GnRH and all the central corticotropic hormones that are polypeptides, FSH belongs to a family of

1 GnRH pulse/h

500

40

400

30

300

20

200

10

100

0

FSH (ng/mL)

1 GnRH pulse/h

Pituitary: Follicle stimulating hormone (FSH)

0 20

15

10

5

0

5

10

15

20

25

30

35

40

Days FIG. 7.3  GnRH pulsatility patterns on LH and FSH excretion. The effects of GnRH pulsatility are discussed in the text. (Reproduced from Koeppen B, Stanton B. Berne and Levy Physiology, 6th ed. 2009. Elsevier © 2009.)

92  The Theory of Endobiogeny

LH secretion patterns Day Night

Plasma gonadotropins

Childhood

Day Night

Puberty

Day Night

Day Night

Reproductive years

Menopause

FSH

1st 2nd 3rd trimesters Fetal life

Birth 6 months Infancy

Childhood

LH

10–14 years Puberty

50 years Reproductive years

Menopause

FIG. 7.4  Variability in FSH, LH throughout life in females. The FSH and LH excretion patterns widely vary in circadian cycles as well as throughout the grand phases of life. During fetogenesis, FSH predominates because androgens are derived from the adrenal cortex. During reproductive years, it is the opposite. Note that both the total output and frequency of variation is key to fertility. (Reproduced from Hoffman BL, et al. Williams Gynecology. 3rd ed. 2008 © McGraw-Hill Education.)

FIG.  7.6  FSH regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits; black broken arrow, blocks release. (© 2015 Systems Biology Research Group.) FIG. 7.5  Synchronized and desynchronized circadian rhythms of GnRH. Optimal GnRH circadian rhythms are noted in black. There is variation in amplitude and frequency throughout the day with a distinct peak after midnight (0000). The red and blue dashed lines represent different types of desynchronization patterns, described in the key. (© 2018 Systems Biology Research Group.)

glycoprotein hormones. The family includes FSH, LH, hCG (human chorionic gonadotropin, an LH-like hormone), and TSH (thyroid-stimulating hormone). This family of hormones has a common α-unit. Each hormone in the family has a unique β-unit that is specific to its receptor.17 Regulation (Fig. 7.6) ●

Stimulation ● Activin ● Low-frequency GnRH ● Reduction in estrogens ● Progesterone

Androgens ACTH Inhibition ● Inhibin ● Estrogens ● Cortisol (blocks release) ● ●

●

Purpose: FSH is the factor of initiation of structure and initiation of reproduction of the organism. FSH stimulates the secretion and excretion of estrogens. This for the foundational and constant purpose of general cellular metabolism at the level of transcription for the production of structural elements such as organelles, enzymes, nucleus, and DNA, all of which are protein-based structures. Reproduction is a rare event in comparison to the constant demand for protein anabolism, despite the preparation that females undergo on a monthly basis.

Gonadotropic axis Chapter | 7  93

Mechanism Similar to ACTH’s actions in the adrenal gland, FSH regulates the rate of entry and metabolism of cholesterol within the gonads. In women, this occurs in various places within the follicles. In men, it occurs exclusively in Sertoli cells. FSH also stimulates various enzymes that convert the intermediate hormone androstenedione to various forms of estrogen (Fig. 7.7).18 As noted earlier, LH is the true regulation and guarantor of gonadotropic function, ultimately of estrogens indirectly, and of progesterone and gonadal androgens directly. Regional genetic polymorphisms exist for both FSH βsubunit and FSH receptor, with most notable differences existing between Southeast Asian and European populations, which impacts both exomorphic appearance and endomorphic function. These variations have been linked to numerous effects: (1) FSH: serum levels, (2) gametogenesis, (3) fertility (men and women), and (4) menstrual cycle regulation in women.19 In addition, posttranslational glycosylation and electric charge influence the potency of FSH.10 We find these observations supportive of the Endobiogenic notion that the evaluation of net effects of a hormone is more efficient at modeling achieved activity than serum levels will be.

Activity FSH plays a complimentary role related to the activity of estrogens. Within cells, it favors mitosis and prevents apoptosis, and, favors proliferation of cells.20 As Dr. Duraffourd hypothesized, as a result of this type of activity, FSH creates a nutritive congestion around tissues, especially mucosal tissues, such as sinuses and the intestines. An insufficient estrogen response to FSH can lead, for example, to a hyper-FSH state in an attempt to adjust

estrogen ­activity, ­incidentally causing mucosal congestion, such as that which occurs in Crohn’s disease (cf. below and The Theory of Endobiogeny, Volume 3, Chapter  11: Inflammatory Bowel Disease). Historically, there have been four shortcomings to endocrine research that make it difficult to cite the scientific literature with the following observations, which arise from an integrative physiologic reflection according to the theory of Endobiogeny. The first is that research on hormones has been conducted on individual hormones in isolation from other hormones whereas cell physiology is complex and multifactorial.21 The second is the reliance on animal models where the physiology lacks similarity to that of humans. As simple example is the question of steroidogenesis from cholesterol. Humans use low-density lipids (LDL) predominantly while for rats it is high-density lipids (HDL).22 Another is the significant difference in human adrenal cortex production of DHEA vs that of other primates or rats.23 The third is an artificial state of end organ deficiency that is created in previously healthy animal, such as ovariectomized rats, followed by short-term observation of changes in the function.24 These manipulated states are not reflective of years of deterioration or dysfunction within the human body, nor should the conclusions of these studies be taken to be reliable in clinical practice. The third is the administration of pharmacologic doses of a hormone with observation of effects where often, pharmacological dosing has effects opposite that of physiologic dosing.25 Finally, much of the research on hormones, especially gonadotropic hormones, has been focused on hypothalamic-pituitary-gonad feed forward, feed through, and feedback activity. However, every hypothalamic and pituitary organ has sites of action outside its axis.26, 27 Thus, the number of scientific studies that referenceable in a discussion of integrative physiology can be lacking at times, and certainly less than sufficient for the

FIG. 7.7  The LH, FSH actions on estrogen production. Thecal cell androstenedione is transported to granulosa cells where it is aromatized to estrogen. Estrone and estradiol are interconvertible. See text for details. (© 2018 Systems Biology Research Group.)

94  The Theory of Endobiogeny

type of rigor that has been—and should be—demanded of scientists. Thus, our presentation below and in other chapters of this volume are at times rooted in our reflection and clinical observations over the past 40 years. Research will need to be conducted by new methodologies that can accommodate complexity theory and human physiology.

Gonadotropic Physiology: FSH upregulates the number of estrogen receptors in the periphery. This compliments in role in production and excretion of estrogens. Pathophysiology: According to the Endobiogenic model of integrative physiology, prolonged stimulation of FSH by ACTH, GnRH, or TRH (via GnRH) can create a peripheral hyperestrogenic state and all that that implies. Insufficient peripheral estrogen response can favor a hyper-FSH state implicated in various disorders from Crohn’s disease to psoriasis to cystitis (cf. The Theory of Endobiogeny, Volume 3, Chapter  11: Inflammatory Bowel Disease).

Thyrotropic Physiology: FSH influences peripheral thyroid activity based on the anticipated response of estrogens. FSH stimulates TSH by horizontal intra-pituitary stimulation to favor a rise in thyroxin (T4). Thyroxin in turn increases free lipids and calcium to participate in the anabolism to be initiated by estrogens thanks to FSH. Pathophysiology: Therefore, by this reasoning, FSH can favor chronic overactivity of TSH, of T4 and peripheral hyperthyroidism, or conversely hypothyroidism. The latter is due the formation of antibodies from oversolicitation of the thyroid beyond its capacity to produce hormones at the demand rate, quantity or both.

Mucosa Physiology: FSH promotes mucosal hypertrophy and congestion of tissues to further augment the quantity and duration of nutrients available for metabolism in a general sense. Pathophysiology: Mucosal congestion can lead to stasis. Stasis increases the risk various types of mucosal disorders: cystitis, colitis, sinusitis, bronchitis, etc.

Immunity Physiology: FSH in its general regulation of proteins plays a role in the formation of immunoglobulins, compliment, and other protein products of the immune system. It also regulates specific elements of immunity such as monocytes.28 Pathophysiology: A chronic oversolicitation of FSH can participate in hyper- and autoimmune states in two ways. The first is oversolicitation of proteins. The second is TSH relaunching. TSH plays a role in the solicitation of the exocrine pancreas, increasing the uptake of exogenous proteins. It stimulates lymphocytes and stimulates the thyroid—all conditions favorable for dysregulation of immunity.

Fertility FSH plays an important role in menstrual physiology, pregnancy and parturition,29 which will be discussed in the related chapters of The theory of Endobiogeny, Volume 3.

Morphology Dr. Duraffourd observes that a right hemihypertrophy was related to disorders in which FSH plays a prominent role in morphology, personality, and/or function. Two associations he made were between FSH predominance and a curvaceous body in women, and, curling of the tips of the eyelashes in certain children and women. He concluded that a relative predominance of FSH in relationship to LH favors a relative predominance of all endocrine receptors on the right side of the body resulting in a right hemi-hypertrophy.

Pituitary: Luteinizing hormone (LH) Location: Anterior pituitary, gonadotrophs Composition: Glycoprotein Regulation (Fig. 7.8) ●

Stimulation ● High-frequency GnRH ● ↓ Androgens ● ↓ Progesterone

Colon Physiology: FSH upregulates absorption of proteins from the ascending and proximal transverse colon to provide proteins for estrogens to use. Pathophysiology: Elevated FSH activity can result in mucosal congestion of the colon with localized colitis in the areas mentioned above.

FIG.  7.8  LH regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits; black broken arrow, blocks release. (© 2015 Systems Biology Research Group.)

Gonadotropic axis Chapter | 7  95

Estrogens ACTH ● Aldosterone Inhibition ● Androgens ● Cortisol (blocks release) ●

GnRH

●

●

Purpose: LH manages the completion of metabolism and that of fertility. FSH regulates a single family of peripheral hormones: estrogens (of which there are three primary active forms). LH manages two completely different types of peripheral hormones: progesterone and androgens. There are two active forms of androgens: testosterone and dihydrotestosterone. Thus, a single pituitary hormone, LH, stimulates two classes of anabolic steroids producing three different peripheral hormones. The key is colocation of other factors. Mechanism: LH, similar to FSH and ACTH stimulates the uptake and metabolism of cholesterol for the production of progesterone and androgens.18

Activity LH plays key roles in ensuring the regulation and finalization of anabolism. Through its peripheral products it ensures a sufficient duration of estrogen activity in the first loop (i.e., progesterone) and androgen activity in the second loop (cf. Progesterone)

Morphology As Dr. Duraffourd observed with right hemihypertrophy, he noted a relationship between left hemihypertrophy and a luteal predominance in personality, morphology, and/or tissue quality. This, he concluded, reflected the relative predominance of LH in relationship to FSH in proliferation of all receptors on the left side of the body during fetogenesis. One example of a luteal woman is one with a stronger inclination to maintain her professional career after having children, and, who has sharper, less curvaceous angulation of facial features. (cf. Chapter 14: Art of the Examination for a more nuanced discussion of physical exam findings, and, cf. The Theory of Endobiogeny, Volume 3, Chapter 3: The Gonadotropic Axis for a detailed listing of psychological, historical, physical examination, and biology of functions findings related to the gonadotropic axis).

Estradiol

FSH

LH

Progesterone

Estriol

Estrone

Androgens

Testosterone

DHT

FIG.  7.9  Gonadotropic hormones according to GnRH pulsatility. (© 2015 Systems Biology Research Group.)

2. Pregane a. Progesterone 3. Androstanes a. Testosterone b. Dihydrotestosterone There is the metabolic and organometabolic activity of these hormones, which occurs in different orders. Metabolic activity refers to the actions of peripheral gonadal hormones. Estrogens initiate metabolism. Progesterone comes at a second time to regulate it. Gonadal androgens come at a third time to finalize anabolism. Organometabolic activity is the production of these hormones from cholesterol in the gonads. Progesterone, is a luteal hormone derived from cholesterol via pregnenolone.30 Progesterone, in turn, is the mother of estrogens and gonadal androgens, through the intermediary of androstenedione (Fig. 7.7).31All roads of metabolism can result in estrogens: gonadal production via androstenedione, estriol, testosterone, or DHT, and, intracrinologic conversion of adrenal DHEA. Estrogens are produced in greatest quantity between puberty and gonadopause.32 Something unique about the gonads compared to the other peripheral endocrine glands is that the location, structure, and function are divergent between the male and female (i.e., testicles vs ovaries).

Estrogens Location: Gonads ●

Female: Ovaries, granulosa cells Male: Testicles, Sertoli cells Composition: C18 steroid Regulation (Fig. 7.10)

There are six peripheral gonadotropic hormones (Fig. 7.9) 1. Estranes a. Estradiol b. Estriol c. Estrone

High frequency

Estrogens

●

An introduction to the Gonads and Peripheral hormones

Low frequency

●

●

Stimulation ● FSH Reduction of serum levels ● Cortisol

96  The Theory of Endobiogeny

●

Regulation ● Progesterone ● TRH (sensitizes cells to estrogens) ● Prolactin (open up peripheral receptorsFig. 7.10)

estrogen

Purpose: Estrogens initiate cellular metabolism and solicit proteins for the construction of cellular elements related to structure and function. They play a key role in fertility and gametogenesis in men and women.

FIG. 7.10  Regulation of estrogens. See text for details. Red arrow, stimulates; green broken arrow, regulates; broken teal arrow, reduces serum levels. (© 2015 Systems Biology Research Group.)

Mechanism: Estrogens act through genomic and nongenomic mechanism to affect cellular metabolism (Fig. 7.11). They initiate transcription of various segments of the DNA directly or indirectly through secondary messengers.33 Again, chronology is key in order for the cell to achieve sufficient anabolism. According to the schematic developing by Dr. Duraffourd, in the first loop, somatotropic growth f­actors (IGF’s, growth hormone) calibrate the activities of estrogens by increasing the entry and utilization of amino acids, lipids, and electrolytes. In the second loop, progesterone and androgens complete the solicitation and utilization of proteins. At the end of the second loop, the entry of glucose under the effects of insulin allows for an augmentation of de novo ATP production and the cellular energy required for the completion of cellular demands, i.e., production of mitochondria, expansion of the cell membrane, cytoskeleton movement, etc. With respect to the three forms of estrogens, it can be said that estradiol is the form of estrogen produced in ­greatest quantity during the period of fertility.32 Estradiol is

Tyrosine kinase receptors

Ion channels

mGluRs

Pathway 2 (ER-dependent) E2

Pathway 1 (ER-dependent)

E2

ER

E2

ER

E2

ER

-IP

E2 E2

ER

Nontranscriptional activities

E2

Membrane-bound ER

TF

Nuclear ER

Promoter

E2 E2 ER ER

ER

Second messengers

P

ER

E2 E ER ER

E2

Gene

P

E2 E2 ER ER

P ER ER

ERE-promoter

Gene

ERE-promoter

Oxidative stress

Gene

E2 E2 ER ER

TF

Promoter

E2

Gene

Nucleus

Key:

E2 Cytoplasm

Protein kinase cascades

DAR DA

EGFR

IGF

IGFR

E2

Pathway 4 (Estrogen-independent)

EGF

Pathway 3 (ER-independent)

TF

Transcription factor

ER-IP

ER-interacting protein

EGFR

EGF receptor

DAR

Dopamine receptor

IGFR

IGF receptor

TRENDS in Molecular Medicine

FIG. 7.11  Cellular actions of estrogens. Pathway 1 is genomic: estrogens enter the cytosol, bind to nuclear estrogen receptors (ER), translocate into the nucleus and affect gene transcription. Pathway 2 (upper right) is mixed: estrogens bind to membrane receptors and activate second messengers, which have nongenomic or genomic effects. Pathway 3 (bottom right) is purely nongenomic. Pathway 4 (bottom left) is estrogen-independent. (Reproduced from Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med 2013;19(3):197-209. doi:https://doi. org/10.1016/j.molmed.2012.12.007. © 2012 Elsevier Ltd.)

Gonadotropic axis Chapter | 7  97

produced from testosterone or conversion of estriol. After menopause, Estriol, derived from androstenedione often from DHEA, is produced in greater quantities. This implicates a greater role of peripheral aromatization of nonestrogen steroids into estrogens during gonadopause. The monthly pulsatility and amplitude of estrogen production also varies widely throughout the lifecycle, most notably in women and declines with age.32

Limits of quantitative measurements of estrogens From the Endobiogenic perspective, quantitative measurements in general and the types of estrogens in particular are not indicative of their effects on metabolism. Estrogen activity involves endocrine, metabolic, and ­tissue functions, both genomic and nongenomic in nature. They can be produced in the ovaries, in the adrenals, and by peripheral conversions in various tissues.34, 35 The pattern of estrogen production (central vs peripheral, adrenal vs gonadic vs hepatic) varies based on hereditary factors, age and parturition status, and is affected by endocrine disrupters.34–37 There are multiple active forms of estrogens as well as varying degrees of activity of estrogen metabolites. There are two types of estrogen receptors (α, β), which have opposing activity with respect to cellular proliferation and various metabolic functions.38 There are genetic polymorphisms in p450 metabolism of estrogens.39–41 In addition, there are polymorphisms in receptor sensitivity and concentration, rate of aromatase activity and nongenomic effects. In total, all these factors create a true challenge in determining the qualitative metabolic effects of estrogens through the measurement of serum levels of active hormones or urinary levels of metabolites.42–48 In their review of estrogen metabolism, Zhu and Connery concluded: Studies that identify genetic and environmental factors influencing estrogen metabolism at or near estrogen receptors in target cells may be of considerable importance since these factors could profoundly modify the biological effects of estrogens in complex manners depending on the pathways of metabolism that are affected and the biological activities of the metabolites that are formed. Such effects need not be associated with an altered profile of estrogen metabolites in the blood or urine. Ref. 45

According to the theory of Endobiogeny the quantitative measurements of each type of estrogen are not a reliable evaluation of their impact as a whole on metabolism. It evaluates neither intrinsic nor synergistic effects with other catabolic and anabolic factors. It does not even evaluate the organotissular output of the gonads. Estrogens can be

derived from peripheral conversion of DHEA in the liver, adipose tissue, or other areas of the body, or intracellular conversion of testosterone or estradiol.49, 50 In evaluating the semiology of estrogens, one may find discrepancies in relationship with serum levels of estrogens. In other words, one may find on evaluation a women who expresses signs of hypoestrogenism, such as dry skin, vaginal dryness, and hair loss, find normal or elevated serum estradiol or vice versa. The physical examination remains, according to an Endobiogenic reflection, a capital point of investigation and evaluation and represents a truer functional expression of the current terrain as managed by the neuroendocrine system.

Activity Cell metabolism: Estrogens initiate the metabolism of proteins for the structure and function of cells, as discussed above. Tissue-general: In addition, certain tissues, organs, and circulating elements within the organism are proteinaceous in nature, and thus estrogens play a particular role in their formation, maintenance, repair, and restoration.38 From an Endobiogenic reflection, one can conclude that estrogens determine the texture of tissues. Texture is derived from the Latin word for “weave.” Thus, one meaning of this is the manner in which tissues are interlinked or connected to each other. Texture also refers to the feeling or composition of the surface of an object. Estrogens contribute to the suppleness, elasticity, and resilience of internal and external structures in their intrinsic formation and in their functional relationship to other structures.51 Estrogens directly influence the activities implicated by FSH as noted earlier:38 1. Mucosal surfaces 2. Immunoglobulins 3. Fertility 4. Bone: Bone and cartilage growth 5. Muscle: Muscle growth and texture 6. Cardiovascular a. Vasodilatation b. Electrical discharge: estrogens lower the rate of depolarization, lowering the threshold of firing 7. Sexual dimorphisms Estrogen receptors are diffusely expressed in the CNS and play a role in divergent CNS activity that culturally and physiologically demonstrates sexually dimorphic expression52: 1. Cingulate cortex: consideration of more options in decision-making 2. Prefrontal cortex: emotive quality of thinking 3. Insular cortex: instinctual knowledge

98  The Theory of Endobiogeny

4. Hippocampus: memory: recall, contextualization of events 5. Periaqueductal gray: Reflective listening and speaking. In general, estrogens favors qualitative relationshipbased analysis as opposed to quantitative, hierarchical assessment favored by androgens

Androgens Androgens are the foundation of structure and initiate the transitions through the grand phases of life. Because of their key role in the formation, survival, and reproduction of the organism, they are the only class of hormone whose production is diversified to two different glands and under the influence of two different pituitary hormones from two different endocrine axes (Fig. 7.12). What is more, androgens metabolically are the precursors to that which assure its own achievement: estrogens (cf. below). Location ● ●

Female: Ovaries, theca cells Male: Testicles, Leydig cells Composition: C19 steroid Regulation (Fig. 7.13)

●

Stimulation ● LH ● Insulin

Corticotropic

Gonadotropic

Pituitary

ACTH

LH

Periphery

DHEA

Testosterone Estradiol

DHT

FIG.  7.12  Diversification of androgen production. (© 2015 Systems Biology Research Group.)

FIG. 7.13  Regulation of gonadal androgens. See text for details. Red arrow, stimulates; green broken arrow, regulates; broken teal arrow, reduces serum levels. (© 2015 Systems Biology Research Group.)

●

●

Inhibition ● Cortisol Regulation ● Progesterone ● Estrogens (by sex hormone binding globulin)

Purpose: Androgens manage the completion of metabolism. Hence, the achievement of anabolism is directly under the influence of androgens, not estrogens.

Mechanisms and action Androgens like other steroidal hormones have genomic and nongenomic effects.53 The genomic of effects of androgens are as follows:53 1. Cellular: Apoptosis 2. Muscles a. Skeletal muscle mass and density b. Smooth muscle proliferation 3. Bone: Epiphyseal lengthening 4. Cartilage: Cartilage closure 5. Cardiovascular: Vasorelaxation 6. Immune a. Monocyte migration b. Foam cell production These effects are associated with serum levels of androgens. They take hours to occur and are linked to many of the classic effects associated with androgens deemed to be harmful when dysregulated. Nongenomic effects of androgens are as follows:54, 55 1. Muscle: Smooth muscle relaxation 2. CNS a. Increased neuromuscular signal transmission by calcium regulation b. Neuroplasticity 3. Cell: Cellular proliferation and migration 4. Endocrinometabolic: Modulation of the transcriptional effects of classical androgen receptors They occur within seconds. Mechanisms of action are believed to include a novel membrane-bound receptor, second messenger activation, and sex-hormone-binding globulin receptors. Many of the nongenomic effects of androgens are physiologically beneficial and, in our opinion, explain the protective effects of androgens observed in studies. What is clinically relevant is that drugs that block androgen receptor activity cannot block these nongenomic effects. This explains two observations: (1) the variability of responsiveness to androgen blockers, (2) factors of risk and protection from disease cannot be reliably assessed by quantitative measurement of serum androgens, sex-­ hormone-binding globulin or free androgen levels—because their effects do not rely solely on receptor activity.

Gonadotropic axis Chapter | 7  99

There are a number of other factors adding to the difficulty of equating quantitative levels of testosterone (free or total) with androgen functionality. Recent studies have demonstrated in vitro and in vivo sex-based variability in androgen receptor sensitivity and concentration in various tissues.55a Approximately 5% of testosterone is converted within the cell to either DHT or estrogens by intracrinologic mechanisms. In summary, the individual effects of testosterone on the body can vary based on: 1. Genomic effects 2. Nongenomic effects 3. Receptor concentration 4. Receptor distribution 5. Intracellular conversion tendency between DHT and estradiol The net effect can be an amplification of genomic or nongenomic effects (DHT), or a counterbalancing effect (estrogens). As discussed extensively, according to the theory of Endobiogeny, the downstream effects of androgens on metabolism will be a more accurate reflection of the final, functional effect of androgens on metabolism. Androgens manage the architecture of structure. The density, number, speed of function, etc. are managed by androgens. Whatever actions estrogens initiate, androgens finalize. Androgens sequentially follow estrogens and the sum total effect of androgens is commensurate to that of estrogens in normal physiology. Androgens influence very particular aspects of biology and physiology related to the structure and function of the organism. Similar to estrogens, androgens influence pubertal and postpubertal life in a sexually dimorphic manner with respect to morphology and comportment. Determination of the type of androgen (DHEA, testosterone and DHT) is relevant, particularly in men because certain structures utilize one of these hormones more than the others. For example, the growth of the prostate is primarily under the management of DHT (cf. The Theory of Endobiogeny, Volume 3, Chapter 7: Disorders of the Prostate).54 With respect to comportment, androgens, like estrogens are widely expressed throughout the brain. There are differences in the size, frequency, and rapidity of function of various areas between men and women, with intra-sex variation as well. The following areas have been found to be relatively more dense in androgen receptors in men in relationship to women:56 1. Hypothalamus: Medial preoptic area: sexual pursuit, initiation of erection 2. Tempero-parietal junction: Problem-solving 3. Dorsal premammillary nucleus: Aggression and fear for territorial defense 4. Rostral cingulated zone: Reduction in overt expressions of emotions 5. Ventral tegmental area: Motivation for reward, related to dopamine activity

In general, androgens—testosterone in particular—favor quantitative, hierarchical assessment over qualitative relationship-based analysis. The genomic effects of androgens, noted above, include not only the proliferation of neurons but also their stability. Estrogens pool calcium in bones and reduce extracellular calcium concentrations, altering neuronal stability, and favoring spasmophilic states. Androgens have the opposite effect, reducing the tendency toward spasmophilic states. In summary, some of the specific actions of androgens are summarized in Table 7.2.57, 58

Progesterone Location ● ●

Female: Ovaries, corpus luteum cells Male: Testicles, Leydig cells Composition: C21 steroid Regulation (Fig. 7.14)

●

●

●

Stimulation ● LH ● DHEA (indirect: LH, aromatization to estrogens) ● Estrogens (LH relaunching) Inhibition ● T4 Regulation ● Estrogens by cortisol binding globulin (CBG)

FIG. 7.14  Regulation of progesterone. See text for details. Red arrow, stimulates; blue arrow, inhibits; broken teal arrow, reduces serum levels. (© 2015 Systems Biology Research Group.)

Purpose: Progesterone is a regulator of anabolism and reproduction. It serves a dual action of being antiandrogenic and antiestrogenic (Fig. 7.15). It favors estrogen activity by being antiandrogenic by delaying the expression of androgens. In the first loop, this action of progesterone allows estrogens a duration of time to initiate metabolism and mobilizes proteins. In the second loop, it favors androgens, which blocks estrogens from further influencing the plenitude of metabolism. These effects are summarized below. With respect to fertility, progesterone plays a key role in ovulation and pregnancy until the time of parturition, hence its name progesterone for its role in gestation.

Mechanisms and actions The general mechanisms of progesterone are similar to that already described for the steroid hormones. Progesterone

100  The Theory of Endobiogeny

TABLE 7.2  Summary of androgen activity by type of androgen Effect

DHEA

Testosterone

DHT

Androgen receptor affinity

1

10

30

Skin moisture

Increases sebum

Hair

Low hair line

Receding hair line

Muscle

Skeletal: Mass, density, strength Smooth: Relaxation, proliferation

Bone

Density, linear growth Epiphyseal closure

Genitals

Epididymis Vas deferens

Thrombosis

Increased clotting

Sexuality

Libido

Prostate Glans penis

Erection

Comportment

Capacity to resist and persevere

Cognition

Neuronal irritability

Neuronal stability Neuroplasticity

has membrane receptors with rapid nongenomic effects at the level of the membrane and cytosol, and genomic effects via translocation into the nucleus.59 Progesterone promotes anabolism. It has a biphasic relationship with estrogens, promoting its activity at low levels, inhibiting it at higher levels of progesterone expression. Its activity is summarized in Table 7.3.60, 61

Integration of gonadotropic function In summary, the gonadotropic axis is an anabolic axis with two key roles: maintenance of the material structure of the individual and propagation of their genetic material. The most fundamental action of this axis that ensures both activities is the initiation of cellular metabolism. The central and peripheral hormones act in a concerted fashion through

GnRH Low frequency

High frequency

FSH

LH

Relaunch estrogens

Estrogens

Progesterone

Androgens

Prolong estrogens

Initiate metabolism

Regulate metabolism

Complete anabolism

Antiandrogenic

First loop Delays androgens

Second loop Closes anabolic loop

FIG. 7.15  Progesterone’s regulation of estrogens and androgens. (© 2015 Systems Biology Research Group.)

Relaunch androgens

Antiestrogenic

Gonadotropic axis Chapter | 7  101

●

TABLE 7.3  Summary of progesterone activity Tissue

Function

Endocrine

Prevents suppression of endorphins by estrogens, allowing reduction in LH, FSH Inhibits expression of estrogen receptors Inhibits intracellular activity of estrogens Relaunches production of testosterone

Cellular

Growth factors Increased cell cycling

Bone

Regulation of bone mass: Antagonism of cortisol receptors

Heart

Antiarrhythmic: faster repolarization: Increased potassium current, reduced depolarizing calcium currents

Brain

Libido

Uterus, ovaries

Ovulation Implantation of fertilized egg Pregnancy

Mammary gland

Lobular alveolar development Suppression of lactation during pregnancy

rhythmic pulses and chronologic passage between different aspects of function within the axis to manage the solicitation and incorporations of amino acids, polypeptides, and proteins for the construction of the cellular elements of the cell and the general activity of the nucleus. Thus, we can summarize the general actions of this axis as follows (Fig. 7.16). First loop ●

Hypothalamus: Low-frequency, high-amplitude GnRH pulses stimulate FSH.

●

Pituitary: FSH stimulates the secretion and excretion of estrogens. Gonad: Estrogens stimulates the transcription of enzymes and growth factors related to the utilization of proteins Second loop

●

●

●

Hypothalamus: High-frequency, low-amplitude pulse GnRH pulses stimulate LH Pituitary: LH stimulates the gonads ● ↑ Estrogens, ↓ Progesterone: LH → Progesterone ● ↑ Progesterone, ↓ Estrogens: LH → Androgens Gonad: ● Progesterone: ▪ ▪

Moderate levels: Supports estrogen activity and delays actions of androgens Increased levels: ● Inhibit intracellular estrogen activity ● Reduce estrogen receptor activity; relaunch androgens

Androgens: Complete anabolism through transcription of enzymes that participate in the assembly of proteins for the production of specific cellular products

●

One of the keys to the complex method of regulation of anabolism is the role of progesterone. As we noted earlier, in a first time, progesterone is antiandrogenic by synergizing the effects of estrogens and favors estrogen relaunching. In a second time, as its levels rise, progesterone is antiestrogenic: it inhibits estrogen activity and receptor sensitivity and relaunches androgens to complete metabolism. There are a number of influences on the timing and function of the gonadotropic axis from the other three endocrine axes at the central and peripheral levels, horizontal

FIG. 7.16  General regulation of the gonadotropic axis. (© 2015 Systems Biology Research Group.)

102  The Theory of Endobiogeny

FIG. 7.17  Elaborated regulation of the gonadotropic axis. Red arrow, stimulation; blue arrow, inhibition. (© 2015 Systems Biology Research Group.)

and radial in nature. These relationships will be discussed in the various subsequent sections (cortico-gonadotropic, gonado-thyrotropic, and somato-gonadotropic). The relationships can be presented in a slightly more elaborated schematic (Fig. 7.17).

Conclusions The Gonadotropic axis is well known for its role in procreation. In addition to this vital role, in all ages and stages of life, in males and females, it plays a pivotal role in initiating metabolism. Thus, it is sequentially the first of the two anabolic axes. The unique quality of having three peripheral hormones from two pituitary regulators creates an ­agonistic-antagonist relationship between estrogens, progesterone, and androgens. Their timing and shifting roles are crucial for the proper achievement of metabolism as well as catamenial function in women and the production of ova and spermatozoa in woman and men. Disorders of amplitude, duration, and chronology of gonadotropic hormones play a role in numerous human disorders. A functional assessment of the gonadotropic signs, symptoms, and activity offers a more nuanced assessment of the gonadotropic axis than serum hormone levels. It can aid in the diagnosis and treatment of a host of disorders. These include disorders classically attributed to this axis, such as infertility, osteopenia, and polycystic ovarian disease. However, it also includes complex multisystem disorders including catamenial migraines and seizures, acne, prostatic adenoma, intrinsic asthma, intrinsic depression, etc. The Endobiogenic approach to terrain offers a particularly nuanced assessment of intrinsic gonadotropic function and its relationship to the other endocrine axes (cf. coupled axes) and emunctories.

References 1. Gardner  FH, Pringle Jr. JC. Androgens and erythropoiesis. I. Preliminary clinical observations. Arch Intern Med. 1961;107:846–862. 2. Naets JP, Wittek M. The mechanism of action of androgens on erythropoiesis. Minerva Nucl. 1965;9(5):281–284. 3. Gardner FH, Nathan DG. Androgens and erythropoiesis. 3. Further evaluation of testosterone treatment of myelofibrosis. N Engl J Med. 1966;274(8):420–426. 4. Naets JP, Wittek M. Mechanism of action of androgens on erythropoiesis. Am J Phys. 1966;210(2):315–320. 5. Fisher JW, Samuels AI, Malgor LA. Androgens and erythropoiesis. Isr J Med Sci. 1971;7(7):892–900. 6. Gardner FH, Gorshein D. Regulation of erythropoiesis by androgens. Trans Am Clin Climatol Assoc. 1973;84:60–70. 7. Evens  RP, Amerson  AB. Androgens and erythropoiesis. J Clin Pharmacol. 1974;14(2):94–101. 8. Bolender DL, Kaplan S. Basic embryology. In: Polin RA, Abman SH, Rowitch  DH, Benitz  WE, Fox  WW, eds. Fetal and Neonatal Physiology. 5th ed.vol. 1. Elsevier; 2017:23–39.e22. [chapter 3]. 9. Marshall  JC, Dalkin  AC, Haisenleder  DJ, Griffin  ML, Kelch  RP. GnRH pulses—the regulators of human reproduction. Trans Am Clin Climatol Assoc. 1993;104:31–46. 10. Nussey  S, Whitehead  S. Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. 11. Duncan  JA, Barkan  A, Herbon  L, Marshall  JC. Regulation of pituitary gonadotropin-releasing hormone (GnRH) receptors by pulsatile GnRH in female rats: effects of estradiol and prolactin. Endocrinology. 1986;118(1):320–327. 12. Perez-Lopez  FR, Abos  MD. Pituitary responsiveness to ­gonadotropin-releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH) during different phases of the same cycle of oral contraceptive steroid therapy. Fertil Steril. 1982;37(6):767–772. 13. la Marca  A, Torricelli  M, Morgante  G, Lanzetta  D, De Leo  V. Effects of dexamethasone and dexamethasone plus naltrexone on pituitary response to GnRH and TRH in normal women. Horm Res. 1999;51(2):85–90.

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Berne RM, Koeppen BM, Stanton BA. Berne & Levy Physiology. 6th ed. Philadelphia, PA: Mosby/Elsevier; 2010. 15. Schorge  JO, Williams  JW. Williams Gynecology. New York: McGraw-Hill Medical; 2008. 16. Bernard DJ, Tran S. Mechanisms of activin-stimulated FSH synthesis: the story of a pig and a FOX. Biol Reprod. 2013;88(3):78. 17. Kaiser  U, Ho  KKY. Pituitary physiology and diagnostic evaluation. In: Melmed  S, Polonsky  KS, Larsen  PR, Kronenberg  HM, eds. Williams Textbook of Endocrinology. Elsevier; 2016:489–555. [chapter 8]. 18. Stehle JH, Saade A, Rawashdeh O, et al. A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases. J Pineal Res. 2011;51(1):17–43. 19. Simoni  M, Casarini  L. Mechanisms in endocrinology: genetics of FSH action: a 2014-and-beyond view. Eur J Endocrinol. 2014;170(3):R91–107. 20. De Pascali F, Tréfier A, Landomiel F, et al. Follicle-stimulating hormone receptor: advances and remaining challenges. Int Rev Cell Mol Biol. 2018;338:1–58. 21. Pitetti  JL, Calvel  P, Zimmermann  C, et  al. An essential role for insulin and IGF1 receptors in regulating sertoli cell proliferation, testis size, and FSH action in mice. Mol Endocrinol. 2013;27(5):814–827. 2 2. Gwynne JT, Strauss III JF. The role of lipoproteins in steroidogenesis and cholesterol metabolism in steroidogenic glands. Endocr Rev. 1982;3(3):299–329. 2 3. Labrie F, Belanger A, Simard J, Van L-T, Labrie C. DHEA and peripheral androgen and estrogen formation: intracinology. Ann N Y Acad Sci. 1995;774:16–28. 2 4. Daendee S, Thongsong B, Kalandakanond-Thongsong S. Effects of time of estrogen deprivation on anxiety-like behavior and GABAA receptor plasticity in ovariectomized rats. Behav Brain Res. 2013;246:86–93. 2 5. Bristow LJ, Bennett GW. Effect of chronic intra-accumbens administration of the TRH analogue CG3509 on histamine-induced behaviour in the rat. Br J Pharmacol. 1989;97(3):745–752. 2 6. Zhu D, Li X, Macrae VE, Simoncini T, Fu X. Extragonadal effects of follicle-stimulating hormone on osteoporosis and cardiovascular disease in women during menopausal transition. Trends Endocrinol Metab. 2018;29(8):571–580. 2 7. Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005;8(5):571–578. 2 8. Robinson LJ, Tourkova I, Wang Y, et al. FSH-receptor isoforms and FSH-dependent gene transcription in human monocytes and osteoclasts. Biochem Biophys Res Commun. 2010;394(1):12–17. 2 9. Jones  RE, Lopez  KH. Human Reproductive Biology. 3rd ed. Amsterdam/Boston: Elsevier Academic Press; 2006. 3 0. SB  K, AM  K. On the mechanism of action of adrenocorticotropic hormone—the stimulation of the activity of enzymes involved in pregnenolone synthesis. J Biol Chem. 1970;245:152–159. 3 1. Lee TC, Miller WL, Auchus RJ. Medroxyprogesterone acetate and dexamethasone are competitive inhibitors of different human steroidogenic enzymes. J Clin Endocrinol Metab. 1999;84(6):2104–2110. 3 2. Lamberts  SW, Van Den Beld  AW. Endocrinology and aging. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. Elsevier; 2016:489–555. [chapter 27]. 3 3. Cui  J, Shen  Y, Li  R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med. 2013;19(3):197–209.

34.

35. 36. 37.

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Masood  DE, Roach  EC, Beauregard  KG, Khalil  RA. Impact of sex hormone metabolism on the vascular effects of menopausal hormone therapy in cardiovascular disease. Curr Drug Metab. 2010;11(8):693–714. Hammond CB, Soules M. Clinical significance of estrogen metabolism and physiology. Contemp Ob/Gyn. 1978;11:41. Gore AC. Neuroendocrine targets of endocrine disruptors. Hormones (Athens). 2010;9(1):16–27. Dickerson  SM, Gore  AC. Estrogenic environmental endocrine-­ disrupting chemical effects on reproductive neuroendocrine function and dysfunction across the life cycle. Rev Endocr Metab Disord. 2007;8(2):143–159. Eyster  KM. The Estrogen Receptors: An Overview from Different Perspectives. Methods Mol Biol. 2016;1366:1–10. Silva SN, Cabral MN, Bezerra de Castro G, et al. Breast cancer risk and polymorphisms in genes involved in metabolism of estrogens (CYP17, HSD17beta1, COMT and MnSOD): possible protective role of MnSOD gene polymorphism Val/Ala and Ala/Ala in women that never breast fed. Oncol Rep. 2006;16(4):781–788. Bergman-Jungestrom M, Wingren S. Catechol-O-Methyltransferase (COMT) gene polymorphism and breast cancer risk in young women. Br J Cancer. 2001;85(6):859–862. Huang  CS, Chern  HD, Chang  KJ, Cheng  CW, Hsu  SM, Shen  CY. Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Cancer Res. 1999;59(19):4870–4875. Matthews J, Gustafsson JA. Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol Interv. 2003;3(5):281–292. Zhao C, Dahlman-Wright K, Gustafsson JA. Estrogen receptor beta: an overview and update. Nucl Recept Signal. 2008;6:e003. Hurvitz  SA, Pietras  RJ. Rational management of endocrine resistance in breast cancer: a comprehensive review of estrogen receptor biology, treatment options, and future directions. Cancer. 2008;113(9):2385–2397. Zhu  BT, Conney  AH. Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis. 1998;19(1):1–27. Pfeffer U, Fecarotta E, Vidali G. Coexpression of multiple estrogen receptor variant messenger RNAs in normal and neoplastic breast tissues and in MCF-7 cells. Cancer Res. 1995;55(10):2158–2165. Nelson LR, Bulun SE. Estrogen production and action. J Am Acad Dermatol. 2001;45(3 Suppl):S116–S124. Feigelson  HS, McKean-Cowdin  R, Pike  MC, et  al. Cytochrome P450c17alpha gene (CYP17) polymorphism predicts use of hormone replacement therapy. Cancer Res. 1999;59(16):3908–3910. Labrie  F, Labrie  C. DHEA and intracrinology at menopause, a positive choice for evolution of the human species. Climacteric. 2013;16(2):205–213. Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol. 2001;22(3):185–212. Lethaby  A, Ayeleke  RO, Roberts  H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2016;8. CD001500. Brizendine  L. The female brain. 1st ed. New York: Morgan Road Books; 2006. Liu PY, Death AK, Handelsman DJ. Androgens and cardiovascular disease. Endocr Rev. 2003;24(3):313–340.

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Heinlein  CA, Chang  C. The roles of androgen receptors and ­androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol. 2002;16(10):2181–2187. Michels  G, Hoppe  UC. Rapid actions of androgens. Front Neuroendocrinol. 2008;29(2):182–198. Papaconstantinou J. Insulin/IGF-1 and ROS signaling pathway crosstalk in aging and longevity determination. Mol Cell Endocrinol. 2009;299(1):89–100. Brizendine L. The male brain. New York: Broadway Books; 2010. Jones RE, Lopez KH. The male reproductive system. In: Jones RE, Lopez  KH, eds. Human Reproductive Biology. 3rd ed.Amsterdam/ Boston: Elsevier Academic Press; 2006. xviii, 604 p. [chapter 4].

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Chapter 8

Thyrotropic axis Introduction to the thyrotropic axis The purpose of the thyrotropic axis is to manage adaptability and growth. The key to understanding the thyrotropic axis lies not in the function of the thyroid gland per se, but the toggling of the axis between the actions of its two central hormones: thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH). It is a dialectic between imagination and ideation, between potential and achievement. The thyrotropic axis has a significant impact on the development of ectodermal tissues, especially the nervous system, the adrenal medulla (βΣ), and immunity.1 The pituitary gland is an ectodermal tissue and hence this axis generates the very essence of peripheral endocrine management.1 As will be demonstrated, the thyrotropic axis is permanently linked to both structure and function, and adaptation and restoration. The thyrotropic axis gives birth to structural home of adrenaline, and adrenaline entrains and enlivens the function of the thyrotropic axis in turn. This axis shares a number of schematic similarities with the corticotropic axis and is above all complimentary in its actions. Both axes are primary catabolic but contain proanabolic factors. Both have a single hypothalamic hormone, a single pituitary hormone and three end organ peripheral hormones (Table  8.1). Both have associated organs that complement the functions of their first and second loop hormones. Most importantly with respect to diseases of adaptation and adaptability, both axes are directly relaunched by αΣ. Thus, both axes are directly linked to conscious, subconscious, and physiologic perceptions of and response to aggression (cf. Chapter  12). Both catabolic axes mobilize all three metabolites and numerous minerals (Fig.  8.1). From the evolutionary perspective, the thyrotropic axis is also closely linked to the sympathetic branch of the ANS. Catecholamines (dopamine, noradrenalin, adrenaline) and peripheral thyroid hormones (T4, T3) are all derived from the amino acid tyrosine.2 Unlike the corticotropic axis, the thyrotropic contains hormones that both mobilize and utilize metabolites (Table 8.2). When evaluating the level of the function of the thyrotropic axis it is capital to understand two concepts from an Endobiogenic perspective. First, a number of the symptoms The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00008-2 © 2019 Elsevier Inc. All rights reserved.

attributed to hypo- and hyperfunctioning of thyroid hormones are due to central thyroid hormones (TRH, TSH), or the sensibilization of other neuroendocrine factors and not the peripheral hormones ipso facto. Second, most signs, symptoms, and disorders related to the thyrotropic axis are relative and qualitative in nature, not absolute or quantitative.

Thyrotropin-releasing hormone (TRH) Location: Hypothalamus, medial neurons of the paraventricular nucleus Composition: Tripeptide Regulation: (Fig. 8.2) ●

●

Stimulation ● Dopamine: Central alpha ● αMSH (direct) ● αΣ (direct) ● βΣ (reactionary/compensatory) ● Thyroxin (T4) (low concentrations in pituitary sensitizes pituitary to TRH stimulation of TSH) ● GnRH ● Cold Inhibition ● TSH ● Triiodothyronine (T3) (increased concentrations in pituitary reduces pituitary sensitivity to TRH stimulation of TSH) ● Somatostatin ● FSH

Purpose: The purpose of TRH is to manage the potentiality of the organism in its mental, emotional, and physiologic spheres of activity. It is a neuropeptide that happens to also regulate the thyrotropic axis because that action serves its larger goals and this, only in certain species, such as humans, and not in others.3 The unique simplicity of TRH as a molecule consisting of three amino acids (tripeptide) suggests its conserved and ancient evolutionary purpose. TRH is derived from a pre-pro-molecule whose enzymatic cleavage yields six TRH tripeptides allowing for ultraefficient high-volume yield of transcription.4 This implicates its importance in the regulation of the terrain and adaptation.

105

106  The Theory of Endobiogeny

TABLE 8.1  Comparison of cortico- and thyrotropic axes in the endocrine loops First loop

Corticotropic

Thyrotropic

Hypothalamic

CRH

TRH

Anterior pituitary

ACTH

TSH

End-organ hormone

Cortisol

Annexal organ(s)

Liver

Thymus parathyroid: PTH

Second loop

Corticotropic

Thyrotropic

Hypothalamic

CRH

TRH

Anterior pituitary

ACTH

TSH

End-organ hormone

Aldosterone

T3

Annexal organs

Liver, lung, kidney: angiotensin II, renin

Skin, liver, kidney: vitamin D

Mobilization

Initiation

of metabolites

of metabolism

T4

Energy

Carbohydrates

Mobilization

from metabolites

of metabolites

Somatotropic

Lipids

Proteins

Proteins

Calcitonin

Thyrotropic

Gonadotropic

Corticotropic

Lipids

DHEA

Carbohydrates

Carbohydrates

Cell Interior Aminos, carbs, lipids, electrolytes

Delivery of metabolites

Energy

Completion

of metabolism Cell exterior FIG. 8.1  Metabolites and the endocrine axes. The thyrotropic axis, similar to the corticotropic axis mobilize lipids, proteins, and carbohydrates. Both are catabolic axes solicited for adaptation demands. (© 2015 Systems Biology Research Group.)

Mechanisms and actions TRH and its receptors are diffusely expressed throughout the central and peripheral tissues.5 Within the brain (green boxes, below), the majority of TRH receptors and TRH concentration is outside of the hypothalamic-pituitary connection (blue boxes, below).6 The general spheres, types of activity and interconnection are schematically shown in Fig. 8.3.

According to the theory of Endobiogeny, TRH is the most diverse hormone with central and peripheral function related to adaptation, growth, energy, comportment, etc. It is implicated in various psychiatric disorders based on its relative degree of hypo- or hyperfunctioning (Tables 8.3 and 8.4). Classical researchers are beginning to appreciate this perspective.6 An interesting conceptual model has been developed by psychiatrists regarding the central activity of TRH based on in  vivo and clinical trials that supports

Thyrotropic axis Chapter | 8  107

TABLE 8.2  Mobilization and utilization of metabolites by the thyrotropic hormones Mobilization Metabolite

TRH

Glucose

•

Amino acids

•

Utilization T4

PTH/D3

•

Lipids

•

Calcium

•

TSH

T3

•

•

•

•

D3

Calcitonin

•

•

• •

•

D3, vitamin D3; PTH, parathyroid hormone.

ric disorders. However, it fails to integrate the peripheral roles of TRH on physiology and lacks a precise concept of what homeostasis means. Furthermore, their conclusions are based in part on animal models of human disease and supraphysiologic administration of synthetic TRH.

Central FIG.  8.2  TRH regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

this general Endobiogenic perspective. They group TRH function by region of the brain: (1) chronbiology (retina, suprachiasmatic nuclei, pineal gland), (2) limbic/cortical (amygdala, hippocampus, frontal cortex), and (3) brainstem/spinal cord (dorsal raphe, caudal raphe, etc.). The model is synthetic and valuable in recognizing the diverse effects of TRH, particularly with respect to neuropsychiat-

For all pathophysiology listed below, excessive TRH is implicated each time. Activity: Neuromodulator/metabolic activity Location: General central and peripheral nervous system Physiology: TRH serves the central physiology. As a neuromodulator its most general metabolic function is to increase the general rate of function of all other activities within the CNS, such turnover of other neurotransmitters.7 Hence the Endobiogenic consideration of TRH is the “central beta-sympathetic.” In general, one can say that TRH is

Limbic system

SCN-pineal

Terrain

Chronobiology

Regulation-adaptation

Cerebral cortex Lower brain Midbrain-brain Stem-spine

Central-metabolic Neuro-modulation

TRH

Peripheral Endocrinometabolic

Pancreas

Cell

Hyperplasia

FIG. 8.3  Schematic representation of TRH activity. (© 2015 Systems Biology Research Group.)

Endocrine Classical function

Calcitonin

T3

TSH

108  The Theory of Endobiogeny

TABLE 8.3  Summary of central TRH physiology and pathophysiology

TABLE 8.4  Peripheral TRH physiology and pathophysiology

Physiology

Pathophysiology

Physiology

Pathophysiology

Neuromodulation: central beta: accelerates central metabolism and neuronal transmission for optimal adaptability, creative response to adaptation demands, vivid dreams, creativity

Fugue states, tremors, anxiety, negative imagination, OCD

Muscle tone, posture: colocates with serotonin in spine to allow for more rapid muscle contractions to regulate posture

Peripheral neuromuscular disorders: clonus, tremors, fasciculation, hypertonicity, Parkinson’s disease. Insufficiency of TRH: ataxia

Chronobiology, pacemakers: modulates SCN activity for diurnal, seasonal adaptation, indirectly augmenting melatonin excretion

Seasonal and circadian dysadaptation: insomnia, seasonal depression, spring allergies, seasonal cancer growth, etc.

Thyrotropic endocrine: stimulates both loops: TSH, T4 → T3, calcitonin

Thyrotropic disorders: hyperthyroidism, adenosis (tonsils, prostate, breasts), amyloses (Alzheimer’s disease, diabetes, atherosclerosis), cysts, thyroid cancer, etc.

Rational adaptation: enhances dopamine-induced analytical function for a more rational, equilibrated response to aggressions

Psychiatric disorders of excess: anxiety, panic attacks, schizophrenia

Thyro-somatotropic endocrine: stimulates prolactin

Contextual adaptation: synapses to limbic area to contextualize current aggression to past events and adaptation responses

Consumption of buffering capacity: traumatic rumination, harmful adaptation responses, seasonal depression, winter bronchitis, etc.

Hyperprolactinosis: implosive adaptation, infertility, schizophrenia, menstrual disorders, pancreatic cancer, metastasis of solid tumors, acceleration of aberrant growths

Qualification of global adaptation response: in quadratic relationship of αΣ, TRH, DA, limbic system, regulates qualitative, quantitative and chronologic intensity of cognitive, emotional and physiologic response to aggressions

Adaptability: States of adaptability, esp. thyrotropic axis, autoimmunity, seasonal depression, winter bronchitis, etc.

Thyro-pancreatic: glycemia: stimulates glucagon to adapt serum glucose to needs of central metabolism driven by TRH

Disorders of adaptative TRH with hyperglycemia: depression with traumatic rumination, ADHD, autoimmune flare ups Disorders of hyperplasia: growth of aberrant tissues by cell multiplication

Cell: accelerates DNA transcription

Oncogenesis: DNA fracture, biologic toxin accumulation

Survival of the most creative: fine tunes threshold of response of reticular activating system, neuroplasticity, introspection, etc.

Overstimulation: diurnal hypervigilance, nocturnal nightmares, night terrors, etc.

Tissue: first loop: myolysis: amino acid mobilization, second loop: T3: tissue reconstruction, adenosis (cell hyperplasia); dromotropy (rate of electro-cardiac impulse transmission)

Adenoidal disorders: tonsils, prostate, breasts (adenofibroids), muscle wasting disorders, arrhythmias

Serotonin-dopamine-TRH: enhanced arousal, pain, pleasure, reward, movement, sleep, cardio-pulmonary rhythms, gastric secretions

Prolonged adaptative states: migraines, depression, suicide, narcolepsy, pain processing, dysrhythmias, gastric hyperacidity

ADHD, attention deficit hyperactivity disorder;

OCD, obsessive-compulsive disorder; SCN, suprachiasmatic nucleus. DA, Dopamine

key for creativity of the adaptation response. It helps the organism recognize new situations that require new responses, increasing the degrees of freedom in decision-making. Particular effects of TRH that have led us to these conclusions are discussed in the following subsections. The key to this is its relationship to central histamine and their relationship with the limbic area: hippocampus, amygdala, etc.7

According to the theory of Endobiogeny, TRH contributes to the vivacity of dreams: their color, intensity, details, etc. TRH is found in the hippocampus and is related, in animals, to states of hypo- and hyperarousal.8 We have observed that physiologic expression of TRH, in conjunction with regulated dopamine and serotonin activity, can augment learning through openness to receipt of new information. According to the theory of Endobiogeny, TRH favors tangential thinking, juxtaposition of ideas, creativity, and learning, particularly experiential and multisensory. The net effect of TRH within the central physiology is to facilitate imagination and emotion, and to open up the mind to potential and possibility.

Thyrotropic axis Chapter | 8  109

Pathophysiology: Excessive TRH is related to fugue states: sudden intense states of activity such as delirium or explosive anger. It is also related to acute, medium term, and chronic neuropsychiatric issues such as tremors, anxiety, negative imagination, and obsessive-compulsive tendencies (discussed below). Activity: Chronobiology/adaptation Location: Suprachiasmatic nucleus-pineal gland Physiology: The retina and the suprachiasmatic nucleus (SCN) are the areas of the brain that have direct contact with sunlight and act as the primary biological pacemaker, respectively. They are rich in TRH receptors.6 TRH is hypothesized to augment the activity of the SCN as a pacemaker, thus augmenting the general metabolic plan of the organism and its physical activity, which varies according to the time of day and the season of the year. In the long adaptation route (cf. Chapter  6, αMSH section), αMSH stimulates TRH in addition to other central hormones to assist in the progression of the general adaptation response.9 Most fundamentally, noradrenaline (alpha), launched from the locus ceruleus in the brainstem relaunches TRH as part of a coordinated catabolic adaptation response, along with CRH and the corticotropic axis.10 Pathophysiology: In general, disorders of seasonal and circadian disadaptation: insomnia, spring allergies, chronobiologically induced cancer growth, etc. are implicated. Because of the SCN’s connection to the pineal gland, which produces melatonin, TRH can affect the quality of the pineal gland’s adaptation of the corticotropic axis as well as its own axis during circadian and seasonal adaptation demands (cf. Chapter 5). A blunted TSH response to TRH has been associated with depression in a subset of depressed patients.11, 12 By relaunching melatonin—at least in hibernating animals—TRH can indirectly calibrate thyroid activity without relying on a TSH response.13 The presence of this mechanism in nonhibernating mammals such as humans needs to be verified. Its relaunching of melatonin favors the activity of β-MSH, which directly stimulates the thyroid as a long-acting stimulator not regulated by T4 negative feedback (cf. Chapter  6).14–17 In turn, beta-endorphins inhibit TRH18 and by extension the activity of βΜSH. According to the theory of Endobiogeny, in a person with low self-esteem depression is a disorder of disadaptation of the adrenal cortex with insufficient βΣ activity and low central serotonin. Insufficient TRH can play a role in a peripheral thyroid insufficiency even when it is relative and subclinical.19 It places a person at risk of depression during certain seasons. According to the theory of Endobiogeny, hyperfunctioning TRH in the face of blunted TSH response can facilitate some of the characteristics of depressed thinking, such as rumination or obsessive-compulsive thoughts (cf. below). Activity: Rational adaptation Location: Cerebral cortex

Physiology: Dopamine plays an important role in executive functioning, perception, decision-making, anticipation of rewards, and externalization of thought.20–22 The general permissive metabolic function of TRH is to increase the rate of ratiocination and perception managed by dopamine. Thus, thought can become suprarational (i.e., intuitive), emotive, or irrational according to the central Endobiogenic terrain of the individual. The mechanism of action of TRH on dopamine is hypothesized to involve a change in oscillatory frequency of discharge of dopamine, from pulsatile to tonic.23 Pathophysiology: A subset of schizophrenics suffers from a cognitive hyperfunctioning and distortion of perception. A hyperfunctioning of DA and TRH as well as a blunted pineal response to melatonin solicitation have been associated with schizophrenia,6, 24–26 linking the effects of TRH across the SCN, pineal gland, and cerebral cortex. A hyperfunctioning of TRH can also play a role in anxiety in a number of ways related to both central and peripheral physiology. Thus, it can drive the general rapid thinking and irrational fears that lead to a panic attack as well as the physiologic symptoms of that attack such as tachycardia and sweating.27, 28 Activity: Contextualized creative adaptation Location: Cerebral cortex Physiology: TRH contextualizes the effects of dopamine by introducing an emotive and qualitative perspective to events (mechanism discussed below). TRH colors perception through nonrational methods of thinking. Through its connection with the SCN, the pineal, the cortex, and the limbic area, TRH favors the general vivacity of the organism, having a cheering, antimelancholic effect on disposition.29 Pathophysiology: Excessively rapid or intense recall decontextualizes perception and impairs the adaptation response. It overstimulates central and peripheral physiologic responses often in a chronic manner, resulting in a consumption of buffering capacity, and all that that implies (cf. Chapter 12). Activity: Memory recall, qualification of global adaptation response. Location: Limbic area. NB: The limbic area contains a number of nuclei and functions, with divergent yet integrated functions that affect the adaptation response and the perception toward the adaptation response. Physiology: TRH projections from the hypothalamus synapse to the limbic area. Our interpretation of the significance of this activity is that TRH contextualizes the current aggression an organism faces to past aggressions and prior responses. TRH along with histamine affect the quality of memory recall.30 Part of the complexity of the activity of TRH in the limbic area is that it is also stimulated by alpha and in turn TRH influences dopamine activity (cf. above). There is quadratic relationship of αΣ, TRH, DA and the limbic system that regulates the qualitative, quantitative, and chronologic intensity of the cognitive, emotional and

110  The Theory of Endobiogeny

been learned, the organism tends to repeat what it did each time prior. Gordon Allport, a leading theorist of personality states it like this: If the inputs to a system cause the same pattern of activity to occur repeatedly, the set of active elements constituting that pattern will become increasingly strongly interassociated. That is, each element will tend to turn on every other element and (with negative weights) to turn off the elements that do not form part of the pattern. To put it another way, the pattern as a whole will become ‘auto-associated’. We may call a learned (auto-associated) pattern an engram. Ref. 32 FIG.  8.4  Quadratic relationship of TRH to other central factors. Red arrow, stimulates; red broken arrow, regulates rate of functioning; blue arrow, inhibits; αΣ, alpha-sympathetic; CRH, corticotropin releasing hormone; DA, dopamine; GHRH, growth hormone releasing hormone; GnRH, gonadotropin releasing hormone; TRH, thyrotropin releasing hormone. (© 2015 Systems Biology Research Group.)

physiologic response to an aggression (Fig.  8.4). When functioning well, it offers the organism rational yet creative response to an aggression that benefits the person in their mental and physiologic activities. Pathophysiology: Dysregulation of this quadratic relationship can play a role in numerous diseases of adaptation and adaptability. For example, the installation of a chronic adaptation state with consumption of the buffering capacity can make a person susceptible to a host of disorders by allowing precritical disease states to enter the liminal phase of expression. It can install adaptability states (i.e., autoimmune thyroiditis) or chronobiologic disorders from seasonal depression to winter bronchitis to metastasis of cancer in the early spring. Activity: Intensity of alertness, survival of the creative. Location: Brain stem Physiology: reticular activating system (RAS) is located within the brainstem. RAS plays an important role in diurnal variations in awareness. TRH helps regulate this activity by RASs.31 TRH increases ordinary consciousness during the day and nonordinary consciousness in the night, hence the intensity and vividness of dreams. From the standpoint of adaptation and survival of the organism, this is an absolutely vital distinction between survivors and nonsurvivors of aggression. The brain is a stimulus-response system that utilizes the principle known has Hebb’s postulate. Hebb stated that repetitive firing of synapses allows for learning by association and mirror learning, where a person engages in reflective expression of what is being expressed or acted in their environment. The more frequently events are associated, the more frequently they are associated in the future. However, because the null state of the human being is to be reactive, repetitive, and categorical, once a pattern has

The starting point of neuronal plasticity, introspection, self-development and novelty is TRH. It is TRH that facilitates tangential thinking and the juxtaposition of variables to offer novel patterns of response. During the general adaptation syndrome, when the organism faces an unknown aggression, the locus ceruleus (alpha) directly stimulates TRH in addition to launching the corticotropic axis. Of course, the implication of this TRH relaunching is more than just the consideration of possibilities; it includes a re-adaptation of the thyrotropic axis and the production of cellular energy. However, all the cellular energy in the world is of no use if you are dead because of lack of plasticity in one’s gross adaptation response to an aggression. To rephrase Darwin, evolutionary advantage is not characterized by the “survival of the fittest,” but “survival of the creative.” Pathophysiology: Overstimulation of the RAS by TRH at night can interrupt sleep, or favor causing nightmares or night terrors. It also relaunches β-MSH too early in the night, favoring a direct release of cortisol from the adrenal cortex and night wakening. Understimulation during the day can lead to states of mental and emotional torpor or diminished learning. Understimulation during the night can blunt neuronal synapsing, evaluation of the day’s events and personal growth. Activity: Relaunching central para-alpha-beta: Serotonin-dopamine-TRH. Location: Diffuse Physiology: The raphes nuclei are the principle sites of production of serotonin.33 and TRH receptors are found throughout these nuclei along with substance P.34 The raphes nuclei are distributed from the caudal to rostral areas of the brain stem. The caudal portions project into the subcortical and cortical regions in the same areas that dopamine does. TRH links, sequences, and entrains the relationship between dopamine and serotonin (Fig. 8.5). The activities that TRH affects through its interactions with serotonin and dopamine are as follows: 1. Cortex a. Arousal/agitation b. Motivation, anticipation of reward

Thyrotropic axis Chapter | 8  111

Dopamine pathways

Serotonin pathways

Frontal cortex

Striatum Substantia nigra

Functions Reward (motivation) Pleasure, euphoria Motor function (fine tuning) Compulsion Perseveration

Nucleus accumbens

VTA Hippocampus

Functions Mood Memory processing Sleep Cognition

Raphe nucleus

FIG. 8.5  TRH projections in cerebral cortex. (Courtesy of National Institutes of Health, public domain.)

c. Pain and pleasure d. Regulation of mood, emotional lability e. Rate of sensory processing f. Electrical state of the brain 2. Thalamus a. Movement 3. Hypothalamus a. Endocrine function 4. Locus ceruleus a. Central and peripheral αΣ b. Adaptation c. Sleep 5. Brain stem a. Neurovegetative function i. Cardiac rhythmicity ii. Respiration rate iii. Gastric secretions Pathophysiology: The implications of TRH’s influence on serotonin-dopamine interaction are far reaching. As mentioned above, TRH is implicated in both installing and prolonging adaptative states and various disorders. TRH is also implicated in the quality, threshold of onset and severity of migraine headaches, depression, suicide, narcolepsy, pain processing, dysrhythmias, and gastric hyperacidity.35, 36

Peripheral In addition to its central effects, TRH affects many areas of peripheral physiology, largely in support of its central implications. (Table 8.4) Activity: Postural tone Location: Spine

Physiology: The rostral portion of the raphe nuclei (where serotonin is produced) also project into the gray matter of the spinal cord (lamina II and IX). TRH and its receptors are colocated throughout these same areas, as well as in proximity to α-motoneurons in the ventral horn.6 α-Motoneurons innervate low-twitch skeletal muscles that play a role in muscle tone, contraction, and posture of the organism. Pathophysiology:TRH is implicated in the peripheral πΣ-αΣ-βΣ sequencing of resting muscle tone, threshold of force, duration of contraction, and the general rate of depolarization and coordination of the contractions. According to the theory of Endobiogeny, increasing levels of TRH activity are implicated commensurately in briskness of deep tendon reflexes, clonus, tremors, fasciculation, and hypertonicity of resting muscle tone. TRH is implicated in various neuromuscular disorders such as hypertonic cerebral palsy and Parkinson disease. Insufficiency of TRH is implicated in ataxic disorders and treatment with exogenous TRH in animal models helps alleviate symptoms.6 Action: Endocrine Location: Thyrotropic axis Physiology: TRH manages the general progression of both loops of thyrotropic function. In the first loop, it stimulates TSH, its classical vertical endocrine feed-forward activity. In the second loop, it stimulates the conversion of T4 to T3,37 and the release of calcitonin. TRH stimulates the extrathyroidal conversion of T4 to T3, mainly in the liver and hypothalamus. In turn, T3 inhibits TRH transcription in the hypothalamus.38 Pathophysiology: According to an Endobiogenic reflection, the implications are wide, relating to intrinsic thyrotropic disorders and those related to gonadotropic and

112  The Theory of Endobiogeny

somatotropic entrainment. Intrinsic disorders include hypoand hyperthyroidism, adenosis (tonsils, prostate, breasts), amyloses (Alzheimer’s disease, diabetes, atherosclerosis), cysts, thyroid cancer, etc. Action: Endocrine Location: Thyro-somatotropic axis Physiology: TRH is the hypothalamic stimulant of prolactin, a somatotropic hormone, creating a thyro-­somatotropic axis3. The effects of prolactin are discussed in Chapter  9: Somatotropic axis. Insulin and the endocrine pancreas are implicated in two ways. First, prolactin stimulates insulin release.39 Second, TRH stimulates a reflexive increase in insulin excretion due to its effects on glucagon (cf. below).5 Pathophysiology: Disorders of adaptability with implosive adaptation with hyperprolactinism, infertility, schizophrenia (prolactin’s relationship with dopamine), menstrual disorders, pancreatic cancer, metastasis of solid tumors and the general acceleration of aberrant growths (i.e., adenoidal and amyloidal growths), and possibly shorter survival time in cancer patients based on altered responsiveness to TRH stimulation.40–45 Action: Glucose metabolism Location: Hypothalamo-pancreatic Physiology: TRH increases the general rate of metabolism, especially in the brain. This occurs as a general function, TRH’s role in creative thinking, as well as through its actions on serotonin, dopamine, the limbic area, etc. is ­discussed in Fig.  8.6. Increased metabolism requires increased glucose utilization. TRH ensures this need as well

through its interaction with the periphery—which is still in service of the central nervous system. Independent of peripheral metabolism, TRH stimulates the endocrine pancreas to release glucagon, which stimulates glycogenolysis in the liver to increase circulating glucose levels.5 This stimulates a reflexive release of insulin, which distributes the glucose in a more regulated manner between the periphery and central metabolism to prevent excess glucose delivery to the brain, which cannot store the glucose or its metabolites. TRH also directly stimulates insulin release from βislet cells of the pancreas.46 The periphery must deal with often unwanted glucose, which implicates TRH in a number of peripheral disorders (Fig. 8.7). Recall that the brain is 2% of total body weight, but receives 25% of total blood flow.47 Thus, it receives 25% of all circulating glucose (and all other nutrients present)—a lion’s share for such a light organ. As a vital organ, the brain does not have a mechanism of insulin resistance. Its requirement for glucose is constant. Thus, the brain has the most privileged relationship to glucose. TRH ensures this privilege. Pathophysiology: All disorders related to an adaptative TRH response and hyperglycemia will be related to this mechanism: depression with traumatic rumination, attention-­deficit hyperactivity disorder, autoimmune flare ups, growth of aberrant tissues (i.e., adenoidal and amyloidal growths), etc. Activity: Various Location: Cells Physiology:

FIG. 8.6  TRH and neurotransmitters influencing thinking style and adaptation. (© 2014 Systems Biology Research Group.)

Thyrotropic axis Chapter | 8  113

Pain

Spine Adaptive thinking

Brain stem

Mental Rate of cognition Dreams

Adaptation

Myofunction First loop

TSH

Second loop

T3

Endocrine CNS

Myogenesis

Calcitonin Emotional

TRH

Dromotropy

Electrophysiologic

Histamine

Histamine

Alpha

Endocrinometabolic

Emotive thinking

Beta Amino acids

Glucose

Histmamine

Endocrino tissular

Exocrine pancreas

Endocrine pancreas

Insulin activity

Myolysis

Estrogen activity

Cell hyperplasia FIG. 8.7  Summary of TRH effects. (© 2015 Systems Biology Research Group.)

Nuclear metabolism: While estrogens solicit the nucleus to transcribe DNA, it is TRH that accelerates the general rate of transcription. This can favor DNA fragmentation, accumulation of biologic toxins within the cytoplasm risk of oncogenesis,48, 49 especially in breast cancer.50 Activity: Various Location: Tissue Amino acids: TRH stimulates myolysis51, 52 and the ­liberation of amino acids. In normal physiology, the stimulation of T3 by TRH favors the restoration of muscle. The pathophysiology includes neuromuscular disorders of wasting. Adenosis: TRH favors hyperplasia: an increase in the number of cells within a gland, also referred to as adenosis. The above-mentioned activities, as well as its lateral coupling with the gonadotropic and somatotropic axes introduce all the elements of anabolism required for physiologic hyperplasia as well as dysregulated growth.49 Rhythmicity: TRH is dromotropic: it accelerates the rate of electrical impulse transmission within the heart.53, 54 It also stimulates the release of histamine, which prolongs alpha-sympathetic activity, which results in a more pronounced βΣ expression, which also augments dromotropy and the risk of arrhythmias. The pathophysiology favors arrhythmias.

The sum total effects of TRH on central and peripheral physiology are summarized in Fig. 8.7.

Thyroid-stimulating hormone (TSH) Location: Anterior pituitary, thyrotroph. Composition: Glycoprotein, in the same family as FSH, LH. Regulation (Fig. 8.8) ●

●

Stimulation ● TRH ● FSH ● LH 5, 55, 56 ● Estrogen Inhibition 57 ● Somatostatin. ● Iodine ● T4 ● Progesterone

Purpose: The purpose of TSH is to promote structuration and achievement of structure. TSH is implicated in every stage of cellular function: formation of structure, function of structure, adaptation, replication, and restoration. The logic of TSH requires its implication not only within the thyroid gland, but across the anabolic axes.

114  The Theory of Endobiogeny

FIG.  8.8  TSH regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

Mechanisms and actions Endocrine, endocrinometabolic There are two classical actions of TSH: secretion (endocrinometabolic) and excretion (endocrine) of thyroid hormones (Fig. 8.9).58 Iodine uptake is the rate-limiting step in the formation of thyroid hormones. TSH upregulates iodine intake for the formation of thyroid hormones. TSH binds to its transmembrane receptor, stimulating intracellular messengers, which upregulate sodium-iodide symporters.59 The greater the rate of iodine uptake, the greater the rate of ­thyroid hormone production will be within thyroid follicles. TSH also stimulates the release of thyroid hormones that have already been formed. The specific mechanism of action is complex. Iodine is taken up from the small intestine and transported in its reduced form, iodide. Thyroid follicles take up iodine and

sodium as noted above. Thyroid peroxidase enzyme (TPO) catalyzes an oxidation reaction between hydrogen peroxide and iodide to form biologically active iodine. Once oxidized, iodine is taken up by thyroglobulin, where TPO catalyzes its attachment to tyrosine-derived residues. TPO also fuses two iodine-tyrosine complexes to form diiodotyrosine (DIT). The fusion of two DIT molecules forms thyroxin, or, T4—because it contains four iodine molecules. A monoiodine-tyrosine (MIT) can fuse with DIT to form T3: triiodothyronine. The thyroglobulin-thyroid hormone complex is stored in the colloid, then released by a TPO-dependent event, upon solicitation by TSH.60 According to the theory of Endobiogeny, antithyroglobulin antibodies represent an attempt by the organism to slow down the production of T4 due to oversolicitation of the thyroid from TSH, estrogens, or both. The presence of anti-TPO antibodies is due to an oversolicitation of the thyroid for the production of T3. In classical medicine, TSH is considered strictly within its interthyroid activity of stimulation of thyroxin (T4) and triiodothyronine (T3), i.e., merely as a barometer of thyroid function. For example, euthyroidism is defined as normal thyroid function that occurs with normal serum levels of TSH and T4. It has been assumed that TSH and serum levels of T4 have an inverse linear relationship based on classical feedback loops, and that this relationship is a reliable indicator of the sufficiency of thyrotropic regulation of metabolism.

FIG. 8.9  Production of thyroid hormones within the follicular cells of the thyroid gland. See text for details. (Illustration by Mikael Häggström [CC0] from Wikimedia Commons.)

Thyrotropic axis Chapter | 8  115

There are a sufficient number of anomalies to this assumption that raise questions about its validity. For example, sick euthyroid syndrome is defined as a clinical condition with normal thyroid function and a normal TSH levels but low serum T4 and T3.61 Subclinical hypothyroidism is a condition in which there is a functional hypothyroid state based on an elevated serum TSH, but a normal serum T4.62, 63 Subclinical hyperthyroidism is a functional hyperthyroid state based on a serum TSH value below the normal limit, but normal T4.63 Finally, patients with normal serum levels of TSH, T4, and T3 may presents with symptoms consistent with hypo- or hyperthyroidism but will be regarded as euthyroid and not treated. Furthermore, patients on thyroid replacement therapy with normal TSH may remain symptomatic.64 More recent studies demonstrated that serum TSH lacks a log-linear relationship to thyroid output of free T4 (fT4) and free T3 (fT3). Hoermann et al. in their evaluation of 3223 untreated patients referred for thyroid testing found poor correlation (R2 =0.236) between TSH and fT4. For example, a serum TSH of 1.0 mU/L (0.4–4.1 mU/L) was associated with an fT4 anywhere between 4 and 28 pmol/L (9.5–25 pmol/L). Conversely, an fT4 of 14.5 pmol/L was associated with TSH between 0.1 and 100 mU/L.65 According to a review of studies published through 2009, the use of TSH as a diagnostic test for hypothyroidism was found to be unsubstantiated according to the standard scientific criteria of diagnostic accuracy: (1) criterion standards, (2) determination of reference interval independently of test subjects and (3) evaluation of the test in a valid target population.66 From the Endobiogenic perspective, serum levels of TSH only reflect the responsiveness of the thyroid to stimulation without determining the final degree of metabolic efficiency of T4 or T3. What is meant by metabolic efficiency is the final functional effect of thyroid hormones. A significant fallacy of the current medical model is the continued assumption of a linear correlation between the quantitative serum levels of free T4 and free T3 and their metabolic effects. The existence of cellular mechanisms of activators and inhibitors of thyroid hormone activity within cells, and the role of free T3 in promoting activators argues strongly against this assumption.67 In addition, the degree to which thyroid catabolic activity has been adapted to anabolic demands from estrogens and in anticipation of somatotropic growth factors must be considered when evaluating the totality of thyrotropic integration.

Nonclassical mechanisms TSH has a number of extrathyroid relationships and functions independent of T4 or T3. TSH receptors are found in divergent tissues throughout the body, from the adrenals to the thymus.59, 68 In addition, TSH plays a fundamental role in the regulation of cell growth. A significant contribution of Dr. Duraffourd was to perceive and conceptualize the primary physiologic actions of TSH are extrathyrotropic, rooted in regulation of cell growth and death. Thus, may

pathophysiologic conditions and disorders can also be related to disproportionality of TSH action in relationship to other endocrine and cellular factors. As we discussed in Chapter 7 under the section on FSH, there are methodological limitations in research for which some observations made by Dr. Duraffourd cannot be definitively proven and thus remain conceptual or theoretical considerations.

Cellular Physiology: TSH favors cell formation and growth. The higher the serum TSH is, the more it favors the growth. Key to this idea in the theory of Endobiogeny, is the appeal of estrogens to increasing the release of TSH from the pituitary that is related to a higher serum TSH level. This appears to be mediated by substance P.69 Recall that estrogens favor the activity of the nucleus and the construction of cellular structures such as organelles.70, 71 In turn, TSH compliments estrogen activity by qualifying, or, modifying the intensity of cellular growth factors such as insulin-like growth factor and vascular endothelial growth factor.72, 73 In this way, the effects of estrogens are complimented, amplified, and synergized. While this effect has been primarily studied in thyroid cancer,74 we extrapolate the observation of TSH cells being present on nearly every cell type and tissue in the body, to infer a general constitutive action of TSH on growth. This all reflects “first loop” activity that lays the foundations for growth in the second loop. Along with other factors, TSH influences a number of key aspects of cell life. According to our theory and as we have observed in clinical practice using the Biology of Functions (Chapter 15), we have concluded that TSH influences along with other factors, the following: ● ● ● ● ● ● ● ●

Apoptosis Necrosis Free radical production Oxidation Reduction Estrogen sensitivity Calcium availability Cellular catabolism

Because TSH promotes anabolic activity before the time of glucose entry, TSH solicits intracellular production and use of amyloid proteins, proportional to its degree of expression and activity.75, 76 It serves as a “bridging” energy between the rapid effects of glucose and the prolonged effects of lipids. According to a theory posited by Dr. Duraffourd, TSH solicits exocrine pancreatic excretion of proteolytic enzymes that break down amyloid proteins and excrete them from cells at a later time.77 Pathophysiology: Accumulation of amyloid proteins due to excess production or insufficient proteolysis places the patient at risk of disorders of amyloidosis. Because of these and the general pro-anabolic activity of TSH, it is

116  The Theory of Endobiogeny

i­mplicated (but never as a sole agent) in a number of disorders (a few are noted for reference and clarity): ● ● ●

Cyst formation78 Mucosal congestion Amyloidosis ● Alzheimer’s disease: βΣ amyloid protein ● Parkinson’s disease: αΣ-synuclein protein ● Huntington’s disease: Huntington protein ● Pancreas: Diabetes mellitus 2: Amylin protein ● Atherosclerosis: Apolipoprotein A1 protein ● Rheumatoid arthritis: Serum amyloid A protein ● Multiple myeloma (systemic amyloid light chain amyloidosis)

We have found from our work using the biology of functions that elevated serum TSH favors hypertrophic disorders and that low serum TSH favors chronic inflammatory conditions, chronic fatigue syndrome, fibromyalgia, and brain fog.

Tissue In general, TSH facilitates the growth of all tissues. TSH is particularly influential in tissues that are rich in estrogen receptors such as muscle and bone.79–81 TSH also influences the rate of fibrosis of tissues according to the theory of Endobiogeny. In summary, TSH has constitutive effects beyond its role in stimulating the thyroid. From a certain perspective, we can consider the stimulation of the thyroid as simply a necessary activity to support its pro-anabolic activity, which is its comprehensive function. After all, TSH’s molecular structure as a glycoprotein shares 50% homology with FSH and LH,59 and 0% homology with TRH, T4, T3, parathyroid hormone (PTH), or calcitonin.

The general purpose of the ensemble of peripheral hormones is to assure cellular energy and the mobilization, distribution, and utilization of lipids and calcium from exogenous and endogenous sources.

Introduction to the thyroid gland The role of the thyroid is in furnishing the entire organism with its required energy. This energy is a functional energy of structure, dedicated to endocrinometabolic and endocrinotissular activity. It is not a functional energy of movement. The thyroid produces three hormones: T4, T3, and calcitonin.58 The interthyroid production of T4:T3 is approximately 14:1.82 Thyroid hormones have high affinity for their binding proteins. Most are bound to thyroglobulin (70%) with a portion bound to transthyretin (15%) or albumin (15%). Most T3 is produced outside of the thyroid gland by the removal of one iodine molecule from T4. This process is stimulated by TRH primarily in liver, and also in the hypothalamus and pituitary to maintain negative feedback on central hormones. More than 99% of thyroid hormones circulate bound. Of the free hormones, the ratio of T4:T3 is 5:1. Furthermore, cells are several-fold more sensitive to T3 than T4, in part because of T3’s role in promoting co-regulators of T4 and T3 action within cells.67 As mentioned in the introduction to the thyrotropic axis, it has a particular tropism for ectodermal tissue, particularly neuronal development. It is excessively reductionist to attribute this complex regulation of the development and growth of the CNS to a single hormone within the axis because it is the ensemble of hormones that initiates, sustains, and finalizes ectodermal growth.

Thyroxin (T4)

Introduction to the peripheral glands of the thyrotropic axis

Composition: Iodinated polypeptide Regulation (Fig. 8.10)

The peripheral glands of the thyrotropic axis include the thyroid gland, the parathyroid glands, thymus, skin, liver, and kidneys (Table 8.5). The first loop hormones are catabolic. The second loop hormones are pro-anabolic, similar to the corticotropic axis.

●

●

Stimulation ● Estrogens ● TSH Regulation: Progesterone (delays, then favors release)

TABLE 8.5  General overview of origin and activity of peripheral thyroid hormones Gland/organ

First loop

Second loop

Thyroid

Thyroxin (T4)

Tri-iodothyronine (T3) calcitonin

Skin, liver, kidney

Vitamin D

Vitamin D

Parathyroid

Parathyroid hormone

Thymus

General

T-lymphocyte maturation

Thyrotropic axis Chapter | 8  117

FIG.  8.10  Regulation of T4 production. See text for details. Red arrow, stimulates; green broken arrow, regulates. (© 2015 Systems Biology Research Group.)

FIG. 8.11  T3 production. See text for details. Red arrow, stimulates. (© 2015 Systems Biology Research Group.)

Triidothyronine (T3) Purpose: T4 is the primary catabolic hormone of the thyrotropic axis. It functions primarily in the first loop. It affects both structuro-function (ATP) and function (adrenaline) energy.

Mechanisms and actions The sum total effect of T4 is the increase in the basal metabolic rate of the organism by sensibilization of central and peripheral amines: dopamine, noradrenaline, and adrenaline,83 and the logic of the use of beta-blockers in thyrotoxicosis.84 Thyroxine also stimulates the liberation of free fatty acids85, 86 and calcium.87, 88 The net effects on adaptation and the functioning of the organism can be summarized as: 1. Sensibilization of catecholamines: a. Motricity of all hollow organs and muscles b. Carbohydrates: hyperglycemia by glycogenolysis 2. Lipolysis: free fatty acids for durable energy ATP production 3. Osteoclasty: liberation of calcium to augment the rate of calcium-depending plasma and cellular enzymatic functions Some clinical implications of the effects of T4 are listed in Table 8.6.

TABLE 8.6  Clinical implications of T4 activity Effect

General

Excessive

Low

Thermogenic

Heat regulation between interior and exterior

Heat intolerance

Cold intolerance

Hair growth

Growth and density of distribution

Increased growth of hair Increased density of hair

Thinning of hair (particularly eyebrows) Diminished rate of growth

Vocal cords

Timbre of voice

Clear

Warble

Composition: Iodinated peptide Regulation (Fig. 8.11) ●

Stimulation ● Progesterone ● TRH: Conversion from T4

Purpose: The purpose of T3 is to facilitate the oxidative metabolism of the cell and thus the general functional energy of structure. Actions and mechanism: The majority of T3 is converted outside the thyroid from circulating T4.89 T3 plays an important role in determining the general effects of T4 and T3 within cells through the modulation of coregulator (repressors and activators) of secondary intracellular actions.67 T3 has genomic affects and nongenomic effects that regulate various aspects of oxidative metabolism, which is the most efficient manner of production of ATP.90 1. Carbohydrates a. Upregulates the number of insulin receptors and entry of glucose b. Increases membrane fluidity (via thermogenesis) and the passive diffusion of carbohydrates 2. Oxidation of carbohydrates a. Upregulates the number of enzymes related to glucose oxidation b. Upregulates the general rate of glucose oxidation 3. Oxygen a. Upregulates the intake of oxygen b. Upregulates the consumption of oxygen 4. Cellular respiration a. Upregulates the rate of oxidative phosphorylation within the mitochondria and hence the rate of ATP production Excessive T3 results in cold sensitivity because the heat of the body is interiorized. Insufficient T3 favors low oxidative states, recurrent infections, and other related disorders.

Parathyroid hormone (PTH) Location: Parathyroid gland Composition: Polypeptide

118  The Theory of Endobiogeny

Regulation: ●

●

the energy for anabolism (especially bone). It counteracts the osteolytic activity of T4 and PTH. The net effects of calcitonin are the lowering of serum calcium in four ways91:

Stimulation ● Diminishing serum calcium levels ● TSH Inhibition ● TRH ● T3 ● Vitamin D3

Purpose: PTH is a first loop hormone that aids in the preparation of anabolism by increasing serum calcium levels Actions and mechanism: The actions of PTH complement that of T4 and are antagonistic to T3 and calcitonin. To be clear, though, the antagonism to calcitonin does not mean PTH opposes it in every way. For example, they both lower serum phosphorous (Table  8.7). In summary, PTH has four qualities91: 1. Antianabolic: Blocks osteoblasty, preventing the deposition of calcium in bone 2. Pro-catabolic: Indirect: Inhibits osteoblasty, stimulates osteoclasty 3. Pro-absorptive: Indirect: stimulates renal conversion of vitamin D to active form → intestinal calcium absorption 4. Pro-resorptive: Increases renal urinary resorption of calcium (and magnesium), and urinary excretion of phosphorus, which allows for more efficient absorption and circulation of calcium.

1. Anabolic/storage: Stimulates osteoblasty, placing calcium in reserve in the bones to augment buffering capacity 2. Anticatabolic: Inhibits osteoclasty 3. Antiabsorptive: Blocks intestinal calcium absorption 4. Antiresorptive: Blocks renal calcium resorption and favors its excretion with phosphorus

Calcitriol (Vitamin D3) Composition: Steroid. Vitamin D is a cholesterol-derived hormone. It goes through a series of conversions first in the skin, then in the liver, and then in the kidney, where it becomes 1,25 dihydroxy Vitamin D3 (D3). The majority of D3 (80%–90%) is derived from dermal ultraviolet light exposure92, which makes sunlight a nutrient for the organism and links D3 to circadian rhythms, including to melatonin and TRH. It witnesses the permanent linkage to cosmobiologic activity for the life of the organism. The remainder of vitamin D is obtained through diet, mainly from mushrooms93 and fatty cold-water fish.94 Smaller contributions are made from full fat cottage cheese and meat.95 Regulation: ●

Calcitonin Location: Thyroid, parafollicular cells. Composition: Polypeptide Regulation: ●

●

Stimulation ● TRH ● Rising serum calcium

Purpose: Calcitonin regulates calcium storage and utilization. Actions and mechanism: Calcitonin is a second loop hormone. It complements the activity of T3 in providing

Stimulation ● Diminishing serum calcium levels ● TRH ● PTH (stimulates conversion of the inactive to active form) ● Prolactin Inhibition ● Cortisol ● TSH ● T4 ● Calcitonin

Purpose: D3 is a constitutional regulator of adaptation by complimenting the effects of thyrotropic hormones. Thus, it works in both loops as well as in basal metabolic

TABLE 8.7  Summary of peripheral thyrotropic hormone effects on mineral ecology Hormone

Ca, serum

Phos, serum

Mg, serum

Resorption, intestines

Resorption, kidney

Vit. D production

Osteoclasty

Osteoblasty

PTH

↑

↓

↑

↑

↑

↑

↑

↓

Vitamin D3

↑

↑

↑

↑

–

Calcitonin

↓

↓

↓

↓

↓

↑ ↓

↑

Thyrotropic axis Chapter | 8  119

activity. It has three main areas of regulation: growth, immunity, and calcium management. Actions and mechanism: Like other steroid hormones, D3 is highly bound to its binding protein, D binding protein (DPB) with 99.96% affinity. Vitamin D receptor (VDR) is diffusely expressed throughout the body, not only in areas that regulate calcium uptake and utilization (kidney, intestines, bone) but also on immune cells, bone marrow, adipocytes, and skeletal muscle.96 D3 has a series of genomic actions related to each of the three areas that it regulates mediated by a retinoid receptor and various regulating elements. The actions can be to stimulate or suppress the expression of genes related to growth and/or calcium management. For example, with respect to calcium regulation, it upregulates the production of calcium-binding protein, which allows for more calcium to be absorbed and transported from the ­intestines.96 The primary nongenomic effect of D3 is to increase the immediate cellular availability of calcium from membrane channel-mediated rapid influx of calcium or release of intracellular stored calcium. A cursory review of the effects of D3 is listed along with the hormone that it compliments

Calcium regulation With respect to calcium regulation and peripheral thyrotropic hormones, D3 plays a role analogous to that of progesterone within the gonadotropic axis. D3 has agonist, antagonist, and unique actions vis-à-vis PTH and calcitonin. D3 compliments the actions of PTH with respect to increases in serum calcium, but opposes its osteolytic activity. PTH stimulates production of D3 and D3 inhibits PTH. D3 compliments the actions of calcitonin with respect to bone production and calcium storage, but opposes it in all other ways. Finally, D3 opposed both PTH and calcitonin in its increase of serum phosphate levels. A summary of action is presented in Table 8.7. According to the theory of Endobiogeny, D3 is a hormone whose exogenous supplementation should be offered after careful consideration of all the areas of function that it regulates: growth, immunity, and calcium regulation. Serum levels of D3 are not indicative of a need for replacement without a full evaluation of the Endobiogenic terrain of the individual throughout all seasons, in basal and adaptive metabolic requirements (Fig. 8.12). Primary neuroendocrine interactions in adaptive metabolism and calcium regulation are summarized in Fig. 8.13.

Growth: TRH, TSH D3 stimulates the pancreas to produce more insulin, which compliments TRH’s actions on the endocrine pancreas and cellular hyperplasia. D3’s main genomic effect is the production of osteopontin, which acts as its primary mediator of anchorage-independent cell growth. Epidemiologic studies suggest that high-normal serum D3 has an inverse relationship with the development of breast cancer but are inconclusive for prostate and colorectal cancers.96 The beneficial relationship between serum vitamin D and cancer may be due to sunlight exposure rather than vitamin D, and the tendency to have healthier diets and increased frequency of exercise in areas with greater annual exposure to sunlight. In vitro studies indicate tissue-dependent effects, with D3 favoring the growth of some cells (osteopontin) and reducing growth of other cells. The latter is mediated by E-cadherin through nongenomic actions of D3.96 D3 as a steroid has permissive effects on various aspects of gonadal function across the fertility cycle in men and women.92 These include: steroidogenesis of gonadic hormones in men and women, folliculogenesis in women and spermatogenesis in men, implantation of a fertilized ovum, and influence on placental endocrine output.

Immunity: TRH, TSH, T3, thymus D3 stimulates lymphocytes, monocytes, and innate immunity, which facilitate the effects of the thyrotropic axis on immunity. It inhibits adaptive immunity.96

FIG. 8.12  Basal regulation of calcium by thyrotropic hormones. See text for details. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

FIG. 8.13  Adaptive regulation of calcium. In addition to the peripheral thyrotropic hormones calcitonin, vitamin D, and parathyroid hormone (PTH), central factors are involved since it occurs during the adaptation syndromes. Alpha stimulates TRH, which stimulates a rise in serum ­calcium in the first loop with vitamin D and PTH, and a restoration of calcium to bone with calcitonin. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

120  The Theory of Endobiogeny

Thymus Composition: Organ containing T-lymphocytes. Regulation (Fig. 8.14) ●

● ●

Stimulation ● αΣ (general metabolism) ● ACTH (maturation of lymphocytes) ● TSH (excretion of lymphocytes) Blocks release: supraphysiologic αΣ Inhibition: cortisol

Purpose: thymus is the cross road of identity: the integrity and integration of intangible self (awareness) with the physical self and the differentiation of this self, versus the nonself. thymus integrates adaptive immunity, neurovegetative, and endocrine activity at every level and every axis be it hypothalamic, pituitary (anterior and posterior), and all peripheral endocrine organs. Thus, the thymus can be considered to be a gage of the degree of integrity of the adaptive capacity of the organism against internal and external aggressions. It also reflects the organism’s ability to know the self and support it, neither attacking and negating it (i.e., autoimmunity), nor debasing and failing to defend it (i.e., hypoimmunity, depression, etc.). Mechanism: The effects of the thyrotropic axis are complex with respect to immunity (cf. The Theory of Endobiogeny, Volume 2, Chapter 3), thus it is presented at the end of this discussion within the context of the thymus. It is crucial to understand that the thyrotropic axis has a fundamental role in the formation and solicitation of the immune system and thus plays a role in allergies, autoimmunity, and cancer. The axis regulates lymphocytes and lymphoid tissue. Lymphocytes are generated in the bone marrow but matured in the thymus.97 They are found in circulation as well as in lymphoid tissue. The majority of lymphoid tissue is found in the intestines, as are the majority of lymphocytes.98, 99 There are three subsets of lymphocytes: natural killer (NK), T, and B cells. NK cells are part of the innate immune system. They survey and directly attack viruses

and tumors. T and B cells comprise the adaptive immune system. T cells manage cell-mediated immunity through the secretion of cytokines, regulate the activity of other immune cells, and lyse cells infected by viruses. T cells also play a role in immunoregulation. B cells form antibodies specific to a unique aggressor and retain a memory of the aggressor in the case of future aggression. Lymphocytes in general play a role in cancer surveillance, immunity, and autoimmunity.100 In general, the thyrotropic axis plays a role in the construction and solicitation of immune elements, including IgE: 1. TRH a. Central: Relaunches histamine b. Peripheral: i. Produced locally by immune cells that stimulates T-lymphocytes, which stimulate B cell, which in turn stimulate IgE which results in allergies ii. Stimulates endocrine pancreas 2. TSH a. Adapts, enhances action of adrenal cortex indirectly: augmentation of lymphocytes b. Stimulates lymphocyte activity c. Stimulates exocrine pancreas for the fabrication of proteinaceous products d. Stimulation of B and T lymphocytes, monocytes and NK cells e. Monocytes and lymphocytes synthesize TSH, which stimulates IL-2 production of phagocytotic activity f. Bone marrow responds to TSH, which leads to increased cytokine production 3. T3 a. Directly effects lymphocytes and monocytes through nuclear receptors. b. Lymphocytes: conversion of T4 to T3 c. Increased oxidative burst capacity, destruction of pathogenic organisms after opsonization Because of its role in the maturation of T-lymphocytes, the thymus is within the thyrotropic axis and thus permanently linked to the adaptation syndromes in which the axis is implicated. The release of lymphocytes is stimulated by ACTH to defend the organism, and diminished by cortisol (cf. corticotropic axis) to prevent a dysregulated immune response. Because of D3’s influence on immunity, lymphocytes in particular D3 is also implicated in the functioning of the thymus.

Integrating the thyrotropic axis FIG.  8.14  Thymus regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits; black broken arrow, blocks release. (© 2015 Systems Biology Research Group.)

Within its own vertical functioning, the thyrotropic axis is catabolic in the first loop and pro-anabolic in the second loop. The general functioning is summarized in Fig. 8.15.

Thyrotropic axis Chapter | 8  121

FIG. 8.15  Regulation of the thyrotropic axis. See text for details. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

First loop: 1. Central: a. TRH stimulates TSH b. TSH stimulates the thyroid, parathyroid and thymus glands 2. Peripheral a. Thyroid: T4 production and excretion: i. Lipolysis: free fatty acids for durable material for ATP production ii. Osteoclasty: calcium as metabolic catalyst b. Parathyroid: Parathyroid hormone i. Increases serum calcium ii. Stimulates vitamin D to counteract bone-­wasting activity of T4 and PTH c. Thymus: maturation of T-lymphocytes (excretion by ACTH) Second loop: 1. Central: TRH a. T3: by converting T4, primarily in liver b. Calcitonin 2. Peripheral a. T3: Preanabolic: Increases rate of ATP production to augment metabolism for anabolic recovery after catabolism b. Calcitonin: Pro-anabolic: restores calcium to bone, favors osteoblasty c. Vitamin D i. Metabolic regulator: 1. Restores calcium and phosphorous stores 2. Anti- and pro-anabolic functions with respect to growth ii. Immunity 1. Supports the immune function initiated in the first loop by TSH and thymus

Conclusions The thyrotropic axis is a primarily catabolic axis that favors anabolism with TSH and peripheral second loop hormones. The key to understanding the axis is the relationship of TRH to TSH, which is the relationship of adenosis to amylosis, imagination to planning, or potential to possibility. The grand purpose of the axis is to manage the creation of neurologic structures and calibrate their function in the service of adaptation. The axis affects all three types of metabolites and numerous minerals related to adaptation and energy production.

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59.

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76.

77.

Kronenberg  HM, eds. Williams Textbook of Endocrinology. Elsevier; 2016:334–368. [chapter 11]. Sarapura  VD, Samuel  MH. Thyroid stimulating hormone. In: Melmed  S, ed. The Pituitary. 4th ed.Academic Press; 2017:163– 201. [chapter 6]. Nussey S, Whitehead S. Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. McMahon  GT. Sick euthyroid syndrome. In: Mushlin  SB, Green  IIHL, eds. Decision Making in Medicine. 3rd ed.Mosby; 2010:148–149. Cooper  DS, Biondi  B. Subclinical thyroid disease. Lancet. 2012;379(9821):1142–1154. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291(2):228–238. Peterson SJ, McAninch EA, Bianco AC. Is a normal TSH synonymous with "euthyroidism" in levothyroxine monotherapy? J Clin Endocrinol Metab. 2016;101(12):4964–4973. Hoermann R, Eckl W, Hoermann C, Larisch R. Complex relationship between free thyroxine and TSH in the regulation of thyroid function. Eur J Endocrinol. 2010;162(6):1123–1129. Wheatland  R. Should the TSH test be utilized in the diagnostic confirmation of suspected hypothyroidism? Med Hypotheses. 2010;75(5):458–463. Mendoza  A, Hollenberg  AN. New insights into thyroid hormone action. Pharmacol Ther. 2017;173:135–145. Dutton  CM, Joba  W, Spitzweg  C, Heufelder  AE, Bahn  RS. Thyrotropin receptor expression in adrenal, kidney, and thymus. Thyroid. 1997;7(6):879–884. Arisawa M, Makino T, McCann SM, Iizuka R. Effect of estrogen on the response of thyroid stimulating hormone to substance P in rats. Endocrinol Jpn. 1989;36(6):899–903. Cui  J, Shen  Y, Li  R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med. 2013;19(3):197–209. Eyster KM. The estrogen receptors: an overview from different perspectives. Methods Mol Biol. 2016;1366:1–10. Hoffmann  S, Hofbauer  LC, Scharrenbach  V, et  al. Thyrotropin (TSH)-induced production of vascular endothelial growth factor in thyroid cancer cells in vitro: evaluation of TSH signal transduction and of angiogenesis-stimulating growth factors. J Clin Endocrinol Metab. 2004;89(12):6139–6145. Krieger  CC, Morgan  SJ, Neumann  S, Gershengorn  MC. Thyroid stimulating hormone (TSH)/insulin-like growth factor 1 (IGF1) receptor cross-talk in human cells. Curr Opin Endocr Metab Res. 2018;2:29–33. Duh QY, Grossman RF. Thyroid growth factors, signal transduction pathways, and oncogenes. Surg Clin North Am. 1995;75(3):421–437. Pietrzik CU, Hoffmann J, Stober K, et al. From differentiation to proliferation: the secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells. Proc Natl Acad Sci U S A. 1998;95(4):1770–1775. Graebert  KS, Popp  GM, Kehle  T, Herzog  V. Regulated O-glycosylation of the Alzheimer beta-A4 amyloid precursor protein in thyrocytes. Eur J Cell Biol. 1995;66(1):39–46. Graebert  KS, Lemansky  P, Kehle  T, Herzog  V. Localization and regulated release of Alzheimer amyloid precursor-like protein in thyrocytes. Lab Investig. 1995;72(5):513–523.

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78. Benetti-Pinto  CL, Piccolo  VB, Yela  DA, Garmes  H. Thyroidstimulating hormone and insulin resistance: their association with polycystic ovary syndrome without overt hypothyroidism. Rev Bras Ginecol Obstet. 2017;. 79. Agrawal M, Zhu G, Sun L, Zaidi M, Iqbal J. The role of FSH and TSH in bone loss and its clinical relevance. Curr Osteoporos Rep. 2010;8(4):205–211. 80. Grimnes  G, Emaus  N, Joakimsen  RM, Figenschau  Y, Jorde  R. The relationship between serum TSH and bone mineral density in men and postmenopausal women: the Tromso study. Thyroid. 2008;18(11):1147–1155. 81. Kim  DJ, Khang  YH, Koh  JM, Shong  YK, Kim  GS. Low normal TSH levels are associated with low bone mineral density in healthy postmenopausal women. Clin Endocrinol. 2006;64(1):86–90. 82. Pilo  A, Iervasi  G, Vitek  F, Ferdeghini  M, Cazzuola  F, Bianchi  R. Thyroidal and peripheral production of 3,5,3'-triiodothyronine in humans by multicompartmental analysis. Am J Phys. 1990;258(4 Pt 1):E715–E726. 83. Engstrom  G, Svensson  TH, Waldeck  B. Thyroxine and brain catecholamines: increased transmitter synthesis and increased receptor sensitivity. Brain Res. 1974;77(3):471–483. 84. Tagami  T, Yambe  Y, Tanaka  T, et  al. Short-term effects of beta-­ adrenergic antagonists and methimazole in new-onset thyrotoxicosis caused by Graves' disease. Intern Med. 2012;51(17):2285–2290. 85. Swierczek  J. Interrelationship between thyroxine and adrenaline in stimulation of lipolysis in the rat. Acta Physiol Pol. 1974;25(5):453–460. 86. Mosinger B. Regulation of lipolysis in adipose tissue homogenate: activating effect of catecholamines, thyroxine, serotonin, EDTA, pyrophosphate and other factors in unsupplemented homogenate. Arch Int Physiol Biochim. 1972;80(1):79–95. 87. Milhaud G, Tsien-Ming L, Moukhtar MS. Synergism and antagonism of thyroxine, parathormone and thyrocalcitonin on calcemia and phosphatemia. C R Acad Sci Hebd Seances Acad Sci D. 1967;264(6):846–849. 88. High  WB, Capen  CC, Black  HE. The effects of 1,25-­dihydroxycholecalciferol, parathyroid hormone, and thyroxine on trabecular bone remodeling in adult dogs. A histomorphometric study. Am J Pathol. 1981;105(3):279–287.

89. Bianco  AC, Salvatore  D, Gereben  B, Berry  MJ, Larsen  PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev. 2002;23(1):38–89. 90. Dorsa KK, Santos MV, Silva MR. Enhancing T3 and cAMP responsive gene participation in the thermogenic regulation of fuel oxidation pathways. Arq Bras Endocrinol Metabol. 2010;54(4):381–389. 91. Bringhurst FR, Demay MB, Kronenberg HM. Hormones and disorders of mineral metabolism. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg  HM, eds. Williams Textbook of Endocrinology. 2016:489–555. Elsevier. [chapter 28]. 92. Lerchbaum E, Obermayer-Pietsch B. Vitamin D and fertility: a systematic review. Eur J Endocrinol. 2012;166(5):765–778. 93. Keegan  RJ, Lu  Z, Bogusz  JM, Williams  JE, Holick  MF. Photobiology of vitamin D in mushrooms and its bioavailability in humans. Dermatoendocrinol. 2013;5(1):165–176. 94. Loznjak  P, Jakobsen  J. Stability of vitamin D3 and vitamin D2 in oil, fish and mushrooms after household cooking. Food Chem. 2018;254:144–149. 95. McDonnell  SL, French  CB, Heaney  RP. Quantifying the food sources of basal vitamin D input. J Steroid Biochem Mol Biol. 2014;144(Pt A):149–151. 96. Campbell FC, Xu H, El-Tanani M, Crowe P, Bingham V. The yin and yang of vitamin D receptor (VDR) signaling in neoplastic progression: operational networks and tissue-specific growth control. Biochem Pharmacol. 2010;79(1):1–9. 97. Moticka EJ. The thymus in lymphocyte maturation. In: Moticka EJ, ed. A Historical Perspective on Evidence-Based Immunology. 2016:69–74. [chapter 9]. 98. Mowat AM, Viney JL. The anatomical basis of intestinal immunity. Immunol Rev. 1997;156:145–166. 99. Banerjee  M, Sanderson  JD, Spencer  J, Dunn-Walters  DK. Immunohistochemical analysis of ageing human B and T cell populations reveals an age-related decline of CD8 T cells in spleen but not gut-associated lymphoid tissue (GALT). Mech Ageing Dev. 2000;115(1–2):85–99. 100. Actor  JK. T-lymphocytes: ringleaders of adaptive immune function. In: Actor JK, ed. Introductory Immunology. 2nd ed.Academic Press; 2019:45–62. [chapter 4].

Chapter 9

Somatotropic axis Introduction to the axis The somatotropic axis is the fourth and final endocrine axis. It is an anabolic axis with two catabolic functions. The somatotropic axis manages nutrients and structure and plays a role in energy and adaptation. ●

● ●

●

●

Nutrients: Extraction, processing, availability, distribution, and timing of entry Storage: Carbohydrates and lipids Architecture: Designs cells into a coherent three-­ dimensional structure Energy: Mobilizes glucose and lipids for ATP production Adaptation: turns and ends the loops of the general adaptation syndrome of Endobiogeny

The somatotropic axis is linked to the embryonic endoderm, the origin of the entire alimentary tract (except mouth and anus), liver, gallbladder, stomach, and pancreas. It also includes the follicular cells of the thyroid where T4 and T3 are produced, and the lungs.1 The pituitary somatotropic hormones maintain a constant structuro-functional and functional relationship with the liver and pancreas, which is the major site of their endocrine activity. In the general plan of growth, the somatotropic axis participates in the endocrinotissular development of all tissues and organs, not just those of endodermal origin. The somatotropic axis has a number of unique features compared to the other axes: 1. Two hypothalamic hormones and two pituitary hormones 2. Majority of anterior pituitary are dedicated to somatotrophins growth hormone (GH) and prolactin (PL) 3. Sole axis where its pituitary hormone (PL) is inhibited by its hypothalamic counterpart (somatostatin (SS)) and stimulated an extra-axial hormone (thyrotropic TRH) 4. Sole axis manages the apportionment and entry of nutrients (Fig. 9.1) 5. Sole anabolic axis with a directly catabolic function 6. Largest number of peripheral hormones 7. Determines the final appearance and integrity of structure 8. Ensures starter energy to initiate adaptation 9. Ensures progression and completion of adaptation The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00009-4 © 2019 Elsevier Inc. All rights reserved.

There are 10 major somatotropic hormones, seven of which will be the focus of this chapter. They have the most fundamental and systemic roles in global physiology. Keep in mind that there are numerous hormones related to digestion produced locally within the GI tract. 1. Central a. Hypothalamic i. GHRH: Growth hormone-releasing hormone ii. SS: Somatostatin b. Pituitary i. GH: Growth hormone ii. PL: Prolactin 2. Peripheral a. Pancreas, endocrine i. Glucagon ii. Insulin b. Liver i. Insulin-like growth factor-1 (IGF-1) ii. Insulin-like growth factor-2 (IGF-2) (not discussed here) c. Stomach/small intestines: Ghrelin (not discussed here) d. Adipocytes: Leptin (not discussed here)

Introduction to the hypothalamic hormones The hypothalamic hormones of the somatotropic axis are two, which is unique amongst the endocrine axes. They are GHRH and SS. The general purpose of the hypothalamic hormones is to initiate and end somatotropic function and all general endocrine function by finalizing anabolism. As one will note below, there are far more safeguards on inhibiting GHRH to prevent dysregulated growth and death from expansion than stimulating factors.

GHRH: Growth hormone-releasing hormone Location: Arcuate nucleus of the hypothalamus Composition: Polypeptide Regulation (Fig. 9.2) ●

Stimulation: TRH 125

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Corticotropic

Gonadotropic

Thyrotropic

Mobilization

Initiation

Energy

of metabolites

of metabolism

Lipids Carbohydrates

of metabolites

Somatotropic

Lipids

Proteins

Proteins

Mobilization

from metabolites

Carbohydrates

Carbohydrates

Cell interior Aminos, carbs, lipids, electrolytes

Delivery of metabolites

Energy

Completion of metabolism Cell exterior

FIG. 9.1  Role of the somatotropic axis in nutrient management. What the catabolic corticotropic and thyrotropic axes mobilized and the anabolic gonadotropic axis initiated in anabolism, the somatotropic axis completes. (© 2015 Systems Biology Research Group.)

FIG. 9.2  GHRH regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.) ●

Inhibition ● TSH ● Somatostatin (SS) ● GH ● Prolactin (PL) ● Insulin

Purpose: GHRH regulates rhythmic culling and building. This occurs in both central and peripheral metabolism and implicates visceral organs. Mechanisms and actions:GHRH is a first loop hormone. It operates in a rhythmic fashion to stimulate GH to initiate the peripheral apportionment, timing, and entry of nutrients for growth.2, 3 GHRH stimulates secretion and excretion of GH by exocytosis from the pituitary.3 In the central physiology, GHRH’s method of culling and consolidation is the installation of non-REM sleep in the first half of the night during a pause in SS.4, 5 Nocturnal physiology is the predominant time of anabolism and GHRH helps install this condition to favor the general anabolic terrain. The stimulation of GH will favor

FIG.  9.3  Role of GHRH, GH, and TRH in memory and dreams. See text for details. Red arrow, stimulates; purple arrow, facilitates. (© 2015 Systems Biology Research Group.)

REM sleep in the milieu of GHRH activity.4 GHRH consolidates declarative-dependent memories in the hippocampus (Fig. 9.3). Declarative memories are long-term memory of facts and knowledge.6 GHRH and GH create a milieu in which memories can be reviewed and reassessed during REM (i.e., dream state), then consolidated for long-term access and retrieval. As noted above, TRH is the primary regulator of GHRH and thus a contributor to the expression of GH. Within the central metabolism the thyro-somatotropic coupling adds two dimensions to dream life: evanescent vividness of and long-term efficacy in the shaping of knowledge. The intensity and realism that TRH brings to a dream provides the emotional charge that favors conscious recall of what has been dreamed and hence learned (Fig. 9.3).

Somatostatin (SS) Location: SS has both central and local peripheral locations of production.7 ●

Central: Hypothalamus, ventromedial nucleus

Somatotropic axis Chapter | 9  127

●

Peripheral: Digestive organs: Stomach, intestines endocrine pancreas: δ-cells of Langerhans

Introduction to the pituitary hormones

The true managers of peripheral somatotropic activity are the pituitary hormones: GH and PL. GH and PL are directly involved in the growth of cells and the storage of nutrients and stimulate the peripheral organs that further manage ● Stimulation these functions. GH and PL have agonist-antagonist func● GH tion that is competitive and additive in nature. The chrono● IGF-1 logic relationship of GH and PL is key to the regulation ● Prolactin (PL) of both somatotropic function and endocrine progression ● Insulin throughout the two loops. ● Inhibition There are a number of unique features of the pituitary ● Cortisol somatotropic hormones. They are two in number like the Purpose: SS safeguards the organism from self-­ pituitary gonadotropic hormones FSH and LH. Such is the consumption by dysregulated growth. It inhibits all thyro- importance of GH and PL, that they have dedicated and somatotropic activities and hence second loop gonadotropic completely separate sections of the pituitary that stimulate activity.8 them: somatotrophs and lactotrophs, respectively. GH and PL belong to a different class of hormones than FSH and LH (which are in the same class as TSH and hCG). Finally, Mechanisms and actions PL is the only hormone that is not stimulated by an interCentral axial hypothalamic hormone such as GHRH or SS. It is also SS is released into the anterior pituitary where it inhibits the only hormone that has an intra-axial hypothalamic horthree hormones: TSH, GH (blocks GHRH stimulation), and mone that only inhibits it (SS) and does not stimulate it. PL.9 The inhibition of PL has two consequences: the indirect completion of the second loop of gonadotropic activity (cf. PL below) and the direct sealing of the growth cycle by Growth hormone (GH) discontinuing the excretion of insulin. Location: Anterior pituitary somatotrophs Composition: Polypeptide Peripheral Regulation (Fig. 9.5)9 In the periphery, SS has local paracrine effects. It inhibits ● Stimulation the following hormones in the following locations within ● αΣ the viscera7: ● GHRH Composition: Polypeptide Regulation (Fig. 9.4)

Stomach: Gastrin ● Intestines: Cholecystokinin (CCK), secretin, motilin, vasoactive intestinal peptide (VIP), gastrointestinal peptide (GIP), enteroglucagon ● Pancreas, exocrine: Excretion of digestive enzymes ● Pancreas, endocrine: Glucagon, insulin The net effect of SS in the periphery is to diminish the uptake of exogenous sources of nutrients that would demand the perpetuation of both first and second loops of somatotropic hormones. In summary, while SS is an inhibitory hormone it is ultimately pro-anabolic because by closing the time of nutrient entry, it allows cells to anabolize that which has been culled within the interior.

●

●

●

FIG. 9.4  Regulation of somatostatin (SS). See text for details. Red arrow, stimulates; blue arrow, inhibits. (©2015 Systems Biology Research Group.)

Ghrelin Estrogens ● Testosterone ● TSH ● Hypoglycemia ● Fasting ● Intense aerobic exercise Inhibition ● Insulin-like growth factor-1 (IGF-1) ● Insulin ● SS ● Serotonin ● Cortisol ● Hyperglycemia ● Free fatty acids Regulation ● PL ● ACTH (calibrates excretion) ●

●

Purpose: GH is a first loop hormone that ensures the proper availability, quantity, and timing of nutrients for anabolism, and their utilization for the growth of cells and tissues.

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FIG.  9.5  Growth Hormone (GH) regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits; green broken arrow, regulates. (© 2015 Systems Biology Research Group.)

Mechanisms and actions GH plays a seminal role in the regulation of the organism. A well-regulated GH participates in the proper regulation of the entire somatotropic axis, ensuring the proper role of the axis in both structural achievement and efficiency of adaptation in its various syndromes. This crucial role of GH is reflected in the fact that the somatotrophs of the anterior pituitary that produce and store GH take up nearly 50% of the size of an adult pituitary.9 GH has a pulsatile release pattern with six circadian peaks of activity, based on the sum total effects of GHRH agonism and SS antagonism (Fig. 9.6).10 In a larger sense, its pulsatility is indirectly the result of all regulatory factors listed earlier. Ghrelin modifies the effects of GHRH on GH production and release much in the same way as α-MSH

does for ACTH on the adrenal cortex. The half-life of GH is only 20 min, which reflects two important aspects of GH’s role in physiology according to an Endobiogenic reflection regarding integrative physiology. First, its role is relatively short because it sets in motion that which is long via insulinlike growth factor (IGF) activity. Second, the earlier point further emphasizes the importance of both the chronology of the peaks within the endocrine cycle and the importance of the amplitude and duration of the peaks at specific times of the day. The peaks are greatest at night when the majority of anabolism occurs and around mid-day after lunch. GH engages in a number of peripheral and central functions related to growth. However, it is important to appreciate that GH and IGFs are neither the initiators nor final guarantors of growth. They facilitate the designing and lengthening of that which have been initiated by the gonadotropic axis and sustained by the ensemble of hormones. There are two immediate implications to this observation. First, one should not put too much stock in animal studies using knockout mice or clinical trials in which nonpulsatile GH is trialed, because they do not reflect the true dynamic multiendocrine chronobiologic activity of the organism in regulating health and longevity. To wit, studies of people born with deficiencies in the production of GH or IGF or even in anencephaly demonstrate normal fetal growth and variable final adult height (the later in the nonanencephalic subjects only).9 Second, when evaluating delayed or insufficient rate of growth in children, one must have a global system approach. There are at minimum six levels of assessment according to the theory of Endobiogeny:

12

Young men

Plasma GH (mg/L)

Old men 8

4

0 08

12

16

20

00

04

08

Clock time FIG. 9.6  Pulsatile growth hormone (GH) excretion. GH amplitude, sustain, and circadian timing diminish with age (young men: blue line, old men red line). (Reproduced from Copinschi G, Caufriez A. Hormonal circadian rhythms and sleep in aging. In: Encyclopedia of Endocrine Diseases. 2nd ed., Academic Press; 2019: 675–689. © 2019 Elsevier Inc.)

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1. Central and peripheral hormones functional activity across all axes 2. Quantitative rate of metabolism 3. Quantitative and relative rates of catabolism and anabolism 4. Efficiency of digestion, nutrient absorption, and processing 5. Efficiency of endocrine distribution of nutrients 6. Secondary factors that impair levels 1–5, i.e., chronic illness, endocrine disruptors, etc. Absolute quantitative GH deficiency is not as frequently found in growth delay in children as is relatively low GH excretion or altered pulsatility. One must look at the anabolic steroids of the gonadotropic axis as well, which work with somatotropic factors for growth.11 To wit, the quantitative serum measurement of GH as an indicator of GH function has several shortcomings, as we have noted with other pituitary hormones such as FSH. Only, the complexity is greater with GH. GH has numerous isoforms, various isoelectric points, and varying degrees of binding to its binding protein. In addition, there are two types of receptors with various subcellular translational pathways.9 There are varying degrees of IGF-1 output and binding to its protein in circulation, which GH also stimulates. Finally, the efficiency of GH activity requires proper gonadotropic, thyrotropic, and general somatotropic function. GH does not work in a vacuum to produce linear growth! To note, serum GH has variable quantitative levels of expression throughout childhood, peaking in adolescences (Fig.  9.7).9 However, from the Endobiogenic perspective, the sum total effect of the somatotropic axis is fairly constant and significantly elevated throughout childhood relative to adulthood despite the changes in quantitative levels. Recall that the axis as a whole has endocrinometabolic, endocrinotissular, and metabolic effects. It manages the summoning, distribution, and timing of utilization of nutrients

for designing tissues and organs and in adaptation. The sum of these effects is reflected in the biology of functions index “Growth Hormone growth score,” defined as follows: It expresses the resultant level of endocrinometabolic activity of growth hormone. By extension, it evaluates the relative part of the somatotropic axis in the general adaptation syndrome. By extension, it evaluates the relative part of the somatotropic axis in the recruitment and repartitioning of energy be it structural or functional. By extension, it evaluates the relative part of growth hormone be it architectural, evolutive or of maintenance, be it chronologic, functional or from adaptation in the repartitioning of metabolic energy. Christian Duraffourd, unpublished.

Thus, the index is qualitative and relative in nature. It is not measuring the quantitative expression of GH at any particular time of the day. Rather, it expresses the general participation of GH and in effect all of its regulating factors and by extension the global role of the entire somatotropic axis in distributing the elements that contribute to the formation of cells, tissues, and glands and the energy required for them to growth. Fig.9.8 shows unpublished data from the evaluation of children of various ages with normal growth patterns conducted in conjunction with Professor M. Ringdahl of Uppsala University, Sweden.

Peripheral Endocrine GH stimulates the production of insulin-like growth factors (IGFs) primarily in the liver.9 IGFs manage many of the classical effects attributed to GH with respect to the growth of bone, cartilage, and muscle.

Endocrinometabolic

Mean circulating concentration GH

GH installs insulin resistance (IR).12 IR is not a hormone, but an intracellular phenomenon where membrane-bound insulin receptors are blocked from responding to the binding of insulin to its receptors. In this way, GH can assure its metabolic effects. The proper timing of the installation and de-installation of IR optimizes the activities discussed below.

Glucose: Gluconeogenesis

Birth childhood puberty

Adult life

Senescence

FIG.  9.7  Mean circulating growth hormone (GH) throughout phases of life. By quantitative serum measurement, growth hormone peaks in puberty and gradually declines thereafter. (Reproduced from Nussey SS, Whitehead SA. Endocrinology: An Integrated Approach. 1st ed., BIOS Scientific Publishers; 2001. © 2001.)

GH stimulates gluconeogenesis and blocks hepatic uptake of glucose,13 to augment and preserve circulating blood glucose levels, respectively.

Lipids: Lipolysis GH stimulates lipolysis of adipocytes.13 This is the first of two catabolic functions of the somatotropic axis, and

130  The Theory of Endobiogeny

FIG. 9.8  Growth hormone (GH) growth score of Endobiogeny. The index evaluates the effective role of GH in distributing nutrients for cellular growth and energy (cf. text for full definition). It is not related to serum levels of GH which are low in childhood and peak in puberty. The GH growth score correlates with the general predominance of growth throughout childhood and puberty. This suggests that other factors (e.g., insulin-like growth factors, antigrowth factors, and metabolic effects of GH) help maintain the steady effectiveness of GH throughout childhood by amplifying its effects in childhood and moderating it in adolescence. NB: The scale is logarithmic and the value has no units. Adult values of the GH growth score is 200–1500 vs 9000–15,000 for children. (Used with permission of Jean-Claude Lapraz, M Harms Ringdahl; Deceased: Christian Duraffourd, unpublished manuscript.)

r­epresents the sole pituitary hormone in an anabolic axis with catabolic function.

Amino acids GH stimulates the cellular uptake of amino acids throughout all cells, with a special tropism for the synthesis of muscles.13 In the context of vigorous exercise, it favors the production of energy for muscle building from the free fatty acids liberated during lipolysis.

Electrolytes According to the theory of Endobiogeny, GH helps calibrate the quantity of various electrolytes mobilized by the corticotropic and thyrotropic axes based on the relative needs of each cell and tissue and organ, i.e., calcium, phosphorous, and sodium.

Endocrinotissular GH regulates the growth of all organs and tissues in general. In particular, it regulates vertical growth: the lengthening of muscle, bone, and cartilage.13 As mentioned in the general discussion of the axis, GH also has a particular tropism for the integrity and function of the liver and endocrine pancreas. GH regulates cell replication, particularly of chondrocytes and osteocytes.13 This occurs directly and indirectly through its regulation of IGF production.

Metabolic The strictly metabolic effects of GH are linked to the restoration and reparation of cellular elements of all classes and structures, i.e., glycolipids, proteoglycans, cell membrane, DNA integrity, etc. Key peripheral effects of GH and IGFs are summarized in Fig. 9.9.

Central GH promotes REM sleep and some aspects of learning and memory (cf. GHRH above). In summary, GH favors directly or indirectly all aspects of nutrient mobilization and entry and its incorporation into cells for cell maintenance, evolution, restoration, reparation, and growth.

Prolactin (PL) Location: Lactotrophs, anterior pituitary Composition: Glycoprotein Regulation (Fig. 9.10) ●

Stimulation ● αΣ ● Estrogens ● TSH (secretion) ● TRH (excretion) ● Suckling (peripartum women only)

Somatotropic axis Chapter | 9  131

– Growth hormone –

Adipose tissue

Muscle

Liver ↑ Gluconeogenesis

↑ Lipolysis

IGFs / IGFBPs

↑ Amino acid uptake ↑ Protein synthesis ↑ Lean body mass

↑ Free fatty acids

↑ Blood glucose

↑ IGFs

↑ Somatic cell growth

↑ Organ/tissue size and function

↑ Chondrocyte function

↑ Linear growth

FIG.  9.9  Effects of growth hormone (GH) and insulin-like growth factors (IGFs). (Reproduced from Nussey SS, Whitehead SA. Endocrinology: An Integrated Approach. 1st ed., BIOS Scientific Publishers; 2001. © 2001.)

the general adaptation response of Endobiogeny. This requires diurnal catabolic activity. The remaining actions require anabolism, and primarily occur at night. Rhythmicity remains key (Figs. 9.11 and 9.6, and Chapter 6, Fig. 6.13: Cortisol rhythmicity). FIG.  9.10  Prolactin (PL) regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits; orange broken arrow, slows liberation. (© 2015 Systems Biology Research Group.) ●

Inhibition ● SS ● Dopamine ● Progesterone ● T4 (slows down its liberation)

Purpose: PL regulates the pace of endocrine running and the plenitude of the organism in its self-protecting, selfhabituating, self-sustaining, and self-perpetuating requirements. Self-protecting refers to the turning of the loops in

Mechanisms and actions PL is perhaps one of the most fundamental and diverseacting hormones in multicellular eukaryotes.14 To wit, PL is the only pituitary hormone whose activity increases when its interaxial hypothalamic hormone SS has diminished function, for SS inhibits PL rather than stimulating it.15 What is more, it is the only pituitary hormone that does not have an interaxial hormone that stimulates it. The primary stimulator of PL is TRH.16–18 Thus, there is a true thyrosomatotropic axis that consists of TRH, PL, and insulin, and a univocal action that it exerts on the gonadotropic axis and the general growth of the organism. PL’s endocrine actions are primarily central, except for its stimulation of insulin.

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Prolactin (µg/L) 30 Young women Postmenopausal women 20

10

0

09

12

15

18

21 Clock time

00

03

06

09

FIG. 9.11  Prolactin circadian output. Prolactin has two peaks. The first is morning, supporting cortisol for adaptation. The second during sleep to support anabolic functions. (Reproduced from Copinschi G, Caufriez A. Hormonal circadian rhythms and sleep in aging. In: Encyclopedia of Endocrine Diseases. 2nd ed., Academic Press; 2019:675–689. © 2019 Elsevier Inc.)

Pacing the endocrine loops First loop PL advances first loop anabolic activity to favor second loop hormones while supporting the peripheral actions of first loop products. Its actions are based in part on the intensity and duration of TRH activity. TRH stimulates FSH and sensitizes cells to the effects of estrogens. Both estrogens and TRH stimulate PL.19 PL affects GnRH pulsatility to reduce the production of FSH and favor LH production for the second loop.20, 21 As is conceived up in the Endobiogenic approach to integrative physiology, estrogen’s stimulation of PL serves increase in the number of estrogen receptors. This amplifies the effects of estrogens while allowing the quantitative output to diminish as GnRH stimulation of the pituitary shifts from FSH to LH, hence androgens and progesterone. As Dr. Duraffourd conceived, TSH stimulates PL by horizontal pituitary mechanisms, and also helps install insulin resistance by stimulating GH, thus preventing early closure of anabolism.

Second loop As the middle of the two loops, PL or an analogue is co-­ secreted with CRH to relaunch ACTH.22 As noted above, PL favors the production of LH within the gonadotropic axis, thus helping to ensure sufficient regulation of estrogens by progesterone and production of gonadal androgens. A peak of TRH in the second loop converts T4 to T3 (cf. Chapter  8, Fig.  8.11). This allows PL to be liberated at a faster rate, which blocks TSH, reducing its stimulation of GH, reducing insulin resistance. PL also inhibits GHRH to downregulate GH production in the second loop.

TRH stimulates PL release and both stimulate the excretion of insulin from the endocrine pancreas, initiating the beginning of the end of the two loops. Insulin under influence of TRH and PL closes the anabolic loop in the periphery, as we say in Endobiogeny. Once insulin levels have sufficiently risen, it evokes a release of SS, which abrogates further expression of endocrinometabolic activity in order to allow cells time to actually anabolize and construct cellular structures and organo-metabolic products for excretion.

Width of structures Where GH and IGF-1 regulate length, PL regulates width (Fig. 9.12). One of the ways that it may do this is through HER-2 receptors, which are tyrosine kinase activators in the epidermal growth factor receptor (EGFR) family.23 HER-2 acts as a signal transducer and activator of transcription (STAT). In other words, it increases the rate of transcription, increases growth, and suppresses apoptosis. It also activates a number of intracellular pathways related to growth and proliferation of cells, rate of cycling of mitosis and suppression of apoptosis through mitogen-activated protein kinases (MAPK).23 These effects are particularly synergistic in conjunction with estrogens and progesterone, clarifying the role of PL in the growth of epithelial cells in mammary glands as well as the growth of the uterus, ovaries, and placenta.14 This PL-estrogen-progesterone trio stimulates IGF-2 to act through paracrine activity to induce similar growth in neighboring cells.

Immunity PL has a variable role in immune function. By relaunching ACTH via CRH, it favors thymic release of T-lymphocytes.

Somatotropic axis Chapter | 9  133

●

Turnkey of fertility and propagation of life ● Estrogens: - Uterine hypertrophy and implantation - Fetal growth - Parturition ●

LH - Ovulation - Menstruation (through its withdrawal)

Endocrinometabolic ●

●

●

FIG.  9.12  Influence of anabolic hormones on structure. In this schematic, the rectangular cuboid represents the body. Prolactin influences width, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) influence length. Estrogens influence texture and depth, androgens architecture and depth of tissue. Thyroid, represented as a glowing heat, provides the energy for growth. (© 2015 Systems Biology Research Group.)

Lymphocytes express PL in a paracrine fashion in order to augment inflammation and extravasation of immune cells out of the circulation.24, 25 However, increased PL activity can suppress immunity through transcriptional mechanisms noted above. This helps prevent autoimmune disorders, but in dysregulated states, PL can promote oncogenesis and metastasis. PL also favors the production of pus.

Angioneogenesis PL participates in angioneogenesis through its STAT activity, especially the Janus kinases.23 PL has paracrine activity through its production by lymphocytes, which favors both extravasation and angioneogenesis. As noted above, in dysregulated states, this can favor metastasis of cancer cells, especially in breast and prostate cancers.23, 24

Lactation: Galactogenesis, and galactopoiesis Perhaps the best-known function of PL is its role in lactation.26 PL stimulates both the production and flow of maternal milk,25 whereas oxytocin stimulates its letdown. The mechanism by which PL stimulates milk production involves the uptake of various enzymes related to the production of the polyamines and casein that are required for the production of maternal milk. The clinical implications of PL’s effects can be summarized as follows: Endocrine ● ●

Accelerator of growth of all cells, tissues, and organs Adrenal competency (ACTH relaunching) in the adaptation syndromes and the seasonal adaptation (cf. chronobiologic effects of PL below)

Allo-sustainer of life: Lactation (hence the name Prolactin) of (nonself) infants Auto-sustainer life: Angioneogenesis with increased supply of nutrients Defender of life: Extravasation of immune cells, immune regulation

The pathophysiologic implications are clear with respect to oversolicitation of PL: disorders of hyperplasia, carcinogenesis, and metastasis,23 hirsutism, acne, polycystic ovarian disease, dysmenorrhea, insomnia, disadaptation states, etc.; likewise with respect to insufficient solicitation of PL: dysmenorrhea, infertility, failure to thrive, disadaptation states, and depression.27

Neuro-metabolic: Adaptation, endocrine, and comportmental effects of PL PL has a number of direct and indirect relationships to the various adaptation syndromes and the general adaptation syndrome. The relationship of alpha sympathetic (αΣ), dopamine (DA), and PL is a special triadic relations. In the theory of Endobiogeny, it is referred to as a trépied (French for “tripod” or “triadic.” A trépied is a triadic relationship in which the first factor “A” stimulates two factors: “B” and “C.” B stimulates C but C inhibits B. The net effect is that A initiates, B and C regulate each other—as long as factor A is diminished through its own regulation mechanisms. In the αΣ-DA-PL relationship, αΣ is “A,” “B” is PL and “C” is DA (Fig. 9.13). This trépied is implicated in a host of issues from functional infertility to insomnia. With respect to adaptation, alpha also has a trépied with Pl and GH. Alpha helps maintain the proper competitiveadditive relationship of GH and PL with respect to glucose metabolism. In this trépied alpha remains factor A, GH is factor B and PL is factor C. In this case, it is PL that inhibits one of its two stimulators (Fig. 9.14). The quality of this relationship impacts the efficiency of adaptation and seeks to prevent both hypo- and hyperfunctioning states of disadaptation, such as hypoglycemia or Crohn’s colitis, respectively (cf. The Theory of Endobiogeny, Volume 3, Chapter 11: Inflammatory Bowel Diseases). Considering the thyro-somatotropic axis and adaptation, we find a triadic relationship in αΣ-TRH-PL. However,

134  The Theory of Endobiogeny

FIG. 9.13  The trépied in Endobiogeny, illustrated by the relationship of alpha sympathetic (αΣ), dopamine, and prolactin. Alpha initiates adaptation. Alpha stimulates prolactin to progress adaptation—to turn the first loop and relaunch the second loop. However, endless adaptation would be deleterious to the organisms. So, alpha also stimulates dopamine. Dopamine slows down adaptation by inhibiting pituitary hormones, including prolactin. Prolactin, to ensure its regulation, also stimulates dopamine to inhibit it. This is because alpha is not inhibited by anything and may become excessively prolonged. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

FIG.  9.14  Trépied of alpha, growth hormone (GH) and prolactin with respect to glucose regulation. Alpha, by initiating adaptation, initiates a glucose demand. It stimulates GH in a first time, to delay glucose entry (by increasing insulin resistance). In a second time, it stimulates prolactin to stimulate insulin excretion to favor glucose entry into the cell for ATP production. Prolactin inhibits GH. As above, to ensure its own inhibition, GH stimulates prolactin, which inhibits GH in turn. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

this is not a trépied because PL does not inhibit TRH. It is a purely stimulatory and initiating triadic relationship (Fig. 9.15). As noted in Fig. 9.13 and adaptation, alpha initiates, PL progresses, and TRH calibrates. Alpha stimulates both TRH and PL. TRH stimulates PL. PL inhibits neither alpha nor TRH. Recall that in the central physiology, TRH has a wideranging effect on cognitive adaptation, mood, and memory (Chapter  8). It is stimulated by and accelerates DA activity. Thus, when we overlay the two relationships of αΣDA-PL and αΣ-TRH-PL, we have a quadratic relationship. This relationship presents a myriad of possibilities with respect to adaptation and comportment, where PL once again serves as the axel of how the body and mind turn. If DA predominates, PL activity will be restrained; if alpha and/ or TRH predominate, PL will have a more pronounced role (Fig. 9.15). There are genetic differences in the responsiveness of lactotrophs to suppression of PL by DA, and DA responsiveness to PL.28 In other words, some people have a greater increase in DA relative to a given PL response than o­ thers.

FIG.  9.15  Overlay triadic relationships of alpha, dopamine, TRH and prolactin. Together, this new quadratic relationship influences mental and physiologic adaptation. Red arrow, stimulates; red broken arrow, makes an appeal; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

Conversely, some people have less suppression of PL by DA than others. Furthermore, with respect to chronobiologic activity, there are seasonal variations in the phase, frequency, amplitude, and duration of PL output from lactotrophs.28 In autumn and winter, PL output, sustain, and amplitude are reduced. In spring and summer, the all increase. Overall, PL and the pars tuberalis play a role in both seasonal and circannual rhythms.29, 30 Furthermore, there is variable response of lactotrophs to this photoperiodic stimulation. The activity is initiated by melatonin from the pineal gland.29 Thus, we can see sustained output, transient pulsatile output, low-frequency high-amplitude short-phase output, high-frequency lowamplitude long-phase activity, etc. We hypothesize that various factors influence the nature of the output of PL and that the pulsatile or sustained output patterns inform the body of where and how PL will have its actions, i.e., PL-GnRH, PL-DA, PL-pancreas, PL-GH, or PL-ACTH. The various factors will likely include αΣ, α-MSH, β-MSH, DA, and TRH. There are a number of implications to this quadratic relationship that are wide ranging and profound, related to adaptation and the mental and peripheral physiologic tolerance of stress. This quadrad is implicated in disorders from spring metastasis of cancer to infertility, from schizophrenia to depression, and from bipolar disorder to insomnia. PL demonstrates a general circadian variation with nocturnal predominance. There is a greater frequency of diurnal PL compared to GH, which witnesses the diurnal role of PL in adaptation and not strictly in its vertical endocrine function. PL peaks in the first half of the night then declines. Because of the particular relationships in nocturnal physiology, PL does not relaunch the corticotropic axis at night. It parallels the rise and purpose of GH. PL’s nocturnal role is primarily growth and restoration. In summary, PL is a pituitary hormone that has several unique and indispensable actions. PL helps nourish cells, regulates growth, regulates

Somatotropic axis Chapter | 9  135

the pacing and progression of adaptation, and plays a role in various psychobiologic phenomenon as well as chronobiologic activity in the alterations of day and night and seasonal changes.

Introduction to the peripheral hormones of the somatotropic axis The purpose of the peripheral somatotropic hormones is not in managing adaptation but in adapting the organism in its basal, immediate, and chronic demands. The peripheral somatotropic hormones, like many other aspects of the somatotropic axis, have anomalies with respect to its general organization. Thus, for example, there are two main peripheral somatotropic organs, not one: liver (IGF) and endocrine pancreas (glucagon and insulin). Of the three hormones noted, glucagon is not stimulated by any of the pituitary or hypothalamic somatotropic hormones, but by TRH for reasons we have discussed in Chapter 8 under “TRH.”

Insulin-like growth factor-1 (IGF-1): Liver Location: Liver Composition: Polypeptide Regulation (Fig. 9.16) ●

●

●

Stimulation ● GH ● Minerals: Zinc (Zn), selenium (Se), magnesium (Mg) ● Protein intake Inhibition ● IGF-1 binding protein (IGF-1 BP): Keeps in inactive form ● Protein malnutrition ● Very low-calorie intake (VLCI) ● Immune dysregulation Regulation ● IGF-2 ● IGF-binding protein 3 (IGF-BP3)

Purpose: IGF-1 manages growth, adhesion, and expansion of cells and serves as a barometer of nutritional integrity and somatotropic synchronization.

FIG.  9.16  Regulation of insulin-like growth factor 1 (IGF-1). See text for details. red arrow, stimulates; blue arrow, inhibits; green broken arrow, regulates, teal broken arrow, reduces serum levels. (© 2015 Systems Biology Research Group.)

Mechanisms and actions IGF-1 is a first loop hormone stimulated by GH and produced in the liver. It mediates the growth of cells in a number of ways. It binds to cells and augments their sensitivity to other growth factors. It has genomic actions related to growth, mitogenesis (cell hyperplasia), and cell adhesion.9 The GH regulates the expression of IGF-1 by also producing its binding globulin IGF-BP3 in the liver, which keeps about 95% of IGF-1 in reserve. Cells can regulate their own sensitivity to IGF-1 by fragmenting their own IGF-1 receptors through protease enzymes.9

Endocrinometabolic effects of IGF-1 IGF-1 inhibits apoptosis, favoring the growth of the cell. IGF-1 and insulin belong to the same family of hormones. They share similar pathways of intracellular activity that involve increased cellular oxidation and production of reactive oxygen species.31 Oxidation is crucial for the production of hydrogen ions from carbohydrates and lipids for ATP production. Furthermore, regulated expression of free radical species provides a defense against tumorigenesis. The belief that oxidative stress and free radicals reduce longevity and the conclusion of supraphysiologic consumption of antioxidants will prolong longevity are fallacious. The correlations mentioned were made in mutant mouse lines raised in cages,31–33 not in humans living in the modern world. Duraffourd and Lapraz as early as 1988 reported that high-dose synthetic antioxidant therapy would increase the risk of cancer and this has been supported by recent clinical trials.34–37

Endocrinotissular effects of IGF-1 The effects of IGF-1 were discussed under “Growth Hormone.” To summarize, IGF-1 favors the lengthening of tissues and organs, particularly bone, cartilage, and muscle.

Nutritional integrity, growth, and longevity Physiology: The expression of IGF-1 is similar to the regulation of alveolar blood flow where the more the exposure to oxygen, the greater the blood flow is. The greater the blood flow is, the greater the amount of oxygen taken in. With respect to IGF-1, the greater the intake of minerals, the greater the expression of IGF-1 and the more efficient anabolic achievement. Zinc, selenium, and magnesium have the most pronounced effects.38 Zinc regulates general pituitary function, selenium thyroid function, and magnesium insulin sensitivity. They each also have key intracellular roles in DNA structure and function. In general, longevity in animals and humans appears to be inversely correlated to IGF-1, GH, and insulin when elevated above appropriate levels. Mild calorie restriction (15%) and genetic polymorphisms that reduce ­sensitivity

136  The Theory of Endobiogeny

to IGF-1 favor increased longevity within a balanced Endobiogenic terrain.32, 33 Pathophysiology: Insufficiency of IGF-1 is related to failure to thrive in children and sarcopenia in elderly patients. IGF-1 levels can be increased through proper supply of calories, protein, and minerals, reversing this trend in clinical studies.38 Furthermore, IGF-1 production can be dissociated from GH excretion, implicating diminished hepatic production and/or altered receptor binding due to immune dysregulation. Oversolicited IGF-1 can act as an accelerator of dysregulated cellular growth, such as atherosclerosis, uterine fibroids, and tumors.32 Hyperinsulinism and excessive GH activity are implicated however these somatotropic factors are necessary but not sufficient. According to the theory of Endobiogeny, a mild calorie restricted diet (15% below basal metabolic requirements) with abstinence from animal proteins, or periodic fasting can diminish hypermetabolic, hyperanabolic states, such as a reduction of tumor burden or uterine fibroids.32 Some evidences for this includes the observation that patients with genetic deficiency of growth factors have a lower-than-average incidence of diabetes and cancer. In patients with type-2 diabetes, cancer risk is inversely related to the degree of glycemic control. Furthermore, diabetics treated with metformin, a sensitizer of insulin activity, have a 40% reduction in the incidence of cancer compared to diabetics treated with other classes of drugs or with poorly managed glucose control.32 However, a more recent trial failed to replicate these results.39 It should be stressed from the Endobiogenic perspective that long-term substitutive therapy with metformin tends to increase the risk of diseases of inflammation and desynchronizes the somatotropic axis. In conclusion, IGF-1 has a biphasic relationship to longevity. Excessive IGF-1 reduces longevity due to an increased risk of disorders of hypermetabolism. Insufficient IGF-1 reduces longevity due to an increased risk of disorders of hypometabolism.

Glucagon: Endocrine pancreas Location: Endocrine pancreas, islet of Langerhans, α-cells Composition: Polypeptide Regulation (Fig. 9.17)

●

Stimulation ● Hypoglycemia ● πΣ (acetylcholine) ● βΣ ● TRH ● Cholecystokinin (CCK) ● Amino acids: - Arginine (Arg) - Alanine (Ala)

●

Inhibition ● SS ● Insulin ● Urea ● Free fatty acids (FFA)

Purpose: Glucagon participates in basal and adaptation states by providing the substrates for structural and functional energy. It augments the circulating levels of glucose and free fatty acids.

Mechanisms and actions Glucagon is the second of two catabolic hormone within the somatotropic axis, the other being GH. Both serve anabolism in their catabolism, and both augment serum glucose40 and fatty acids.41 They both have second loop counterparts with which they function in an agonist-antagonist and competitive-additive manner: GH with PL, glucagon with insulin. Glucagon is unique among peripheral hormones. Its central regulator of excretion is extra-axial. Conceptually, we link it to the thyrotropic hormone TRH42 (similar to TRH’s action on somatotropic PL in the anterior pituitary). Glucagon does not belong to any loop. It is without and within the loops. It is in the basal and adaptive metabolism and in the structural and functional demands. But it is squarely within the somatotropic axis because it manages glucose and contributes to the somatotropic goals of growth and adaptation. Glucagon is its own hormone. It has casual and fluid relationships with a variety of neuroendocrine and metabolic factors. Parasympathetic regulates its secretion within islet cells.43 TRH and adrenaline stimulate its excretion, as does hypoglycemia.44 SS45 and insulin46 act as local regulators.

Glucose and adaptation

FIG. 9.17  Glucagon regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

Glucagon augments circulating glucose levels in two ways: glycogenolysis and gluconeogenesis.47 Thus, it both liberates glucose stores and stimulates de novo glucose production from noncarbohydrate substrates. Glucagon’s effects are nearly constant as it is the primary hyperglycemic hormone and regulates the basal levels of serum glucose. Thus, insulin’s inhibition of glucagon in response to hyperglycemia is pulsatile, reactive, brief, and repetitive.46 If it were

Somatotropic axis Chapter | 9  137

constant or tonic, it would seriously compromise physiologic glycemia. The general adaptation syndrome and the syndromes of adaptation produce increased levels of serum glucose from several sources (cortisol, exocrine pancreas, etc.). All hormones that affect glucose levels are hyperglycemic except insulin. As is said in business, “it takes money to make money,” so in integrative physiology we say “it takes energy to make energy.” The energy that precedes the making of energy is referred to in Endobiogeny as the “starter” energy, similar to an automobile starter. (A starter engine is a noncombustion engine that starts the combustion engine so that it can run the car per the demands of the driver.) The organism has two ways of making energy for adaptation, of liberating glucose from glycogen stores: glucagon and adrenaline (βΣ).44 Both are used constantly, but the relative predominance varies. What we have observed in performing over 40,000 biology of functions is that in children, adrenaline is used more than glucagon (low-normal or low starter index—cf. The Theory of Endobiogeny, Volume 2, Chapter 1, “Starter index” section). In adults, glucagon predominates relative to adrenaline (high normal or elevated starter index). Adrenaline causes short-lived bursts of hyperglycemia by accelerating glycogenolysis 2000 times above basal rates. Glucagon provides repetitive, modest adjustments of circulating glucose. From an integrative physiologic reflection according to the theory of Endobiogeny, there is a logic to why βΣ stimulates glucagon to do a job that adrenaline can do. Both can increase serum glucose by liberating stored carbohydrates in the liver (glycogenolysis). However, glucagon also stimulates de novo production of glucose from noncarbohydrate material (gluconeogenesis). Thus, βΣ hedges its bets in case its brief and rapid adjustment of serum glucose levels is not sufficient, or hepatic glycogen stores are not sufficient for the duration of appeal for glucose.

Free fatty acids Glucagon stimulates lipolysis to provide a second source of material besides glucose for ATP production. Insulin and the free fatty acids themselves inhibit glucagon.43 In summary, glucagon is a catabolic hormone within the somatotropic axis that regulates the basal and adaptive availability of glucose, enabling adaptation states by providing starter substrate for energy production before additional substrate is mobilized.

Insulin: Endocrine pancreas Location: Endocrine pancreas, β-islet cells of Langerhans Composition: Polypeptide Regulation (Fig. 9.18)

FIG. 9.18  Insulin regulation. See text for details. Red arrow, stimulates; blue arrow, inhibits. (© 2015 Systems Biology Research Group.)

●

Stimulation ● Hyperglycemia ● Hyperglycemic hormones - βΣ - Glucagon

T4 (secretion) TRH (excretion) ● PL Inhibition ● Somatostatin (SS) ● ●

●

Purpose: Insulin is the restorative hormone, counteracting nearly all the catabolic actions that preceded it in both loops and serves as the growth hormone par excellence.

Mechanisms and actions Peripheral Insulin has three classical peripheral activities (Fig. 9.19). As the sole hypoglycemiant hormone, it regulates the entry of glucose into the cell, glucose being the most efficient substrate for the aerobic production of ATP. The genomic actions of insulin upregulate the activity of enzymes involved in glycogenesis—the storage of glucose as glycogen,48 and block glycogenolysis stimulated by glucagon and adrenaline.40 Insulin stimulates lipogenesis from fatty acids and carbohydrates.49 Thus, insulin has a conservative role in the storage of metabolic substrates for future energy production. Cells that are richest in insulin receptors are muscle and adipocytes. In adipocytes, glucose can be converted into triglycerides. In either case insulin displays a rhythmic excretion of every 8–10 min, lengthening with age.50 The conservative effects of insulin are summarized in Table 9.1.49 Insulin’s genomic effects are regulated through a complex series of postreceptor downstream kinase and phosphorylase activity that increases tumor necrosis factor-α. Through this, and its ingress of glucose, hyperinsulinism favors inflammation, inappropriate glycosylation of proteins and receptors, and other deleterious effects associated with hyperglycemic disorders such as diabetes.51 Like IGF1, which belongs to the same family of hormones, insulin favors oxidation, free radical species, and mitosis.

138  The Theory of Endobiogeny

Amino acids

Glucose

Insulin receptor FFA

Amino acids Glucose Protein

Triglyceride

FFA

Glycolysis/oxidation Glycogen

FIG. 9.19  Actions of insulin on glucose, amino acids, and free fatty acids (FFA). (Reproduced from Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and lipid metabolism. Nature 2001;414:799–806. doi:https://doi.org/10.1038/414799a. © 2018 Springer Nature Limited.)

TABLE 9.1  Conservative effects of insulin Substance/location

Utilization

Preservation

Storage

Carbohydrates

Glucose entry into cells

Inhibits glycogenolysis

Glycogenesis

Lipids

Free fatty acid entry into cells

Blocks Lipolysis

Lipogenesis

Proteins

Blocks proteolysis

Blocks gluconeogenesis (from amino acids)

–

Electrolytes

Potassium entry into cells

Diminishes renal sodium excretion

–

Cell

–

Reduces autophagy of organelles

–

Cardiovascular

Vasodilator: improves microvascular flow for nutrient distribution

–

–

Brain

–

Synaptic plasticity

Memory: formation, consolidation, recall

A brief summary of the interaxial activity of somatotropic hormones can be summarized like this: First loop

ii. Increases the uptake of minerals and amino acids iii. Stimulates IGF-1 release from the liver iv. Stimulates PL, to start preparing the actions of insulin v. Installs insulin resistance to prevent the early closing of anabolism by insulin vi. GH inhibits GHRH by classical negative feedback c. PL: Turns the loop 2. Peripheral a. IGF-1 initiates factors related to growth and prepares the cell for insulin b. IGF-1 inhibits GH by classical negative feedback Second loop

1. Central: a. GHRH stimulates GH b. GH is released in pulsatile fashion: i. Increases circulating amount of free fatty acids

1. Central a. TRH i. Stimulates PL ii. Stimulates the release of insulin

Central In central physiology, insulin does not regulate glucose entry—that role is played by serotonin through passive ­ ­diffusion.52 Rather, it has a permissive role on synaptic plasticity, and, memory formation, consolidation, and recall.51 In this way, insulin’s activity compliments that of GHRH and GH.

Integrating the somatotropic axis



Somatotropic axis Chapter | 9  139

b. PL i. Inhibits GH, releasing insulin resistance from insulin receptors ii. Stimulates the release of insulin 2. Peripheral a. Insulin i. Conserves carbohydrates, proteins, and lipids ii. Provides substrates for ATP production iii. Stimulates growth of the cell and finalizes all that was prepared by the axes preceding it iv. Insulin “closes the door of anabolism” 3. Central/peripheral a. Somatostatin i. Inhibits all somatotropic hormones and central thyrotropic hormones that relaunch the somatotropic axis: 1. GHRH 2. PL 3. IGF-1 4. Insulin 5. TSH

Somatotropic synchronization According to the theory of Endobiogeny GH is not truly anabolic in its direct actions—it is catabolic. But in reality, it has triple action. It is catabolic but also antianabolic because it delays the onset of insulin (by insulin resistance) and hence anabolism. However, this very delay is ultimately pro-anabolic because the nutrients it brings into the cell (amino acids, electrolytes) enhances the anabolism that insulin affects through its broad actions. Thus, the key to the proper functioning of the axis is in its synchronization between catabolism and preanabolism in loop one and anabolism at the very close of loop two. The careful interplay of GH, PL, glucagon, and insulin ensures a proper regulation of serum glucose and all that that implies for movement, consciousness, and memory, for basal and adaptive metabolism, and for structural and functional energy. The sum of this activity is the result of somatotropic synchronization.

Conclusions The somatotropic axis plays many diverse roles in the organism. It is primarily thought of an axis of nutrient regulation: distribution and storage. Despite its predominantly anabolic function, it does contain catabolic activity which relates to another key aspect of its function: adaptation and adaptability. The central hormones play important roles in memory, dreams, and circadian transitions. Another capital role of the axis is ending processes started by other axes. It ends adaptation syndromes initiated by the corticotropic axis, and anabolic growth initiated by the gonadotropic axis. Understanding the fullness of the somatotropic axis

aids the clinician in treating much more than diabetes or Alzheimer’s disease. It allows for a proper treatment of eczema, infertility, cancer, and many other disorders.

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20.

21.

22.

23.

24.

25.

26. 27.

28.

29.

30. 31.

32.

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Duncan  JA, Barkan  A, Herbon  L, Marshall  JC. Regulation of pituitary gonadotropin-releasing hormone (GnRH) receptors by pulsatile GnRH in female rats: effects of estradiol and prolactin. Endocrinology. 1986;118(1):320–327. Perez-Lopez FR, Abos MD. Pituitary responsiveness to gonadotropin-­ releasing hormone (GnRH) and thyrotropin-releasing hormone (TRH) during different phases of the same cycle of oral contraceptive steroid therapy. Fertil Steril. 1982;37(6):767–772. Hokfelt  T, Fahrenkrug  J, Tatemoto  K, et  al. The PHI (PHI-27)/­ corticotropin-releasing factor/enkephalin immunoreactive hypothalamic neuron: possible morphological basis for integrated control of prolactin, corticotropin, and growth hormone secretion. Proc Natl Acad Sci U S A. 1983;80(3):895–898. Jacobson EM, Hugo ER, Borcherding DC, Ben-Jonathan N. Prolactin in breast and prostate cancer: molecular and genetic perspectives. Discov Med. 2011;11(59):315–324. Reuwer  AQ, Nowak-Sliwinska  P, Mans  LA, et  al. Functional consequences of prolactin signalling in endothelial cells: a potential link with angiogenesis in pathophysiology? J Cell Mol Med. 2012;16(9):2035–2048. Ignacak A, Kasztelnik M, Sliwa T, Korbut RA, Rajda K, Guzik TJ. Prolactin—not only lactotrophin. A "new" view of the "old" hormone. J Physiol Pharmacol. 2012;63(5):435–443. Vander Laan WP. Changing concepts of prolactin in man. Calif Med. 1973;118(2):28–37. Faron-Gorecka A, Kusmider M, Solich J, et al. Involvement of prolactin and somatostatin in depression and the mechanism of action of antidepressant drugs. Pharmacol Rep. 2013;65(6):1640–1646. Johnston  JD. Photoperiodic regulation of prolactin secretion: changes in intra-pituitary signalling and lactotroph heterogeneity. J Endocrinol. 2004;180(3):351–356. Korf HW. Signaling pathways to and from the hypophysial pars tuberalis, an important center for the control of seasonal rhythms. Gen Comp Endocrinol. 2018;258:236–243. Wood  S, Loudon  A. The pars tuberalis: the site of the circannual clock in mammals? Gen Comp Endocrinol. 2018;258:222–235. Papaconstantinou J. Insulin/IGF-1 and ROS signaling pathway crosstalk in aging and longevity determination. Mol Cell Endocrinol. 2009;299(1):89–100. Anisimov VN, Bartke A. The key role of growth hormone-­insulinIGF-1 signaling in aging and cancer. Crit Rev Oncol Hematol. 2013;87(3):201–223. Junnila  RK, List  EO, Berryman  DE, Murrey  JW, Kopchick  JJ. The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol. 2013;9(6):366–376. Selenium and vitamin E raise risk of prostate cancer. Harv Mens Health Watch. 2014;18(10):8. Potter  JD. The failure of cancer chemoprevention. Carcinogenesis. 2014;35(5):974–982. Shiels  MS, Albanes  D, Virtamo  J, Engels  EA. Increased risk of lung cancer in men with tuberculosis in the alpha-tocopherol,

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Chapter 10

Endocrine associations: Coupling, linking, and yoking Introduction Axes have intrinsic vertical endocrine action. A hypothalamic hormone stimulates its pituitary hormone, which stimulates its end organ hormone(s). These actions have a univocal effect on metabolism: net catabolic or net anabolic. For example, when the corticotropic axis excretes cortisol, there are catabolic effects. There must be a way to calibrate an anabolic response to these actions. This calibration is coupling. When an anabolic axis initiates anabolic activity, the other anabolic axis must be linked to this for anabolism to be appropriately completed. This is linking. If alphasympathetic initiates a response to an aggression, both catabolic axes must respond to ensure an appropriate response. This is yoking. According to the theory of Endobiogeny, these associations serve to calibrate the actions of one axis to another to ensure proportionality of response.

Coupling Coupling is the linking of adjacent axes. The goal is to achieve complimentary of metabolic effects through proportionality of response. It ensures commensurate action and prevents disorders of expansion or wasting. The general relationship involves all three types of endocrine activities: vertical, horizontal, and radial. It begins with vertical feedforward endocrine activity: hormone (H) H1a stimulates H1b in its axis at level 2 (Fig. 10.1). Coupling starts with horizontal action: H1a, level 1, stimulates H2a in the adjacent axis but at the same level. This is to inform H2a of what it has done with its own hormone H1b. This allows H2a to prepare a similar level of solicitation of its corresponding downstream hormone, H2b. However, H1a only informs H2a of what might occur with H1b. Stimulation is not always equivalent to result. Rhythmicity, binding proteins, receptor binding, and other factors will determine its final functional effect. A second level of coupling occurs in which H1b radially calibrates H2a according to its actual achievement. This occurs in three stages: (1) H1b levels rise: calibration of production of H2a, (2) H1b levels peak: blockage of excretion of H2a, and (3) H1b levels fall due to negative feedback on H1a: H2a excreted (Fig. 10.1). The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00010-0 © 2019 Elsevier Inc. All rights reserved.

The relationship can be depicted as follows: ●

●

Level 1: Hypothalamus ● H1a ● H2a Level 2: Pituitary ● H1b ● H2b

The relationship is fractal. If we bring the level down one turn, we can evaluate the relationship between the pituitary and periphery. H1b, which was downstream is now the upstream stimulating hormone H1c. ●

●

Level 1: Pituitary ● H1b ● H2b Level 2: Periphery ● H1c ● H2c

As Dr. Duraffourd described it, the hormone involved in coupling act in an ANS-like fashion. Horizontal stimulation by H1a on H2a is para-like: it stimulates production of H2a. First time the radial stimulation is alpha-like: H1b calibrates the production of H2a. Second time the radial stimulation is an extension of alpha-like activity, similar to the effects of its autacoid histamine in prolonging the effects of alpha. The third time the radial stimulation is (a passive) beta-like action: falling levels of H1b allow H2a to be excreted. This is what ensures the complementarity of the alternating metabolic effects. These relationships must be appropriate in timing, intensity, duration, and resolution. When this occurs, it assures the maintenance, survival, restoration, and propagation of the organization. As advantageous as this associations are, they are the seed of dysendocrinism when they are disproportionate. Dysendocrinism is an improper relationship of hormones with each other. Table  10.1 summarizes some forms of dysendocrinism and their implication in various disorders. Understanding these relationships of hormones provides a key point of evaluation of the terrain. It opens a pathway for the selection of rational clinical therapeutics that address symptoms and causes of disease, and, determinants of health and longevity. 141

142  The Theory of Endobiogeny

FIG. 10.1  General adjacent axial coupling, where H is hormone, a is the stimulating hormone, and b is the stimulated hormone. See text for details. (© 2015 Systems Biology Research Group.)

Cortico-gonadotropic axis

Estrogens increase the binding of cortisol to CBG, reducing cortisol’s bioavailability. The SHBG binds estrogens and androgens to keep them in reserve, allowing only about 2%–4% in circulation. The SHBG has a higher affinity for androgens than estrogens and is stimulated by estrogens to increase the binding of androgens to SHBG (Table 10.2). Thus, the bioavailability of estrogens and androgens are inversely related to each other.1,2 Estrogens ensure the duration of their own estrogenic function in two ways: (1) CGB stimulation to reduce cortisol and progesterone, and (2) SHBG stimulation to reduced androgens. With respect to cortisol, estrogens, progesterone, and androgens their quantitative levels can be high, low, or normal. It is the relative availability of estrogens that affects the relative availability of these related hormones in relationship to that of estrogens.

First loop central-central coupling

Introduction The corticotropic and gonadotropic axes are adjacent axes of alternating catabolic-anabolic activity. They ensure the most fundamental and existential functions of the organism: origination, crystallization, defense, restoration, reparation, and propagation. Thus, they must possess a way at the central and peripheral levels of promoting, regulating, inhibiting, and timing the actions of one to the other. A particular mechanism that ensures these goals is multiple binding globulins. Binding globulins are an important part of the buffering capacity of the organism. They keep circulating hormones in reserve. The cortico-gonadotropic relationship involves a careful interplay between three binding globulins: albumen, cortisol-binding globulin (CBG), and sex hormone-binding globulin (SHBG). The binding globulin of the corticotropic axis is CBG, also known as corticosteroid binding globulin, or, transcortin. The CBG keeps corticosteroids (and progesterone a precursor of corticosteroids) in reserve. It has a weak effect on aldosterone, and no effect on DHEA.

●

●

Axis 1: Corticotropic ● H1a: CRH ● H1b: GnRH Axis 2: Gonadotropic ● H2a: ACTH ● H2b: FSH or LH

The CRH stimulates ACTH. For central-central adjacent cortico-gonadotropic coupling CRH stimulates ACTH. The CRH couples itself to GnRH to calibrate the FSH or LH response in anticipation of how much ACTH may be excreted (Fig.  10.2). The ACTH in radial coupling first calibrates productio of GnRH, then blocks its excretion for a time, then, as the levels of ACTH diminish by its own negative feedback on CRH, GnRH is able to be excreted to stimulate its downstream hormone. In the gonadotropic axis, one hypothalamic hormone, GnRH stimulates two different pituitary hormones: FSH and LH, determined by its pulsatility and amplitude. The primary regulators of GnRH (Chapter 7) regulate it based on the intrinsic requirements

TABLE 10.1  Forms of dysendocrinism Dysendocrinism

Example

Clinical condition

Centrally excessive + peripherally insufficiency

↑ FSH, ↑ TSH, ↑ PL > GH > estrogens, peripheral thyroid

Ovarian cyst, cystic acne

Excessive central ≫ excessive peripheral hormones

ACTH ≫ cortisol FSH ≫ estrogens

Crohn’s colitis

Proportional, absolutely insufficient central + peripheral

↓ FSH, estrogens, progesterone ↓ TSH, peripheral thyroid

Amenorrhea

Disproportional endocrine response, second axis > first axis

FSH > ACTH Estrogens > cortisol

Atopic disease

Endocrinometabolic > endocrine

Testosterone + insulin > estrogens

Uterine fibroids

Endocrine associations: Coupling, linking, and yoking Chapter | 10  143

TABLE 10.2  Binding globulin activity and hormone concentration

Steroid

Total concentration (nmol/L)

Unbound/ concentration

% bound to CBG

SHBG

Albumin

t½ (min)

Cortisol

400

4%/100 nmol/L

90

0.1

6

100

Aldosterone

0.4

40%/0.16 nmol/L

0.2

0.1

39.7

10

Progesterone

0.6

2.4%/0.014 nmol/L

17

0.6

80

5

Testosterone †

20

2.0%/0.4 nmol/L

3

55

40

10

Estradiol §

0.1

2.0%/0.002 nmol/L

0

30

68

20

CBG, cortisol binding globulin; SHBG, sex hormone binding globulin; t½, half-life in circulation; †, values for adult men; §, values for adult females. Based on Nussey S, Whitehead S. Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001.

FIG. 10.2  First loop central-central adjacent cortico-gonadotropic coupling. The downstream hormone FSH or LH is shown faded to indicate that it has not yet been excreted. (© 2015 Systems Biology Research Group.)

of the gonadotropic axis or the chronobiologic unfolding (e.g., puberty, pregnancy, etc.). In this case of coupling, it is ACTH (Fig. 10.2) that brings another level of influence on GnRH. However, it is based on the interests of the corticotropic axis and the needs for proportionality of response. Dysendocrinism at this level can be related to amenorrhea, menorrhagia, atopic disease, hypercholesterolemia, and many other types of disorders of adaptation or metabolism.

First loop central-peripheral coupling In clinical Endobiogeny, this relationship is more frequently discussed. That is because it could be more easily evaluated by history, examination, and biology of functions than the hypothalamic hormones. In this schematic: ●

●

Axis 1: Corticotropic ● H1a: ACTH ● H1b: Cortisol Axis 2: Gonadotropic ● H2a: FSH ● H2b: Estrogens

FIG. 10.3  First loop central-peripheral cortico-gonadotropic regulation. See text for details. (© 2015 Systems Biology Research Group.)

In addition to the dynamics of coupling (Fig.  10.3), there is an added level of complexity: binding globulins. As mentioned earlier, CBG, SHBG, and albumen influence the active, circulating level of hormones. Thus, while ACTH stimulates cortisol, circulating estrogens stimulate CBG to reduce free cortisol. Cortisol, thought, stimulates SHBG to bind estrogens so that it has a time to liberate material that estrogens will use at a later time for anabolism. The ACTH stimulates FSH in order to calibrate the intensity of FSH’s future action to the intensity of ACTH’s current vertical action. The rising levels of cortisol stimulated by ACTH allow for cortisol to calibrate and delay the release of FSH while cortisol engages in its action. Calibration and delay mean that the alpha-like effect of cortisol allows more time for the pituitary to produce and store FSH before it is excreted. Recall that amplitude and sustain of release influence how a hormone acts (Chapters  5–9). Cortisol calibrates FSH to what it anticipates will be achieved in the periphery based on its actual functional value, recalling that CBG reduces available cortisol, and there are numerous receptors, genomic and nongenomic actions of cortisol, etc. (Chapter 6).

144  The Theory of Endobiogeny

At peak levels, cortisol has four effects:

TABLE 10.3  Examples of hyperestrogenism from ANS and endocrine coupling

1. Vertical: Inhibition of ACTH: prevents production of excessive cortisol. 2. Horizontal: ACTH inhibition by cortisol diminishes the horizontal, para-like actions of ACTH on FSH production. 3. Radial: Central-central: Moving back up to the ­central-central relationship, the falling ACTH levels release GnRH from ACTH inhibition (Fig. 10.2). 4. Radial: Peripheral-central: Now that cortisol has inhibited ACTH, its own levels decline, which allows cortisol to have beta-like effect: it allows for the liberation of FSH. Ultimately, the rise in cortisol and then its subsequent fall favors the stimulation of estrogens by FSH based on three considerations: (1) final functional first loop ­corticotropic achievement, (2) quality of corticotropic solicitation of the gonadotropic axis, and (3) intrinsic needs of the gonadotropic axis. The rising level of estrogens has three main effects within the cortico-gonadotropic axis: 1. Peripheral gonado-corticotropic: Further reduction in cortisol by CBG binding. 2. Peripheral gonado-gonadotropic: Reduction in progesterone in the first loop by stimulation of its binding to CBG. A premature rise in progesterone could end the actions of estrogens too soon. 3. Central: Classical vertical feedback: slows down excretion of FSH to avoid hyperestrogenism. The DHEA is released in the first loop and plays a permissive role. The clinical and the therapeutic significance of all these interactions in toto relates to the understanding of the level(s) of intervention in the management of ACTH, cortisol, FSH, and estrogens in various disorders from allergies to menstrual disorders to cancer. The Endobiogenist must assess, through history, physical examination and the biology of functions, the etiology and teleology of altered levels of function. For example, hyperestrogenism can be due to various permutations of the following imbalances just from within the ­cortico-gonadotropic axis and ANS activity (Table 10.3): One can conclude from this partial list that a multilevel, multiaxis approach to treatment will typically result in the most efficient and effective results. Simply increasing the cortisol production and activity to manage estrogens may not be sufficient if the origin of the hyperestrogenism is a hyper alpha and/or oversolicitation of the pituitary. The same is true for imbalances in all other hormones and their relative relationship with each other.

Second loop In the second loop, ACTH plays a similar role with respect to the calibration of the production of LH. However, the sum to-

Condition

Example

Basic hyperendocrinism

GnRH → FSH → estrogens

Insufficient intra axial regulation

GnRH → FSH → insufficient SHBG → insufficient binding of estrogens to SHBG

Insufficient clearance of downstream products

GnRH → FSH → estrogens → insufficient hepatic clearance of estrogen metabolites

Horizontal overstimulation

ACTH → insufficient or delayed adrenal response → hyper-FSH → estrogens

Hyperendocrinism from sympathetic overstimulation + horizontal overstimulation response

αΣ → ACTH → FSH → estrogens

Hyperendocrinism from sympathetic overstimulation + insufficient intra axial regulation

αΣ → ACTH → insufficient cortisol → insufficient binding of estrogens to SHBG

tal of effects is more complex, because ACTH stimulates three hormones (cortisol, DHEA, and aldosterone) and two LHs (progesterone, androgens). Below we show the schematic related to the regulation of the cortico-gonadotropic relationship. Intrinsic regulation is discussed in Chapters 6 and 7. ●

●

Axis 1: Corticotropic ● H1a: ACTH ● H1b: Cortisol Axis 2: Gonadotropic ● H2a: LH ● H2b: Androgens

The primary relationship and logic are the same as in the first loop. The ACTH relaunches cortisol, which plays its alpha-like role on LH with respect to gonadal androgen production (Fig. 10.4). There is, however, another corticogonadotropic relationship that does not follow the pattern above. It is the permissive effect of aldosterone. Aldosterone does not directly regulate central LH release the way cortisol does. It favors LH’s actions on the gonads in the excretion of progesterone. Aldosterone compliments estrogens in their cellular hydroelectric activity and nutrition. Recall that progesterone regulates estrogens and androgens (Chapter  7). The logic of aldosterone favoring progesterone is that it ensures a regulation of its co-participation in cellular nutrition with estrogens. There is an additional gonado-corticotropic action that is not one of ANS-like regulation: LH favoring the intracrine conversion of DHEA to androgens during the time of progesterone.

Endocrine associations: Coupling, linking, and yoking Chapter | 10  145

FIG.  10.4  Second loop central-peripheral cortico-gonadotropic coupling. See text for details. (© 2015 Systems Biology Research Group.)

Gonado-thyrotropic axis The gonado-thyrotropic axis is the key initiator (gonadotropic) and sustainer (thyrotropic) of metabolism. It is implicated in a number of disorders. Its hypofunctioning is implicated to disorders such as Alzheimer’s disease, infertility, and menstrual dysregulation. Its hyperfunctioning is related to cancers, infertility, and menstrual dysregulation. This coupling is the subject of much consideration in Endobiogeny.

First loop central-central coupling ●

●

Axis 1: Gonadotropic ● H1a: GnRH ● H1b: FSH Axis 2: Thyrotropic ● H2a: TRH ● H2b: TSH

implicated in the formation of cysts (ovarian, breast, thyroid, etc.), and adenomas (prostate, breast, etc.). The effects of cortico-gonadotropic coupling are naturally implicated in any discussion of gonado-thyrotropic coupling. For example, the effects of ACTH on calibrating GnRH, of cortisol calibrating FSH, of cortisol inhibiting ACTH, etc. must all be considered when evaluating the coherence of gonadothyrotropic action. In the Endobiogenic reflection, one must transpose overlapping assessments of two-axis coupling. What is the calibrator at one time was the calibrated at an earlier time. For example, FSH calibrates TRH, but it was itself calibrated by cortisol (Fig.  10.3), and ACTH calibrated GnRH for additional calibration of FSH output (Fig. 10.2).

TRH-GnRH-estrogens During the time of cortisol in the first loop, when FSH is still blocked, TRH has three actions on the gonadotropic axis. It stimulates GnRH to assist in the production of FSH according to thyrotropic requirements. It stimulates nongonadal estrogen production, primarily hepatic. Finally, it acts on estrogen receptors. The final logic of TRH is to create an anabolic terrain in which the other thyrotropic hormones can participate.

First loop central-peripheral coupling This level of interaction is directly related to anabolic initiation: ●

Axis 1: Gonadotropic ● H1a: FSH ● H1b: Estrogens Axis 2: Thyrotropic ● H2a: TSH ● H2b: T4

Central-central coupling is key to ensure the proper foundation of growth: both the creation of a matrix for growth and the energy for growth. The logic is the same as described in the discussion of the cortico-gonadotropic regulation. In short, FSH calibrates TRH to ensure that TSH is attuned to the level of FSH expression, which relaunches GnRH (Fig. 10.5). Hyperfunctioning of this relationship is

●

FIG.  10.5  First loop central-central gonado-thyrotropic coupling. See text for discussion. (© 2015 Systems Biology Research Group.)

FIG.  10.6  First loop central-peripheral gonado-thyrotropic coupling. See text for discussion. (© 2015 Systems Biology Research Group.)

The FSH stimulates estrogens. As estrogens initiate anabolism, T4 must be calibrated to the degree of anabolic solicitation of estrogens (Fig.  10.6). The FSH has

146  The Theory of Endobiogeny

the ­para-like effect of stimulating TSH. Estrogens play the alpha- and beta-like effect. A decrease in estrogens allows for a release of TSH and the relaunching of T4 to catabolize material and make it available to cells. Later in the first loop, a rise in T4 inhibits both TSH and estrogens in order to prevent excessive anabolism and excessive solicitation of the thyroid gland.

Second loop central-central coupling This level of interaction regulates the management anabolic achievement: ●

●

Axis 1: Gonadotropic ● H1a: GnRH ● H1b: LH Axis 2: Thyrotropic ● H2a: TRH ● H2b: TSH

T4 released in the first loop is catabolic (cf. Chapter 8). T3 promotes anabolism. Its primary function is to increase the rate of oxidative phosphorylation for ATP production (cf. Theory of Endobiogeny, Volume 3, disorders of glucose metabolism). The primary goal of coupling at this level is to create an environment within the thyroid in which TRH stimulation now favors T3 over T4. The LH calibration of TRH will also affect conversion of T4 to T3 within the liver, where most of T3 is produced (Fig. 10.7).

Second loop central-peripheral coupling: Progesterone This level of interaction is related to anabolic regulation: ●

●

Axis 1: Gonadotropic ● H1a: LH ● H1b: Progesterone Axis 2: Thyrotropic ● H2a: TSH ● H2b: T4, T3 (c.f. below)

FIG. 10.8  Second loop central-peripheral gonado-thyrotropic coupling. See text for discussion. (© 2015 Systems Biology Research Group.)

In the first stage, progesterone favors the production of T4 (Fig. 10.8). In the second stage (not an alpha-like effect) it inhibits LH and favors the excretion of the existing T3 from the thyroid before the time of TRH stimulation of conversion of T4 to T3. In the third stage, progesterone favors excretion of T4. This burst of T4 inhibits both TSH and estrogens and “closes” the door to the opening of anabolism. T4, as we will discuss later also has a thyro-somatotropic action. The net effect of progesterone is to slow down pituitary stimulation of peripheral endocrine activity allowing the finalization of anabolism by androgens (cf. cortico-­ gonadotropic coupling). NB: Gonadal androgens do not have a coupling relationship with the thyrotropic action. They have a particular relationship with the somatotropic axis due to the structuring and architectural action of gonadal androgens on the interior of the cell.

Thyro-somatotropic axis coupling This section refers to coupling of the thyrotropic and somatotropic axes in the manner we have already described. This is to be distinguished from the thyro-somatotropic linkage, where TRH, a thyrotropic hypothalamic hormone, is the stimulating hormone for prolactin a somatotropic pituitary hormone (Chapter 9). Gonado-thyrotropic coupling creates the matrix for structure and ensures the material to achieve it. For thyro-somatotropic coupling apportioning of the nutrients is required for elaboration of structure and the energy to achieve it (Fig. 10.9).

First loop central-central coupling ●

●

FIG. 10.7  Second loop central-central gonado-thyrotropic coupling. See text for discussion. (© 2015 Systems Biology Research Group.)

Axis 1: Thyrotropic ● H1a: TRH ● H1b: TSH Axis 2: Somatotropic ● H2a: GHRH ● H2b: GH

Endocrine associations: Coupling, linking, and yoking Chapter | 10  147

T4, a catabolic hormone, calibrates GH so that insulin-like growth hormone 1 (IGF-1) acts proportionally by incorporating those nutrients, and, fashioning and expanding structures relative to the nutrients liberates (also in conjunction with gonadotropic activity, cf. gonado-somatotropic coupling).

Second loop

FIG.  10.9  First loop central-central thyro-somatotropic coupling. See text for details. (© 2015 Systems Biology Research Group.)

The timing for the finalization of nutrient apportionment is strongly influenced by this coupling. Higher levels of TSH and growth hormone (GH) favor prolonged insulin resistance. This allows for more material to enter the cell prior to the time that prolactin, insulin, and somatostatin closes it in the second loop. Hyperfunctioning of the gonado-thyrotropic and thyro-somatotropic coupling can result in cysts or adenoidal growths. According to the theory of Endobiogeny, the specific structure is dependent upon the relative prominence of prolactin (cysts) relative to growth hormone (adenoidal growth).

First loop central-peripheral coupling This is the coupling of final apportionment of electrolytes and nutrients before the arrival of glucose and the closing of the cell for anabolism to occur. ●

●

Axis 1: Thyrotropic ● H1a: TSH ● H1b: T4 Axis 2: Somatotropic ● H2a: GH ● H2b: IGF-1, prolonged insulin resistance

The TSH stimulates GH by horizontal intra-pituitary stimulation, and T4 by vertical stimulation (Fig.  10.10).

FIG.  10.10  First loop central-peripheral thyro-somatotropic coupling. See text for details. (© 2015 Systems Biology Research Group.)

Because of the special relationship of TRH to prolactin, and prolactin having an inhibitor (not stimulating) hypothalamic somatotropic hormone, the action of coupling does not function as it does with the other axes. The theme of the sequencing is to close the door on nutrient entry so that the cell can begin the function of completing anabolism for maintaining or proliferating elements of the interior, and for fashioning the exterior.

Constitutional effects of cortisol on endocrine function Recall that one of the endocrine actions of cortisol is to run the pace of all the other hormones (Chapter 6). In sequential activity, cortisol influences the general timing of hormone excretion and hormone-receptor efficiency. In other words, it harmonizes the endocrine function of other hormones. What follows is a series of actions related to cortisol.

Cortico-somatotropic coupling: Central-peripheral The somatotropic axis is at the crossroads of first and second loops. While prolactin relaunches CRH to turn the loop, the coupling, as we have described it is cortico-­somatotropic, not somato-corticotropic. Before the loop is turned, the ­corticotropic axis needs to inform the somatotropic axis what it accomplished at the start of the first loop. In this way, relaunching of second loop corticotropic by prolactin is rational and coherent to earlier achievement (Fig. 10.11).

FIG. 10.11  First loop central-peripheral cortico-somatotropic coupling. See text for details. (© 2015 Systems Biology Research Group.)

148  The Theory of Endobiogeny

FIG. 10.12  Central-peripheral, multiaxial regulation by cortisol within the first loop. See text for details. (© 2015 Systems Biology Research Group.)

●

●

Axis 1: Corticotropic ● H1a: ACTH ● H1b: Cortisol Axis 2: Somatotropic ● H2a: GH ● H2b: IGF-1, prolonged insulin resistance

Recall that in cortico-gonadotropic regulation, cortisol calibrates FSH secretion and excretion (Fig.  10.3). When we combine, compressing space and time, we can create a schematic of cortico-gonado-somatotropic relationship (Fig. 10.12) with more complex relationships. The ACTH has one vertical action stimulating cortisol. It has two horizontal actions stimulating FSH and in a second time GH. Cortisol regulates both FSH and GH, which regulates in time their respective hormones: estrogens and IGF-1.

Turning of the loops: Central-central Another key coupling is that which turns the loops from first to second. This relationship is complex because while the somatotropic pituitary hormone prolactin is the regulator, it is regulated by the thyrotropic hypothalamic hormone TRH. The object of regulation is CRH. Thus, we have in effect a special type of thyro-somato-corticotropic coupling (Fig. 10.13). ●

●

Axis 1: Thyro-Somatotropic ● H1a: TRH ● H1b: PL Axis 2: Corticotropic ● H2a: CRH ● H2b: ACTH

The actions of prolactin are not only on CRH as shown in Fig. 10.13. It also alters GnRH pulsatility to favor LH. Prolactin ensures not only the turning of the loops, but its progression across the second loop: PL →ACTH → LH → TSH → PL → somatostatin, which ends the second loop. Insufficient horizontal prolactin activity can delay the

FIG.  10.13  Thyro-somato-corticotropic coupling, central-central. This relationship turns the loops. See text for details. (© 2015 Systems Biology Research Group.)

s­ econd loop of endocrine function and/or entrain a hyperfunctioning of first loop hormones. Physiologic depression is an example of this. Alpha and CRH/ACTH have the primary and secondary roles of ensuring adequate adrenal response to aggressions. However, when this is not sufficient, prolactin can assist. When prolactin is insufficient or excessive in its actions, it can favor a depressive terrain, especially one with rumination and looped negative thinking (cf. Chapters 8 and 9, and The theory of Endobiogeny, Volume 3, Depression). When prolactin is not able to readapt adrenal cortex function, TRH is oversolicited to relaunch prolactin. The TRH entrains emotive, ruminative thinking that results in anxiety and insomnia comorbid with depression. Prolactin stimulates dopamine, which favors the looped, negative thinking.

Anabolic-anabolic linking Anabolic linking helps calibrate the somatotropic fashioning of the exterior to gonadotropic structuration of the interior, e.g., the rate of organelles production relative to the rate of membrane expansion or the determination of tissue growth as normal, cystic, or adenoidal. The two anabolic axes, gonadotropic and somatotropic, are linked to each other in two different relationships. The first is gonadosomatotropic. Estrogens and gonadal androgens stimulate GH (c.f. Chapter  9). This occurs in the first loop and the second loop. Across the first to second loop, the somato-gonadotropic relationship occurs. As noted earlier, prolactin alters GnRH release to favor LH for progesterone and gonadal androgens. The PL diminishes output of estrogens but assures their activity by upregulating the number of estrogen receptors in the periphery. In a complimentary activity, progesterone slows down the activity of prolactin. The management of prolactin can hold the key to regulating dysmenorrhea with respect to its physiologic, mental, and emotional sequelae, as well as physiologic fertility. It also plays a role in various types of cancers and ponderal disorders such as obesity.

Endocrine associations: Coupling, linking, and yoking Chapter | 10  149

complementary role in calibrating immune function. For example, ACTH upregulates the number of histamine receptors. The TRH stimulates release of histamines and cortisol downregulates histamine activity. Cortisol mobilizes immune elements and thyroid hormones accelerate the rate of their action. The third is that their yoking allows for compensatory responses from both anabolic axes, adjacent to each of the two catabolic axes in our model of endocrine axes.

Conclusions

FIG.  10.14  Catabolic-catabolic yoking. Alpha-sympathetic (αΣ) stimulates both catabolic axes: corticotropic and thyrotropic. Each runs its course but is yoked to the general adaptation response by alpha. They influence each other. TRH fixes cortisol to its receptors, and cortisol sensibilizes cells to T4. (© 2015 Systems Biology Research Group.)

Catabolic-catabolic yoking Yoking is the parallel but interrelated action of endocrine axes, like two horses pulling the same carriage and responding to the same driver. Here, the driver is alpha. The horses—the catabolic axes—are the corticotropic and thyrotropic axes. The interrelation is between TRH, cortisol, and T4. The TRH fixes cortisol to its receptors. Cortisol sensibilizes cells to T4 (Fig. 10.14). Catabolic yoking ensures a number of coordinated responses. The first is mobilization of metabolites by both axes in the first loop, and their usage in second loop by the thyrotropic (cf. Chapters 6 and 8). The second is their

There are three types of association between hormones. The first is coupling. Coupling is usually between adjacent axes. It ensures the regulated and commensurate type, quality, and timing of action of catabolic and anabolic hormones. The second type is linking. Linking is between the two anabolic axes and ensures the complimentary of anabolic actions. The third is yoking, which is between the two catabolic axes. It ensures a coordinated response to aggressions. They are yoked by alpha. The development of every type of human disease can be related to dysregulation of central-central, central-peripheral dysendocrinism and the decoupling of the relative and commensurate quality of endocrine, endocrinometabolic, metabolic, endocrinotissular, and organo-tissular actions of hormones.

References 1. Simon  JA. Safety of estrogen/androgen regimens. J Reprod Med. 2001;46(3 suppl):281–290. 2. Caldwell  JD, Suleman  F, Chou  SH, Shapiro  RA, Herbert  Z, Jirikowski  GF. Emerging roles of steroid-binding globulins. Horm Metab Res. 2006;38(4):206–218.

Chapter 11

Endocrine-organ relationships: Drainage, detoxification, and disease Introduction The endocrine system regulates metabolism. How one line of endocrine activity calibrates or affects another has been discussed Chapter 10. This chapter focuses on how the endocrine system affects organs. Endocrine demand solicits organs to do something. The targeted organ(s) may serve one or more of the following roles: (1) intake, (2) uptake, (3) processing, (4) excretion, (5) detoxification, (6) growth, or (7) production. For example, when ACTH stimulates the adrenal gland to produce aldosterone (#7), it anticipates that aldosterone will affect electrolyte and water balance. To accommodate that, ACTH also stimulates the colon (#4) to reabsorb electrolytes and water from stool that aldosterone will require for its actions. During the adaptation response, FSH stimulates the ovaries (#7) to produce estrogens for the construction of immune factors. The FSH solicits the colon (#4) to absorb more proteins, and estrogens solicit the liver (#7) to produce immune factors. However, the liver is at risk of being congested, impairing its detoxification of the blood (#5) and its management of nutrients through portal circulation (#3). Each axis has its particular organs that it solicits for various functions (Chapter  2). Prolonged or intense solicitation diminishes buffering capacity and adaptability (Fig. 11.1). When the organ solicited cannot keep up with the demands imposed by the endocrine system it can become congested. In determine that can affect drainage or detoxification. These dysfunctions are implicated in precritical and critical terrains of every disorder, according to the theory of Endobiogeny (cf. The theory of Endobiogeny, Volumes 2–4).

Concept of congestion Congestion is an alteration in hemodynamics that results in impaired egress of liquids from a space. There are four general causes of congestion, implicating various levels of neuroendocrine, lymphatic, and organ dysfunction. They are

The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00011-2 © 2019 Elsevier Inc. All rights reserved.

interrelated and interconnected. When congestion occurs due to a change in the metabolic demand it is initially adaptive in nature because it brings in additional metabolites, electrolytes, and fluids required for cellular metabolism. The ANS, the endocrine system, or both solicit a change in the rate of metabolism of a gland, which allows it to benefit from the increased exposure to nutrients. Parasympathetic alters the general rate of cellular metabolism. Alpha causes postcapillary vasoconstriction, which allows blood to dwell longer within the organ. Beta allows for an increase in blood flow into the organ (Fig. 11.2). A prolonged duration of this activity can solicit an adaptative state that begins to diminish the metabolic capabilities of an organ. This may occur if the demand is excessive in duration or intensity relative to the capabilities of the organ, because the organ is oversolicited relative to its capacities, or both. In order to adapt the duration of alpha, histamine activity as an autacoid increases. However, prolonged histamine expression will result in the loss of capillary tight junctions and thus extravasation of water and proteins into the extravascular space. This then results in extravascular oncotic pressure exceeding intravascular pressure with further movement of water to equilibrate the osmolar imbalance. This increase in tissue pressure will compress the thin-walled lymphatics and veins, causing a pathologic accumulation of metabolic toxins. The factors are summarized below: 1. Augmented metabolic demand a. ANS b. Endocrine 2. Vascular a. Increased ingress: βΣ, cardiac b. Delayed egress: αΣ c. Permeability: Inflammation 3. Lymphatic a. Comprised flow b. Compromised structure c. Valve dysfunction

151

152  The Theory of Endobiogeny

FIG. 11.1  Diminished buffering capacity and the onset of congestion. Any pairing of elements of buffering can lead to congestion: digestive glandemunctory, emunctory-neuroendocrine, or digestive gland-neuroendocrine. There are implications for numerous disorders. Restoring buffering capacity can improve adaptability and relieve congestion. (© 2015 Systems Biology research Group.)

FIG. 11.2  Mechanisms of active and passive congestion. Passive congestion (left) involves alpha-sympathetic (αΣ) congestion of venules and veins prolonging the dwell time of nutrients in the liver. Active congestion (right) involves three possible mechanisms: beta-sympathetic (βΣ) vasodilation of inflow into the liver, parasympathic (πΣ) increase in resting vascular tone and reduced vascular resistance, and parasympathetic increase in metabolism. Prolonged or adaptive congestion, especially passive congestion, results in increased histamine activity, in part in its role as the autacoid that prolongs alpha-sympathetic. This results in capillary leak, interstitial edema, and ultimately lymphatic and/or venous congestion from hydrostatic compression. (© 2014 Systems Biology Research Group.)

4. Hydrodynamic a. Hydrostatic pressure i. Increased intravascular: Kidneys ii. Diminished extravascular b. Oncotic pressure: i. Diminised intravascular: Liver, kidney ii. Increased extravascular: Vascular permeability

Endocrine-digestive glands couplings Each endocrine axis mobilizes, utilizes, or influences absorption or excretion of various metabolites (Chapters 6–9).

This implicates a relationship between the endocrine system and various organs. What follows is an expanded discussion of these relationships.

Hypothalamus, pituitary, large intestine Stool contains various metabolites and nutrients. They arise from three sources: (1) partially undigested food, (2) intestinal microbial metabolism, and (3) excreted biological waste. Central hormones stimulate peripheral hormones which influence metabolism and demand particular metabolites. Central hormones solicit the colon to

Endocrine-organ relationships: Drainage, detoxification, and disease Chapter | 11  153

FIG. 11.3  Central endocrine-colon association. See text for discussion. (© 2015 Systems Biology Research Group.)

s­ cavenge stool for metabolites related to the function of their peripheral hormones (Fig. 11.3). Below, the relationship of each location of the colon to a central hormone, its peripheral hormone, and the related metabolite or fluid is related: 1. Terminal ileum and cecum: ACTH, structural adaptation: a. Gland: Adrenals b. Endocrine: Aldosterone c. Nutrients: Water, electrolytes 2. Ascending colon, right transverse colon: FSH: a. Gland: Gonads b. Hormone: Estrogens for metabolic activity c. Nutrients: Proteins 3. Hepatic flexure: TRH/TSH: a. Glands: Pancreas, gallbladder b. Hormone: Glucagon, insulin c. Nutrient: Augmentation of binding and absorption of fats 4. Left transverse colon: LH: a. Gland: Gonads b. Hormone: Androgens for completion of structure c. Nutrients: Compensatory absorption of proteins 5. Splenic flexure: TSH a Gland: Spleen b Immunity: Spleno-humoral c Nutrients: Iron, proteins 6. Descending colon: GH/prolactin: a. Gland: Endocrine pancreas

b. Hormone: Insulin; relaunching of second loop of adaptation and augmentation of ACTH c. Nutrient: Fats 7. Rectosigmoid: ACTH, functional adaptation: a. Gland: Adrenals b. Endocrine: Aldosterone c. Nutrients: Water, electrolytes This relationship can be evaluated by deep palpation of the colon on physical exam. Tenderness on palpation reflects an oversolicitation of the central hormones at that area for nutrients related to the functioning of their respective peripheral glands. This information can be integrated with additional signs and historical data to form a more detailed understanding of the patient’s condition. Consider a patient who presents with a history of migraines. You wish to determine what the role of central metabolism is in the oversolicitation of glucose from the liver. You find the following on history and physical examination which all suggest strong TRH activity: 1. History: Dreams in color, dreams of flying 2. Physical: a. Tenderness at the hepatic flexure of the colon b. Rapid deep tendon reflexes c. Three-beat clonus d. Spontaneous fluttering of the eyelids when speaking In addition to this, you find tenderness of palpation of the superiomedial hepatic border. This is linked to v­ ascular

154  The Theory of Endobiogeny

congestion of the liver. This is linked to a demand for more glycogenolysis. The TRH stimulates glucagon from the endocrine pancreas, which would make such a demand. If that is not sufficient to meet the glucose demands of the brain, alpha-sympathetic is solicited to install a congestion of the liver. One concludes from this elevated alpha and TRH with hepatic congestion and elevated glucose demand. A rational, clinical integrative physiologic treatment should include support of all three of these factors in treating the migraine terrain. In addition with respect to selecting a hepatic drainer, since glucose storage is implied, Arctium lappa (Burdock) would be a rational choice (cf. Materia medica in Volumes 2–3).

Corticotropic: Stomach, small intestines, kidney Cortisol increases gastric acidity. It also increases the uptake of lipids from the small intestines (Fig. 11.4). Gastric acidity serves as both a protection against pathogens as well as an augmentation of the hydrolysis of proteins. The uptake of lipids anticipates the later reconstruction of lipid-based structures in the body such as the cell membrane at a later time (Fig.  11.4). Lipids also are a substrate for cortisol production. Aldosterone regulates fluid and electrolytes. Within the kidney it stimulates retention of sodium and water and excretion of potassium (cf. Chapter 6).

Gonadotropic: Liver, gallbladder The gonadotropic axis consists of steroids composed of cholesterol. Bile is produced in the liver, then refined and stored in the gallbladder. Bile activity is inversely related to cholesterol reuptake and directly related to excretion of toxins. Estrogens and progesterone favor the retention of bile (Fig. 11.4). This increases reuptake of cholesterol, which provides more substrate for steroidogenesis. However, prolonged stasis of bile can lead to the formation of biliary calculi as well as impair the evacuation of lipidsoluble toxins.

Thyrotropic: Exocrine pancreas, intestines The TSH stimulates the exocrine pancreas in the excretion of digestive enzymes, particularly proteolytic ones (Fig.  11.4). This is related to two functions of TSH. The first is its pro-anabolic action on cells (Chapter 8), and the second is its role in soliciting amyloid proteins as a bridging energy before the time in which glucose or lipids are oxidized for ATP production. The PTH and D3 both act on the intestines to influence the absorption of calcium.

Somatotropic: Liver Glucagon diminishes glycogen stores in the liver and insulin increases them.

FIG. 11.4  Endocrine-organ associations according to the theory of endobiogeny. (© 2015–18 Systems Biology Research Group.)

Endocrine-organ relationships: Drainage, detoxification, and disease Chapter | 11  155

TABLE 11.1  Overview of endocrine-emunctory relationships Axis

Organ

Corticotropic + thyrotropic

Liver

Waste product(s) General

Hydrophilic toxins

Gallbladder

Corticotropic

Lipophilic toxins

Gastrointestinal

General

Lipophilic toxins

Skin

Water, electrolytes

Lipophilic toxins

Kidney, bladder Thyrotropic

Lungs

Hydrophilic toxins Water, carbon dioxide

Endocrine-emunctory relationships An emunctory is an organ that drains waste products. The two catabolic axes regulate emunctories as they are a source of surges in waste products related to catabolism (Table 11.1).

General catabolic: Liver, digestive tract The general catabolic activity managed by the corticotropic and thyrotropic axes require a general functioning of the liver as an organ of detoxification, and secondarily of the gallbladder for the excretion of lipophilic toxins. The digestive tract must maintain a proper rate of motricity and commensal flora in order to complete the detoxification proper and evacuation of waste products bound to stool.

Corticotropic: Kidney, skin The corticotropic axis specifically relies on the drainage of hydrophilic toxins from the kidneys. The efficiency of this drainage affects the resorptive rate of electrolytes and water required by the corticotropic axis in its adaptation response. The logic of efficiency of medicinal plants that serve as ­hepato-renal drainers is now clear (e.g., Betula ssp., Zea mais, etc.)1–3 The skin is another point of egress and is

the largest organ of drainage by surface area in the body. Its connection to the corticotropic axis is that both serve as a defense against noxious external agents.

Thyrotropic: Lungs The thyrotropic axis regulates the rate of cellular metabolism, thus the rate of glucose oxidation and cellular respiration for ATP production. The greater the rate of oxidation, the greater the production of carbon dioxide will be. Carbon dioxide is exhaled from the lungs, hence the relationship to the thyrotropic axis.

Endocrine-emunctory interaction and disease The interaction of the endocrine system to emunctories is key to understanding the precritical and critical terrains of general categories of disease. In clinical practice, even if one cannot recall the entirety of the critical terrain, one can still institute an effective drainage of key emunctories. According to the theory of Endobiogeny, relieving even one element of the critical terrain may be enough to induce remission into a precritical state (Table 11.2).

TABLE 11.2  Endocrine-emunctory interaction and disease expression Endocrine axis

1 Emunctory

2 Emunctory

Disorders

Medicinal plant

Gonadotropic

Liver-gallbladder

Colon

Skin, e.g., acne

Viola tricolor

Somatotropic

Liver

Pancreas, exocrine

Joints: e.g., osteoarthritis

Plantago major

Thyrotropicsomatotropic

Pancreas, exocrine

Kidney

Lungs: e.g., bronchitis

Agrimonia eupatora + Avena sativa

Cortico-thyrosomatotropic

Gallbladder

Pancreas, exocrine

ENT infections, e.g., tonsillitis

Plantago major + Avena sativa

ENT, ear, nose and throat.

156  The Theory of Endobiogeny

Consider a 14-year-old boy undergoing typical pubertal changes with acne papules and constipation. If you are not clear on the acne terrain (The theory of Endobiogeny, Volumes 3 and 4), use Viola tricolor (wild pansy) as an emunctory drainer. It is a polyvalent drainer of liver, intestines, kidneys, and skin. It is also antiinflammatory, depurative, and a mild laxative.1, 3 Consider a 47-year-old woman with acute onset bronchitis with fever and wet, productive cough. She has a history of dull hair and brittle nails. If you are not sure of how to treat the neuroendocrine terrain of bronchitis (The theory of Endobiogeny, Volumes 2 and 4), drain the pancreas and the kidney. This can be accomplished with a combination

of Agrimonia eupatoria (agrimony) and Avena sativa (wild oats) or Viola tricolor (wild pansy).1, 3

References 1. Lapraz  JC, Carillon  A, Charrié  J-C, et  al. Plantes Médicinales: Phytothérapie Clinique Intégrative et Médecine Endobiogénique. Paris: Lavoisier; 2017. 2. Greaves M. Gemmotherapy and Oligotherapy Regenerators of Dying Intoxicated Cells: Tridosha of Cellular Regeneration. Philadelphia: Xlibris Corp; 2002. 3. Duraffourd C, Lapraz JC. Traité de Phytothérapie Clinique: Médecine et Endobiogénie. Paris: Masson; 2002.

Chapter 13

Art of history taking in Endobiogeny Introduction The research that formed the basis of the Endobiogenic approach began in 1972 with Dr. Christian Duraffourd. It was based from its outset on two principles: scientific research and humanistic medicine. Its fruit is a clinical approach in which the patients and their experience of disease are at the very center of its evaluation. The clinical practice of Endobiogeny is based on three levels of evaluation: 1. Listening to the patient 2. Examining the patient 3. Studying the patient’s blood results Listening to the patient is a process that allows the history of the person and his/her illness to unfold in an organic manner. The Endobiogenist manages the process through strategic questions that guide this unfolding. The history offers subjective symptoms. Examining the patient uncovers objective signs. Studying the patient’s blood offers a unitary synthesis of signs and symptoms with quantitative numeration of qualitative physiologic activity. The result is a therapeutic approach that is personalized for each patient. The Endobiogenic consultation creates a holographic and hierarchical assessment of the patient as a living being moving through space and time in ceaseless dynamism, and reaction to its internal and external environments. The essence of Endobiogenic medicine is evaluation of the neuroendocrine management of terrain. Applying this to the threefold process noted above, we find that the history of illness demonstrates the trajectory and evolution of terrain from conception to present time. The physical examination reveals the patient’s current morphology, temperament, and personality. The Biology of Functions offers a quantification of the Endobiogenic terrain and capabilities of the organism in structure and function. Each level of the evaluation offers unique and overlapping data that will be integrated into the final assessment of the Endobiogenic terrain of the patient. Fig. 13.1 each sign or symptom must be contextualized and corroborated with other signs and symptoms before a final conclusion is reached. The greater the tentative conclusions from each level of evaluation are, the greater the probability that one’s final conclusions will The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00013-6 © 2019 Elsevier Inc. All rights reserved.

be accurate. Thus, there is a complete coherence between the three levels that cannot be dissociated if it is to remain within the Endobiogenic method. In this chapter we discuss the first of the three levels of evaluation: the history.

Overview of the elements of the history There are four elements to the history: (1) present illness, (2) review of systems, (3) past history, and, (4) family history Fig. 13.2. Just as each level of analysis (history, examination, and blood analysis) provides unique and corroborating evidence of the Endobiogenic terrain, so does each element within the history. The goal of the history is to call forth a story from the person seeking healing. The motto of the Endobiogenist during consultation is: Nothing is nothing. The patient’s history is fractal. Only a careful listening and reflection will uncover the recurring themes. There are stories within stories, physiologies within physiologies, chronobiologic timelines with chronologic time lines, etc. Fig. 13.3 suggests visually what a patient history looks like as a Mandelbrot equation. For example, a 66-year-old man presented for treatment of prostatic hypertrophy. Before our first meeting, he had sent me a few years of lab results. I (KMH) noticed that every spring his prostate specific antigen (PSA) increased threefold compared to his autumn values. I also noticed on the biology of functions that his cortisol activity and indices related to limbic and locus ceruleus charge from emotional trauma also increased, then normalized later in the year. On our first meeting, I inquired if there was an emotionally traumatizing event that occurred in the spring. He said that 3 years ago his wife died of breast cancer. There was a story within the story of his elevated PSA that needed to be called forth with a simple question. Once he remarried, this pattern of seasonal PSA variation resolved. Any word, phrase, metaphor, simile, hyperbole, or detail may be the key to integrating the totality of the patient’s information (cf. Chapter 17, Case study 1). The history taken by the Endobiogenist is not just a history of illness but also a history of the patient’s life. It evaluates the inductive and reactive elements of the internal and external terrains in 173

174  The Theory of Endobiogeny

FIG.  13.1  Probability Venn diagram. See text for details. (© 2015 Systems Biology Research Group.)

time and space. It develops the interplay between genetics, epigenetics, and environment throughout the grand phases of development (discussed later in this chapter). It witnesses the transgenerational continuity of life through genetics and culture. For example, the man with elevated PSA was referred for evaluation by his daughter, who was treated for leukemia as a child and presented shortly after her mother’s death from breast cancer with complaints of fatigue and

FIG.  13.3  Fractal representation of the aural unfolding of histories within histories during a full Endobiogenic historical intake. (Reproduced from https://White Haven/Shutterstock.com.)

poor memory. Both father and daughter share the love of their wife/mother, and both operate wineries.

History of present illness The history of present illness (HPI) is the history of the chief complaint—the issue for which the patient has requested a consultation. The Endobiogenist may choose to

FIG. 13.2  Schematic of history. Each aspect of the historical intake has various subareas of investigation that are possible. The depth of evaluation will depend on the expertise and time of the Endobiogenist and willingness and trust of the patient in the Endobiogenist. ROS, review of systems. (© 2015 Systems Biology Research Group.)

Art of history taking in Endobiogeny Chapter | 13  175

create a different hierarchy of treatment based on their complete Endobiogenic assessment; nevertheless, it is of value to allow the patient to express what is of greatest concern to him/her. The depth, complexity, and honesty of the HPI are augmented when the Endobiogenist sits face to face with the patient, maintaining appropriate eye contact throughout the interview. We sit down with our patients with them fully clothed around a table or desk and begin our discussion. This comes as a pleasant surprise to most patients who are used to considerably shorter and more formal doctor’s visits. When meeting a patient for the first time we offer a verbal Rorschach test by asking: What do you hope to accomplish from our time together. The question is posed in a nonjudgmental way in contrast to So, what’s wrong today? or What are you here for today? The Endobiogenic approach decontextualizes the visit from the expectations of a typical biomedical consultation. It allows the patient to interpret the question in an open manner, free of judgment, permitting an unguarded aspect of the patient’s ­personality to reveal itself. By this method one finds that patients converse with their Endobiogenist. Not infrequently, the patient will not begin with the symptoms listed in an intake form because of the question. And not infrequently, what they speak of is the true concern that they have, not what was listed on the intake form. Table 13.1 lists four types of often heard responses to the question, What do you hope to accomplish from our consultation? Some patients jump into a litany of complaints. Of these, some are quite linear and orderly. These patients come having written down exactly what they plan to say—indicative of the relative predominance of their TSH over TRH (see Chapter 8). Others present a heuristic history of symptoms based on various considerations ranging from chronologic to degree of suffering to a stream of consciousness description of events. This favors a relative predominance of TRH over TSH. Not only is how and when the patient speaks

i­mportant but also the metaphors they use. A physician in his mid-50s, e.g., used war metaphors to describe his illness, even alluding to a nuclear explosion. It suggested that at the level of subconscious mind, he felt attacked and devastated by his illness. Metaphors reveal how patients experience their illness. Once the patient has established his/her chief and secondary complaints, the Endobiogenist proceeds to evaluate them one by one. There are two ways the HPI can be approached. The first is to create a comprehensive history of development of each discrete illness. This works best in adults with multiple complex illnesses that span a large number of years. The second method is to create a timeline of events. In this method, all symptoms of all disorders are listed according to a timeline. The timeline can be arranged by various considerations, such as chronologic time, developmental phases of life, seasons, relationships to traumatic or notable events in patient’s life, etc. This method works well in children, or when the patient does not have a discrete disease, but a series of symptoms and gradual evolution of the terrain. We will give detailed examples later in this chapter. For example, let us say a 57-year-old man lists atheromas, prostatic adenoma, and seasonal allergies as his current, active illnesses. According to the first method, we would evaluate the history of each illnesses allowing for overlapping events in time. These multiple events may have occurred in the same year in different systems. This method does not make this readily apparent. It focuses on the evolution of each individual disorder or system of the body. Atheroma 44: Hypercholesterolemia 52: Exertional angina 54: Loss of libido 55: 75% blockage of left anterior descending coronary artery

TABLE 13.1  Often heard responses to “What do you hope to accomplish today?” Response

Case

Statement

Direct

13-year-old boy with new onset mild Crohn’s disease

“Support immune system while taking 6MP, treat root cause, improve growth, and come off medications if possible”

Indirect

27-year-old man with a 13-year history of diabetes and hypothyroidism

To address feeling of fatigue and shame of pornography addiction

Vague

34-year-old woman presented with a history of multisystem disease: fibromyalgia, Lyme, irritable bowel syndrome, panic attacks, chronic headaches, etc.

To feel better

Existential

47-year-old man

“The continuation, cultivation & organization toward physiological coherency between all body systems supporting fluid, easeful access to my full sense of vitality”

176  The Theory of Endobiogeny

Seasonal allergies 15: Seasonal allergies 18: Allergies resolved 52: Allergies resumed Prostatic adenoma 52: Lower urinary tract symptoms (LUTS): Night urination twice per night 54: Progressive worsening of LUTS: Night urination four times per night The advantage of this approach is that one may inquire about imaging studies, evaluations, and treatments tried according to each discrete disease entity. At another level of analysis, the advanced Endobiogenist will overlay the precritical and critical terrains of each of these disorders and consider the elements shared by each condition and those that are particular to each disorder. In this case, a very efficient treatment can be developed. For example, in the example of this man, supporting the adrenal cortex, draining the liver and pelvis, inhibiting luteinizing hormone (LH), and improving coronary blood flow will prove to be quite efficient. For example, one could prescribe Ribes nigrum bud (adrenals), Pygeum africanum (inhibits LH), Urtica dioica leaf and root (antiallergic, antiinflammatory, inhibits conversion of testosterone to dihydrotestosterone, pelvic drainer) and Agrimonia eupatora (hepatobiliary drainer, antiallergic), and Olea europaea bud (coronary dilator). If one’s goal were to evaluate the general terrain, axis by axis, one could list all the events in order of time like this: 15: Seasonal allergies 18: Allergies resolved 44: Hypercholesterolemia 52: Allergies resumed 52: Lower urinary tract symptoms (LUTS): Night urination twice per night 52: Angina with exertion 54: Loss of libido 54: Progressive worsening of LUTS: Night urination four times per night 55: 75% blockage of left anterior descending coronary artery However, the organization of treatments and evaluation would not be clear according to each discrete entity. In contrast, when evaluating young children, the timeline approach works well. This will be demonstrated in a case study below. It is not always apparent at the outset which method will serve the Endobiogenist best, or if both methods are needed. This emphasizes the importance of not merely being a stenographer for the patient, but of actively listening and analyzing the content of the history. The Endobiogenist generates considerably more information from an initial

visit than the typical medical evaluation. The most efficient manner in which to organize this information is by utilizing contextual frameworks to organize the information provided by the patient. This allows for the integration of information within the context of the inner life and outer relationship of the patient with others, with nature, and with the cosmobiologic phenomenon (Table 13.2).

Example of history by timeline and season of occurrence A 48-year-old woman presents with a history of thyroid cancer. Since 40 years of age, she has been experiencing recurrent sinusitis and heavier menstrual bleeding—but only between November and February. At 42 she was noted to have elevated cholesterol and elevated thyroid antibodies. At 44 she was noted to have thyroid nodules on examination, confirmed by ultrasound. The nodules were too small for fine needle aspirate to rule out cancer. At 46 her husband filed for divorce and her son was arrested and found guilty of manslaughter for drunk driving. At 47 she started having premenopausal oligomenorrhea. At 48 she was diagnosed with thyroid cancer. Table 13.3 presents her history by linear time line. The experienced Endobiogenist, as noted above, will consider the evolution of the terrain as she hears the development of the story over time. Evaluation of the history in this manner offers a consideration of the initial and current level of the Endobiogenic terrain most implicated in her current illness of thyroid cancer. It also demonstrates the evolution of the terrain and suggests the most efficient level of treatment.

A note regarding the general depth of history Regardless of the method of organization, be sure to thoroughly assess each symptom in Table 13.4. This ensures a

TABLE 13.2  Organization frameworks for historical intake Organizational frameworks Age and developmental stage when the symptom first occurred Season in which it occurred Other new illnesses that occurred with the primary illness Aggravation of existing or dormant illnesses during the liminal expression of current symptoms Metaphors the patient uses to describe their illness The patient’s emotionality in relationship to the symptoms or illness

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TABLE 13.3  Linear timeline of events with evolution of the Endobiogenic terrain Age

Event

Terrain

40

General

Time of gonadic recycling (cf. later in the chapter)

Fall disorders

Insufficient thyroid and adrenal adaptation to winter (cf. Chapter 12)

Sinusitis

Elevated TSH, Pancreatic oversolicitation, and as above

Menorrhagia

Elevated estrogens with overproliferation of the endometrium

Hypercholesterolemia

Elevated estrogens, hepato-biliary insufficiency, colonic congestion

Thyroid antibodies

Estrogen oversolicitation of thyroid activity

46

Personal stressors

Elevated alpha, relaunching thyrotropic axis, increasing oversolicitation of thyroid gland initiated by estrogens at 42

47

Premenopause: oligomenorrhea

Elevated cortisol activity with entraining of additional oversolicitation of thyroid function, periodic hyperestrogenism and hyper-FSH state further soliciting TSH and thyroid activity by horizontal stimulation (cf. Chapter 10)

48

Thyroid cancer

Conjunction of above factors

42

TABLE 13.4  Clarifying questions related to symptoms Clarifying questions Age of onset Duration of illness Frequency of recurrence Severity and quality of discomfort Location of discomfort Ameliorating factors Aggravating factors Evaluations to date Treatments and interventions tried Efficacy of those treatments and interventions

proper understanding of each complaint. It also creates a more or less objective metric by which to compare the patient’s evolution under treatment. An example is given with respect to migraine headaches presented in Table 13.5 and follow-up data.

Review of systems Traditionally, “review of systems” (ROS) refers to a checklist of liminal symptoms by organ system. For example, for a comprehensive evaluation the United States Centers for Medicare and Medicaid Services requires the information listed in Table 13.6.

This type of review is certainly encouraged. The challenge faced in a typical private practice is that the only thing more troublesome than not asking these questions is asking them. Should the patient state that they have any of these problems, the physician does not have the time to explore them at that visit due to time limitations. Should the patient list multiple complaints across multiple organ systems, the physician will not have had the training in integrative physiology to determine interconnectedness of the symptoms. In Endobiogeny the ROS is a systematic evaluation of global neuroendocrine functioning according to functional spheres of activity. It indicates the patient’s past, present, and possible futures. It uncovers layers of history the patient often does not even think are worth mentioning. A careful HPI provides breadth, a thorough review of systems provides depth to the Endobiogenist’s assessment of terrain. The ROS for children is presented in Table 13.7. This approach incorporates social and psychosocial elements that help develop an understanding of the child’s trajectory of personality development, as well as traditional milestones or organic development. There is a slight variation to the five key systems between children and adults (viz., women). The Endobiogenist is encouraged to explore the ROS of childhood in adults. The key to many current health issues in the adults can be found in the ROS of childhood. Let us give two examples. A woman with secondary amenorrhea witnessed her father physically abusing her mother at 15, the gonadotropic endocrine phase of development (cf. life cycles below). She continued to have menstrual cycles of normal duration, but with heavy bleeding. At 19, she spent 1 year studying overseas. She experienced a second emotional shock when she felt lonely and isolated. At that time, she experienced secondary amenorrhea.

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TABLE 13.5  Clarifying questions for a patient with migraine headaches with aura Clarifying questions

Presentation

Follow-up

Age of onset

15 years

Not applicable

Duration of illness

72 h

12 h

Frequency of recurrence

6 per month

2 per month

Severity of pain

8/10

6/10

Location of pain

Temples, left > right

No change

Quality of pain

Throbbing with aura, no radiation or movement

Throbbing. resolved: aura

Ameliorating factors

Prevention: avoiding sugar and coffee, frequent eating During attack: coffee, resting in a dark, quiet place, being still

As before, except stillness not necessary

Aggravating factors

Emotional stress, premenstrual phase of menstrual cycle, insufficient sleep, high-pressure weather

As before, except tolerates all weather patterns

Evaluations to date

CT scan of brain: masses ruled out

Not applicable

Treatments and interventions tried

Not helpful: ergotamines, chiropractic, beta-blockers Helpful, not sufficient: nonsteroidal antiinflammatories, Valerian tea during migraine

Endobiogenic treatment of terrain

TABLE 13.6  Typical approach to review of systems System

Examples

Constitutional

Unexplained weight loss, night sweats, fatigue/malaise/lethargy, sleeping pattern, appetite, fever, itch/ rash, recent trauma, lumps/bumps/masses, unexplained falls

Eyes

visual changes, headache, eye pain, double vision, scotomas (blind spots), floaters or “feeling like a curtain got pulled down” (retinal hemorrhage vs amaurosis fugax)

Ears, nose, mouth, and throat (ENT)

Runny nose, frequent nose bleeds (epistaxis), sinus pain, stuffy ears, ear pain, ringing in ears (tinnitus), gingival bleeding, toothache, sore throat, pain with swallowing (odynophagia)

Cardio-vascular

Chest pain, shortness of breath, exercise intolerance, orthopnea, edema, palpitations, faintness, loss of consciousness, claudication

Respiratory

Cough, sputum, wheeze, hemoptysis, shortness of breath, exercise intolerance

Gastro-intestinal

Abdominal pain, unintentional weight loss, difficulty swallowing (solids vs liquids), indigestion, bloating, cramping, anorexia, food avoidance, nausea/vomiting, diarrhea/constipation, inability to pass gas (obstipation), vomiting blood (hematemesis), bright red blood per rectum (BRBPR, hematochezia), foul smelling dark black tarry stools (melaena), dry heaves of the bowels (tenesmus)

A 56-year-old man presented with obesity and “uncontrollable” sugar cravings. He had a terrain that indicated mixed-type obesity due to multiple neuroendocrine and emunctory dysfunctions. Dietary changes and an Endobiogenic treatment assisted in him loosing 10 kg of weight, after which he experienced no further reduction in weight. In his ROS of childhood, we found that he felt abandoned by his mother due to her mental illness and tendency to stay in her room for days at a time. His maternal aunt would provide “comfort foods” as an emotional s­upport,

primarily fatty and sweet desserts. Once the emotional relationship with food was addressed the patient lost an additional 7 kg of weight (Table 13.8).

Past medical history (PMH) Introduction Hippocrates said, “It is more important to know what sort of person has a disease than to know what sort of disease a

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TABLE 13.7  Endobiogenic review of systems for children System

Significance

Development

Evaluation of the standard development milestones: language, gross motor, fine motor and social interactions; development of temperament from infancy: e.g., patient liked to be held by strangers or only by particular caregivers, patient colicky vs. calm, precocious vs infantilization, etc.

Personal and interpersonal

Family life: relationship with parents, siblings, other family members; hobbies and interests, etc.: e.g., a child who loves to draw vs read vs engage in athletics; a child who is interested in caring for animals vs injuring animals, etc.; School and personal life: performance, participation in activities, friends; reliance on others for emotional support and protection; spiritual and/or religious life

Sleep-wake architecture

Neuroendocrine and chronobiologic physiologic integration; caregiver-patient interaction and power struggles; dreams and interior life; emunctory function (night wakening, enuresis)

Alimentation and eating habits

Neuroendocrine and emunctory strain from diet; cravings and consumption of nonfood items indicate alimentary demands from the Endobiogenic terrain or signs of vitamin/mineral/amino acid deficiencies; e.g., a child who eats only macaroni and cheese vs hot chicken soup vs ground meat; e.g., craves cold drinks vs warm drinks or cheese vs grapes, the consumption of dirt vs paper

Bowel movements

Neuroendocrine and dietary factors, rearing practices and power struggles with primary caregiver (“Children controls two things in their life: what goes in their mouth and what comes out their anus”a); evaluate quality and frequency of stools, ease of evacuation, presence of undigested food, floating stools, odor, size, etc.

a

Dr. Soheil Gebara, pediatric gastroenterologist, William Beaumont Hospital, Royal Oak, MI, United States, said to Kamyar M. Hedayat during pediatric residency training.

TABLE 13.8  Endobiogenic review of systems for adults with special consideration of women System

Significance

Menstrual cycles

Neuroendocrine, emunctory and circulatory functions across time and general integrity and adaptability of central and peripheral endocrine relationships; n.b.: evaluate presence of current or prior catamenial disorders

Personal and interpersonal

Cf. Table 13.7. Also, professional satisfaction, spiritual and/or religious life

Sleep-wake architecture

Cf. Table 13.7

Alimentation and eating habits

Cf. Table 13.7; note change in diet related to menstrual cycle in women

Bowel movements

Cf. Table 13.7

person has.” To understand the person who sits in front of us, we must understand what transpired before they came to us. The past medical history (PMH) involves four categories, which elucidate aspects that influence the terrain of the patient:

1. Adult Medical history 2. Adult Surgical history 3. Childhood history 4. Family history There are six factors to consider when evaluating the four categories of the PMH: 1. Genetics 2. Epigenetics 3. Phenotype 4. Culture 5. Environment 6. Geography Throughout this section, we will cite studies related to asthma and these various factors.

Genetics, epigenetics, and phenotype Genetics is the pure potentiality of the organism. It contains the mechanisms for the maximum and minimum physiologic range. Epigenetics elevates genetics from probability to directed possibility (cf. Epigenetics, below). It modifies the expression of the genome beyond what was anticipated by the genetic heritage by adapting it to environmental exigencies. Phenotype is the functional dynamic expression of the epigenotype in a given moment in time and development (cf. Chapter  2). For example, with respect to genetics, children born to parents with atopy have a higher

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incidence of asthma and their asthma is more severe and commences earlier in childhood on average.1, 2 With respect to ­epigenetics, prenatal maternal use of antibiotics increases the risk of asthma in children.3

Culture The term culture is derived from the Latin word cultura meaning “to cultivate.” With respect to humans, cultivation implies that the intrinsic, genetic program of development is developed and modified by a force external to it. Where genetics provides the basis of the physiologic range, culture provides the basis for the range of beliefs and behaviors. It cultivates genetics. It contains programmatic paradigms that favor behaviors not implicitly encoded in the genetic heritage. Culture determines whether a physical symptom, a syndrome, or behavior is a disease or not, and, what it means to have that disorder.4 It influences the words we chose to describe our symptoms. It also affects our beliefs about the possibility of healing, the role of suffering, and the relationship with the practitioner. For example, a 36-year-old Hispanic-American woman presented for treatment of posttraumatic stress disorder and dysautonomia. Her history was replete with traumatic physical and emotional events. She was born prematurely and felt abandoned in the neonatal intensive care unit. Her twin sister cutoff relations with her. She has a love/hate codependency with her mother and was in multiple car accidents that occur within a week of the initial accident. However, she did not consider prolonged and repeated corporal punishment by her parents as a traumatic event because, as she noted, “it was common in our culture.” In the general secular culture of the United States, hearing voices in one’s head may

be a cause for concern. In the subculture of evangelical and charismatic Christians, it may be a blessing if it identified as the voice of Jesus or the Holy Spirit. The former will seek counseling while the later will feel uplifted. Culture also includes the diet consumed because various cultures and subcultures have various degrees of adherence to moderate, seasonal eating of minimally refined foods. For example with respect to asthma, elevated consumption of refined grains, sugar, saturated fats, red meat3, 5 and/or reduced consumption of fresh fruits, vegetables, omega-3 rich foods3, 6 is associated with a higher incidence of asthma.

Environment and geography The term “environment” refers to three types of ecology: social (interpersonal), domicile, and habitat. Social ecology refers to the interpersonal dynamics with family, friends, and colleagues as well as birth order, number of siblings, etc. Domicile refers to the location and surrounding of one’s residence: rural vs urban vs suburban, home vs apartment vs shanty, multifamily vs single-family household, etc. All these factors play a role in the development of the immune system and the risk of asthma.6–9 Habitat refers to the quality of the air, water, and soil of both domicile and agriculture (i.e., nutritional density). Lower air quality is associated with increased risk of asthma.3, 10, 11 Finally, geography is the influence of topography, longitude, latitude, weather, and exposure to geopathic and cosmologic electromagnetic phenomenon. With respect to asthma, humidity plays an important role in seasonal variations of asthma admissions in temperate climates.12, 13 With these considerations one can create a matrix to reflect in sum these complex interactions (Table 13.9).

TABLE 13.9  Physiologic and nonphysiologic factors influencing expression of the terrain. Factors Category

Subcategory

Genetic

Epigenetic

Phenotype

Culture

Environment

Geography

Childhood

Conception

•

•

•

Birth

•

•

•

Infancy

•

•

•

•

•

•

Toddlerhood

•

•

•

•

•

•

Adolescence

•

•

•

•

•

•

Medical

N/A

•

•

•

•

Surgical

N/A

•

•

•

•

Family history

N/A

•

•

•

•

•

•

•

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A discussion on epigenetics and introduction to the concept of hologenetics An epigenetic framework helps to define how environmental experiences (whether internal or external, biotic, or abiotic) modify the molecular factors and processes around DNA to regulate genomic activity “independent of the DNA sequence”, essentially establishing an “imprint” that provides temporal and spatial control of genomic activity. The functional consequences are that the organism responds differently to its environment—and in a way not predicted from a structural analysis of the genome Burggren and Crews, Epigenetics in comparative biology: why we should pay attention.14

According to the theory of Endobiogeny, epigenetics is the strategy of modification of the organism’s genetic potential in order to adapt the phenotype to the demands of the internal and external environments. Epigenetics represents a robust scientific approach to explain how the final, functional, and dynamic expression of morphology, temperament, and personality is not constrained to deterministic expressions of genetic information. The French scientist Lamarck developed a prototypic concept of epigenetics in the early 19th century. His ideas were rejected due to the popularity of Darwin’s theory of evolution and Mendelian genetics. The concept came back into favor through the work of embryologists and biologists. The term “epigenotype” was coined in 1942 by CH Waddington in his seminal article “The Epigenotype.”15 Waddington framed the central challenge in the opening paragraph of his article: Of all the branches of biology it is genetics, the science of heredity, which has been most successful in finding a way of analyzing an animal into representative units, so that its nature can be indicated by a formula, as we represent a chemical compound by its appropriate symbols. Genetics has been able to do this because it studies animals in their simplest form, namely as fertilized eggs, in which all the complexity of the fully developed animal is implicit but not yet present. But knowledge about the nature of the fertilized egg is not derived directly from an examination of eggs; it is deduced from a consideration of the numbers and kinds of adults into which they develop. Thus genetics has to observe the phenotypes, the adult characteristics of animals, in order to reach conclusions about the genotypes, the hereditary constitutions which are its basic subject-matter (emphasis ours). Ref. 15

While we agree with Waddington’s conclusions, we take issue with some of the observations that led to his conclusion. First, genetics does not study animals as “units of activity.” It studies packets of information—packets of potentiality—an

abstraction from “units of activity” which refers to phenotype in our view. These packets of information, these genetic sequences contain information for the structuration of units of activity: cells, tissues, and organs, which then function in their basal and adaptive capacities in a ceaselessly dynamic fashion within their Endobiogenic terrain. As long as the organism is alive, even in its most rudimentary form of embryonic life, one will always be studying phenotype and evaluating what Waddington referred to as the epigenotype. Finally, each stage of the development of an organism is onto itself with implicit orders of potentiality of later stages of development that are dependent on time, space, and prior experience. We will elaborate on this below. There are, according to Burggren, three schools of thought in epigenetics: intragenerational, transgenerational, and holistic.14 The first school, intragenerational, is most prominent among medical researchers and focuses on mechanisms of disease risk, i.e., carcinogenesis due to epigenetic factors. Over 96% of articles during a 3-year period of 2010–13 focused on intragenerational epigenetics. This school comes out of the reductionist paradigm of genocentric biology and studies what it considers to be the interaction of the gene with its environment. The second school, transgenerational, is more prominent among the biologists and psychologists. It considers epigenetic changes as occurring as an adaptative mechanism in response to environmental demands and how these changes are propagated across generations by nongenetic means. This school evaluates which external environments alter the expression of the genotype through gross behaviors and traits (molar epigenesis). The third school, the holistic school, promulgated by Burggren et  al. views epigenetics as a “perspective.” It takes a systems biology approach that contextualizes the organism in and of itself (intragenerational), within the context of embryonic development, and the entire ecologic framework of its environment (molar epigenesis), thus the term “holistic.” They have taken a multiscale to ecosystem, an approach we support (Fig. 13.4). From the Endobiogenic perspective we can say that epigenetics is a probabilistic phenomenon between the potentiality of genotype and actuality of phenotype. It is important to emphasize that we do not consider epigenetics to be a mechanism, but a strategy that allows for maximum adaptability of the organism. It explains changes in physiology, behavior, and traits that occur in a single generation without alteration of genetic sequencing. To note, there are mechanisms that have been identified—methylation, histone modification, etc. that affect the intensity and duration of expression of genes. However, the Endobiogenic approach is far broader than the mechanisms of genomic modification. Thus, we propose a fourth school of thought that we call hologenetics. Hologenetics is the study of an organism’s Endobiogenic terrain as a result of genetic, epigenetic, and environmental

182  The Theory of Endobiogeny

FIG. 13.4  A multiscale holistic approach to epigenetics. This approach considers the levels of function and structure from the molecular to molar. The molecular levels refer to levels from genetics to expressed physiology. The molar refers to individual behavioral and higher organizational levels and environments. (Reproduced from Burggren WW, Crews D. Epigenetics in comparative biology: why we should pay attention. Integr Comp Biol. 2014;54(1):7–20. https://doi.org/10.1093/icb/icu013. Oxford University Press.)

demands across generations, time, and space. Hologenetics evaluates intrinsic intragenerational demands of survival, secondary intragenerational integration demands within the hierarchical ecologic scales of unity, and transgenerational demands of survival as expressed within time, space, and phases of development. Epigenetics occurs during embryonic and fetal development (fetal, materno-fetal, and maternal demands), intergenerational epigenetic history, internal adaptation demands on the mother, external ecologic demands on the materno-fetal unit, and the intragenerational adaptation demands that modify the expression of the genome beyond what was anticipated by the genetic heritage. It helps explain how children and grandchildren “inherit” adaptative physiology of ancestors and how the unprecedented exposure to nonpulsatile electromagnetic fields,16–18 industrial toxins,3, 11 and altered biorhythms from artificial light may be altering our physiology and disease patterns faster than Darwinian mechanisms of genetics can explain.

An example of PMH as a tool for prevention of disease There has been much discussion regarding the screening of adults for breast cancer. This approach arises from an approach to medicine that does not know how to evaluate the terrain of the individual. It does nothing for prevention, but can detect some cancers early at a time that is easier to treat.19, 20 However, for every one case detected

by screening three women will be falsely diagnosed and undergo unnecessary biopsies.20 The prevention of breast cancer on the other hand is a proactive approach. It illustrates the true value of an in-depth review of systems and PMH. According to current studies, the majority of factors related to a woman’s lifetime risk of breast cancer are preventable.21, 22 More than 80% of risk factors are preventable or have an element of choice for many women. For example, lifestyle account for 68% of breast cancer risk for US women. These researchers state, quite correctly that prevention of breast cancer starts at 2 years of age. We support these measures as they impact the Endobiogenic terrain. However, we find that an individualized approach to cancer must be taken to truly understand the individual person’s risk (cf. Chapter 17, “Case 2: A study in disease prevention” section). The risk of breast cancer is transgenerational and decisions by mother and daughter affect each other’s risk of breast cancer. Because most of the factors are lifestyle related, culture is implicated in breast cancer.21–23 According to Colditz et  al., 68% of all the cases of breast cancer in women can be prevented with appropriate childhood and adult interventions: postmenopausal weight (32%), breastfeeding (15%), physical activity (11%), diet, and alcohol consumption (8%). Another 18% related to age of first birth and number of pregnancies. Thus, we see the importance of a thorough ROS of childhood in an adult patient: rate of growth, age of first menses, diet, lifestyle, etc.21, 22, 24 In the PMH, we see the convergence of genetics, epigenetics, and phenotype. We see the role of culture, such as diet, lifestyle, and reproductive decisions: age of first child, breastfeeding, use of oral contraception, etc. We also see the influence of the environment (e.g., nutritional density of food). In this single example we see the complexity in breadth and depth of the history of the patient that must be obtained in order to assess the risk of a single illness. In summary, there are six factors that influence four categories of the history of the patient. These six factors alter the terrain in nonprogrammed and unanticipated manner. This history allows the Endobiogenist to evaluate the initial terrain of the patient and how various events have altered the trajectory of development of the Endobiogenic terrain. It also offers possible treatment modalities that empower the patient to manage aspects of their life and environment.

Seven phases of life, their endocrine programs, and subprograms The terrain evolves based on seven programmed chronobiologic intragenerational evolutions: (1) embryogenesis, (2) fetogenesis, (3) infancy, (4) toddlerhood, (5) puberty, (6) adulthood, and (7) gonadopause, based on genetic inheritance, with the hologenetic modifications noted earlier. They reflect the requirements of each phase of development based on the requirements of survival, growth (­physical, emotional,

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intellectual, and social), reproduction, and death. The terrain changes throughout life in an anticipated manner. However, these changes occur in the midst of unanticipated demands from the environment. Thus, the possibility of adaptative states is augmented during these phases of life.

TABLE 13.10  Endocrine recycling phases 1 and 2: embryogenesis and fetogenesis

Phases 1 and 2: Embryogenesis and fetogenesis: 0–40 weeks gestation The general endocrine program is ACTH and adrenal androgens (Table 13.10). Embryogenesis occurs in the first 8 weeks of life, fetogenesis thereafter. The first trimester (weeks 1–13) encompasses embryogenesis and the initiation of fetogenesis. It is significant for the definition of structure. Embryogenesis is the most influential period of development. Gastrulation, neurulation, and cardiogenesis occur during this time. All three types of histological tissues are distinguished as well. Any aberrations that occur during this time will have pronounced implications for fetal and human development. Many women do not realize that they are pregnant until the embryo is well under development. Fetogenesis represents the majority of growth and differentiation of embryonic material. The second trimester defines the functional capabilities of the fetus. Structure is further elaborated with the launching of FSH and LH. Toward the end of the second trimester, the somatotropic axis is launched. Into the third trimester GH, and then TSH further elaborate and fashion growth. Finally, PL rises reaching a peak at the time of parturition.

NB: The table below lists the fetal endocrine development and not the maternal evolution.

Phase 3: Infancy: 0–11 months Infancy is the period from birth through the completion of the 12th month of life. For the entirety of preadulthood, the general plan of development is under the management of the somatotropic axis (Table 13.11). During infancy the parasympathetic nervous system is particularly predominant. Infancy represents the most pronounced period of postnatal growth. A child doubles the birth weight by 5 months and triples it by 12 months of age. Length increases by 50% by the end of the first year of life. From 1 year of life, it takes approximately 10 years to triple one’s weight again, and 6 years to increase one’s height by 50% once more.

TABLE 13.11  Endocrine recycling phase 3: infancy

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For the first 9 months of life, within the general paradigm of para-somatotropic predominance, the catabolic axes play a special role. They provide the energy required to “nourish” anabolism with catabolic products in order to support this period of growth. Recall that this growth is not just physical, but cognitive and requires a special participation by the thyrotropic axis in neuronal development.

TABLE 13.13  Endocrine recycling phase 5: puberty

Phases 4: Childhood: 1–11 years Childhood is from 1 to 11 years of age. It has three phases: early (toddlerhood): 1–4, mid (school age): 5–7, and late: 8–11 (preadolescence). Within the general somatotropic plan, once again we see a relay of the catabolic axes (Table 13.12). From 1 to 7 it is the thyrotropic axis, which favors a greater velocity of linear growth relative to mass. From 8 to 11, it is the corticotropic axis, which favors a greater velocity of weight gain relative to height—the final time that the organism will grow with this velocity under a genetic chronobiologic programming. Prepuberty is the second of the three grand phases of life in which DHEA plays a key role, the first being fetal development, and the third being gonadopause.

Phases 5: Adolescence: 12–21 years In the Endobiogenic concept of development, puberty, the end of the exterior fashioning, occurs from 12 to 21 years of age. The same is true for the development of the ­personality, which is finalized by the end of puberty. Any further refinement of temperament and personality will only occur by i­ntentional self-development (cf. “temperament” below). Most of puberty is regulated by the gonadotropic axis u­ nder the ­general TABLE 13.12  Endocrine recycling phase 4: childhood

­ anagement of the somatotropic axis for the finalization of the m adult form (Table 13.13). Here the gonadotropic axis participates in expressing secondary sexual characteristics as well as fertility and aspects of personality. The plan of pubertal development is initiated by an increase in metabolic activity of the cell favoring predominance of the anabolic axes, in contrast to the predominance of the catabolic axes in infancy and childhood. To wit, children are highly anabolic in their relative predominance of m ­ etabolism, but the role of the catabolic and anabolic axes varies throughout childhood. In the second phase, the tissular mass increases, as is noted by an increase in muscle mass, breast mass and configuration, and lengthening of the penis. In the final phase of puberty, the final endocrine relationships are established for the remainder of the adult state of fertility.

Phase 6: Adulthood: 22–46 years With the onset of adulthood at 22 years of age, the organism continues to grow and refine itself. During this time as it is under the direction of the gonadotropic system, the growth of the organism is in the interior. While liberation and separation occurred at birth, emancipation and individuation will not completed for another 8–10 years, on average around 30 plus or minus 3 years. Emancipation requires the alignment of five threads of development to become braided together by the end of the second decade of life: relationship to self, to family, to an intimate partner, general social relationships, and professional life. When there is a lag in one or more areas during the first genital recycling, the patient is susceptible to new onset of disease or exacerbation of existing illnesses. For example, a man presented in his late 40s with chronic pain and chronic fatigue syndrome. He was in ­excellent health until at 29, he experienced a loss of friends, his job, and a break up with his romantic partner. That same year, he started presenting symptoms. A woman presented

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at 30 years for the treatment of a skin disorder, which we successfully treated. At 31 years, she had sudden onset of excruciating pelvic pain unresponsive to all forms of intervention. Based on her biology of functions, she was referred to a psychologist. She came to learn how she was suppressing strong and negative emotional responses and judgements regarding her childhood, unfulfilling job, and lack of romantic partner. The pain resolved within 6 months of therapy, with corresponding changes in her biology of functions. For the remainder of the organisms’ existence, it will remain under the general management of the gonadotropic axis, as it initiates the general metabolic demand (Table 13.14). As such, the organism will undergo a series of genital pauses approximately every 7 years. The purpose of these pauses is to allow the organism to restructure the level of general gonadotropic function and hence the entrainment of thyrotropic and somatotropic function as well. Genital pauses can entrain adaptative states that create a terrain favorable to conditions such as cysts, fibroids, thyroiditis, and cancer. The liminal expression of disease is often TABLE 13.14  Endocrine recycling phase 6: adulthood

seen within 2–5 years of the onset of the genital pause. Not infrequently, women will note symptoms that occur within 1–2 weeks of their 39th, 40th, or 41st birthday.

Phase 7: Gonadopause: 47 years until death Gonadopause for women marks the end of fertility. For men, it marks a decline in fertility. In both the restructuring of genital function can impact structure, function, and personality more than during the other times of genital pause (Table 13.15).

TABLE 13.15  Endocrine recycling phase 7: Gonadopause to death

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Stages of disease development According to the theory of Endobiogeny, there are five stages related to the liminal manifestation of disease. These factors are (1) precritical terrain (cause), (2) provoking agent (aggressor), (3) critical terrain (response), (4) mechanism, and (5) effect. The precritical terrain helps explain why some people are more susceptible to the development of a disorder than others. It is the precritical terrain that fragilizes the organism and compromises buffering capacity. It is subliminal in that the patient shows no symptoms, but may have signs on evaluation. The careful Endobiogenic physical examination (cf. Chapter  14) offers the Endobiogenic physician the opportunity to truly prevent or cure disease by addressing these precritical factors, such as a hyperparasympathetic state or vascular liver congestion Fig. 13.5). Underlying the precritical terrain are genetic and epigenetic factors, such as the threshold of reactivity of the pancreas to carbohydrates, bronchial cilia beat frequency, etc. However, practically speaking, the precritical Endobiogenic terrain will be considered to be a particular combination of autonomic, endocrine, and emunctory dysfunction that are assessable by the clinician. The precritical terrain may be an autopathogenic factor (cf. below). Alternatively, it may be entrained from dysfunctions induced by another disorder, e.g., postviral autoimmune disease (cf. critical terrain below). As long as all the precritical factors are not present, many patients will not express disease, even in the face of the aggressor. For example, if a vagotonic patient has hepatobiliary congestion but a well-adapted adrenal cortex (cf. The theory of Endobiogeny, Volume 2, Chapters 3, 7, and 9), in the face of an ordinary exposure to a virus circulating in the community, they will not contract an infectious disease. However, if they have just returned from a voyage and faced time zone changes which exhausted their adrenal function, they may in fact contract the illness like others in their ­environment, because by now all three critical factors would have been expressed in the face of an aggressor. For others in the community, they may have had a precritical infectious terrain of adrenal insufficiency and a h­ yperparasympathetic

FIG.  13.5  Five stages of manifestation of disease. (© 2016 Systems Biology Research Group.)

state and the emergence of hepatobiliary congestion, say, from excess consumption of alcoholic beverages during a weekend may be what makes them susceptible to the viral illness. All three factors of the precritical terrain must be present at the time of exposure to the provoking agent in order for disease to manifest. Conversely, resolving even one aspect of the precritical terrain would be considered to be a true cure in Endobiogeny. Thus, the adage that when it doubt, drain the key emunctory. The agent, or, aggressor, is the factor that solicits a response by the organism. The aggressor is merely an agent provocateur. It does not cause disease. It is the patient’s response to the aggression that installs the disease, in the face of the precritical terrain. This is why the exploration of the individual patient’s terrain is so important to assess. For example, in inflammatory bowel disease, the consumption of a low-fiber, refined carbohydrate and dairy are implicated in the development of disease.25, 26 However, not all or even most patients who consume this type of diet develop an inflammatory bowel disorders such as Crohn’s colitis (cf. The theory of Endobiogeny, Volume 3, Chapter  11). It is only those with the precritical terrain, which is partially inherited, who face the risk. This also explains why generations may pass before a patient develops Crohn’s disease. If their family ate a whole-grain diet, minimal red meat, and fermented dairy from animals never fed genetically modified corn and soy produced with synthetic fertilizers, they would not have been exposed to the fragilizing factors, this even though they may have expressed the precritical terrain all their lives, generation after generation. In fact, studies show that the incidence of Crohn’s disease correlates to societal shifts to a diet rich in refined and pro-inflammatory foods.27 Implicated in this observation is the change in the intestinal microbiome.28 The critical terrain is the maladapted response that installs the disease. These are actions that are necessary to address the aggression. If the necessary response is excessive or insufficient in intensity, duration, quality, etc., it becomes the source of illness. For example, when confronted with a viral infection, the organism must adapt endocrine factors to adapt immune cell function.29–34 If this response is excessive or prolonged, it overadapts the immune system: a hyperimmune state. A critical terrain can itself be the agent of another disorder. For example, in the prior example, the viral infection is a critical state of disease. If the hyperimmune response occurs in a patient with a ­precritical autoimmune terrain, the immune response can become hyperimmune. Thus, the critical viral terrain was the agent that brought about the autoimmune disease. To say that Epstein Bar Virus (EBV) is the cause of Hashimoto’s thyroiditis is absurd. The number of patients with EBV far exceeds those with Hashimoto’s thyroiditis. In addition, only a particular subsection of thyroiditis patients have positive EBV titers. If EBV were the cause, the correlation would have been 100%.

Art of history taking in Endobiogeny Chapter | 13  187

The ability to resolve, the aggressor, or, one of the critical factors (even temporarily) is sufficient to bring the patient into a precritical state. This helps explain why symptomatic use of pharmaceutical interventions or medicinal plants appears to “cure” disease. If the aggressor occurs only once, or the presence of an aspect of the precritical terrain appears only once, the use of a symptomatic, suppressive treatment will, in fact, favor a resolution of symptoms and perhaps future risk of disease. An example of this is a single episode of otitis media in a child treated with antibiotics. Let us say that this patient has aspects of the precritical terrain but not the autonomic dysfunction. Then, she experiences a rise in vagal tone correlated to a growth spurt, resulting in increased middle ear fluid. In the face of this, when exposed to the bacteria with tropism for this fluid, she experiences an infection. The antibiotic kills the bacteria—the aggressor. It does nothing to address the precritical terrain. Let us say that her vagal time returns to baseline before she is exposed to similar bacteria, say, in preschool. She will be declared “cured” and the antibiotics a successful treatment. The antibiotic eliminated the bacteria, but the organism’s endogenous self-regulating capabilities truly cured the precritical terrain. If the patient faces the aggression repeatedly and if even a single aspect of the precritical terrain is not addressed, the illness will recur in the face of subsequent exposure to the aggressor. A child with recurrent otitis media repeatedly treated with antibiotics is an example of this. Let us say she is vagotonic with chronically elevated vagal tone and the other aspects of the precritical terrain. Every time she is exposed to the bacteria in sufficient quantity that exhausts her buffering capacity, she will have a recurrent infection. We will declare her case recidivistic and submit her to the most common childhood surgery, myringotomy tubes. Saying that the child will outgrow recurrent otitis media simply refers to the evolution of some aspect of the structural or functional precritical terrain that occurs thanks to a chronobiologic unfolding of the genetic programming. It has nothing to do with any ingenious iatrogenic intervention. The mechanism is the how of manifestation of symptoms and signs. Contemporary approaches to medicine start here and consider mechanisms to be the cause disease. This is the fruit of the reductionist approach that cannot conceive of a terrain from which the organism develops and is regulated. Thus, the focus of therapeutics is to inhibit these downstream mechanisms. Following our example of an infection, the overstimulation of the immune system results in the release of inflammatory cytokines, histamines, etc. They may be the cause of symptoms, but are not the cause of the disease state. The effects of these mechanisms are congestion, which damage tissues where the infection is occurring, and solicit a congestion to isolate the infectious agent and the inflammatory elements (Table 13.16).

TABLE 13.16  Summary of the five stages of disease manifestation Example: Viral rhinopharyngitis

Name

Summary

1-Precritical

Susceptibility to disease, or, terrain of remission

Hyperpara state Hepato-biliary congestion Adrenal cortex insufficiency

2-Agent (aggressor)

Provokes critical terrain

Virus

3-Critical terrain

Physiologic terrain of active disease

Spasmophilia with hyper para- and hyper-alpha, elevated thyrotropic

4-Mechanism

How symptoms and signs manifest

Inflammatory cytokines, mast cell degranulation, etc.

5-Effects

What symptoms and signs manifest

Inflammation, heat, congestion, fever, chills, pain, etc.

Autopathogenecity The autopathogenic axis is the axis genetically most susceptible to dysfunction for a given individual. Each person has an autopathogenic endocrine axis. An aggression of sufficient intensity, duration, or repetition especially during the corresponding phase of development can entrain pathologic function of the axis. For example, a 7-monthold child presented to our office with a diagnosis of embryonic myosarcoma of the peritoneum. The fact that it was a myosarcoma indicated it was of mesodermal origin, related to gonadotropic function. Since it was embryonic in origin, this implicates the second trimester of growth (weeks 14–24, cf. Table  13.10). However, the mass was not palpated until 6 months of age and seemed to appear “out of nowhere.” This is 1 month into the phase of thyroid relaunching in infancy (Table 13.11). The autopathogenic axis of this patient is gonadotropic. The patient can be considered to be at risk of other disorders of hyper-FSH such as Crohn’s disease, or, of hyperestrogenism, such as atopic disease, among others. There are two mechanisms of autopathogenicity: entrainment of the autopathogenic axis and entrainment of a secondary factor. In the first case, the patient has an initiating factor of structure (IFS) that brings the person into a precritical (infraliminal) state. All factors necessary for disease are present except the activation of the autopathogenic axis therefore there is no disease (Fig. 13.6).

188  The Theory of Endobiogeny

FIG.  13.6  Entrainment of the autopathogenic factor. (© 2015 Systems Biology Research Group.)

FIG. 13.8  Buffering capacity and course of disease. The organism has a certain Endobiogenic buffering capacity. In the face of a precritical terrain and the appropriate aggressors, the organism enters into a critical terrain, consuming its buffering capacity. When the response to the aggression consumes the requisite amount of buffering capacity, the organism expresses disease. In the cartoon, the further away from the lower limit of the buffering capacity, the greater the severity of disease. The course of disease over time is shown. In the case of a single episode (black line), the aggressor is faced once and the organism recovers. In the second case of remitting disease (blue line), the patient expresses disease, and recovers, but expresses disease repeatedly because the elements of the precritical terrain have not resolved, and the aggressor is repeatedly faced. In the third example (red line), the disease has a progressive, degenerative course because the critical terrain becomes adaptative. It degrades the organism even in the absence of a subsequent exposure to the aggressor. (© 2015 Systems Biology Research Group.)

FIG. 13.7  Manifestation of disease with the represent of the liminal autopathogenic factor. (© 2015 Systems Biology Research Group.)

When the autopathogenic axis becomes affected (hypo-, hyper-, under-, or overfunctioning) the disease manifests itself (Fig. 13.7). Multiple sclerosis (MS) is a good example. In the case of MS, the IFS is the pancreas and the autopathogenic axis is somatotropic, with hyperfunctioning parasympathetic. There are a number of neuroendocrine factors that individually or together may oversolicit the pancreas, revealing its insufficiency. Thus, for each MS patient, one must still determine which factors are most implicated in oversolicitation of the pancreas. If and when a person faces an aggression that overwhelms the buffering capacity of the compensatory mechanisms and the autopathogenic axis is entrained, then the neurons demyelinate and one diagnoses this event as MS. The phenotypic expression of disease reflects the sum of epigenetic influences and thus we can explain the phenotypic variation in disease expression: single episode vs. relapsing vs. chronic-progressive disease, as well as the particular triggers and severity of presentation for each individual patient (Fig. 13.8). The second physiologic mechanism is when the autopathogenic axis has been affected, but additional components of disease have not been expressed. Thus, in the precritical state, the axis is disadapted, but there is no disease. In the theoretical case below, it is emunctory dysfunction that is absent (Fig. 13.9). Once the emunctory dysfunction is present, and the patient faces the provocative agent, the disease manifests (Fig. 13.10). If there is a second disease that also

FIG.  13.9  Expression of the autopathogenic axis but absence of the necessary emunctory in the precritical terrain. (© 2015 Systems Biology Research Group.)

FIG. 13.10  Manifestation of disease of the autopathogenic axis when all elements of the precritical terrain are expressed in the face of an aggression. (© 2015 Systems Biology Research Group.)

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relies on that axis, once another emunctory function is compromised, then a second disease will also appear. In both cases, addressing the key axis can bring a person back to a precritical disease state. They would not be considered “cured” unless additional factors are also addressed in a lasting fashion. Consider a 56-year-old man with an autopathogenic gonadotropic axis. He experienced severe acne as an adolescent requiring antibiotics. At 56, during a genital pause, he has an overexpression of the gonadotropic axis in the face of hepatobiliary congestion and pancreatic ­exhaustion. He develops a hypermetabolic, hyperanabolic terrain. At 57, he develops diabetes and hypertension. This affects his renal function. At 60 given he develops osteoarthritis. Both the diabetes and osteoarthritis share the critical terrain of hyperanabolic hypermetabolism, but differ in the emunctories implicated. The concept of autopathogenicity helps explain two key questions regarding “stress” and illness (cf. Chapter  12). The first is why the same stressor induces various types of diseases, why in a given disease there are various symptoms with various degrees of severity among various patients. Consider history of 10 women who experience a divorce at 40 years of age. They experience various effects on their terrain (Table 13.17). Most practitioners and patients are inclined to conclude that the aggressor—the stressor—“caused” the disease(s). However, this does not explain why the same event, in this case divorce, had no effect in one woman, reduced severity of symptoms in another, and induced various combinations of disorders in the remaining eight. Autopathogenicty, the IFS, the general state of the terrain, and the chronobiologic phase of genital pause as an ensemble explain the impact of divorce on these 40-year-old women. It is our ­empirical

observation that the impact of divorce at 24 and 54, for example, is quite different than between 38 and 48 years of age for all the reasons noted above. Consider a second case in which 10 women of various ages are diagnosed with a cluster of various symptoms and disorders after exposure to black mold (Stachybotrys spp.) (Table 13.18). Considering the inconclusive pattern of disorders after exposure to black mold, the classically trained physician will conclude that the mold had no role on the development of these disorders and will not treat it. The “alternative” practitioner will conclude that black mold “caused” all these disorders and must be treated. As we noted earlier, according to the theory of Endobiogeny, an aggressor provokes a response from the organism and the organism’s response to the aggression, given its terrain and buffering capacity, is responsible for disease and its particular manifestations. The second question autopathogenicity helps answer is why a disorder appears with variable frequency between generations when there is a change in diet, weather, or residence. The autopathogenic axis can be occult for generations because the necessary factors in the internal and external terrains did not bring out the pathogenicity. For example, the incidence of cancer among people from the Indian subcontinent increases as they migrate. The lowest rates occur in those residing in India, increases moderately for those residing in Singapore, and are highest for those living in the United Kingdom or North America.35, 36 In summary, the autopathogenic axis helps explain the general susceptibility to certain disorders, the predominance of certain symptoms over others, and the timing of onset of those disorders.

TABLE 13.17  Effects of divorce on the terrain of 10 different women Case

No effect

1

•

2

Improved health

Depression

Anxiety

Insomnia

Hypothyroidism

•

3

•

4

•

•

5

•

•

•

6

•

•

•

7

•

8

•

•

•

•

•

•

•

•

9 10

•

•

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TABLE 13.18  Effects of black mold on the terrain of 10 different women Case

No effect

1

•

Brain fog

2

•

3

•

4

Depression

Indigestion

Chronic fatigue

•

Hypothyroidism

•

• •

5

•

•

6

•

•

7

•

• • •

•

•

•

8

•

9

•

10

•

•

Example of autopathogenicity: Thyrotropic axis We now present a full case history applying the all the concepts discussed thus far. Chief Complaint A 5.5-year-old girl presented 8 months status post resection of right subthalamic grade 1 pilocytic astrocytoma desiring evaluation of the current carcinogenic terrain. Key elements of the HPI are placed on the figure of seasonal adaptation (cf. Fig. 13.11).

•

•

•

•

History of present illness Spring May 1, 2008: Patient develops signs of ipsilateral left motor weakness ● ● ●

Left eyelid cannot close independent of right eyelid Paresis of left arm and foot Jerking and fasciculation of large muscle groups when walking

May 7: Misdiagnosed with cerebral palsy May 16: Has developmental assessment including vision: Passes all but gross motor evaluation

FIG. 13.11  Key elements of the history of present illness are placed on the figure of seasonal adaptation. See text for details. Key: B’Day, birthday; Bx, biopsy; MRI, magnetic resonance imaging; Sx, symptoms. (© 2015 Systems Biology Research Group.)

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Presummer June 11: The MRI shows right thalamic tumor in the basal ganglia June 16: Biopsy confirms diagnosis as astrocytoma, grade 1

●

●

Social Second of two siblings; older sister 5 years older; either loves her sister or fights with her. Mother states that the patient has a good relationship with both parents at this time

Summer August 15: Tumor resection 15  days before her birthday August 30: Birthday Current (April 2009) There was no subsequent treatment. Current therapy is MRI every 4 months.

Review of Systems Grinds her teeth ● Sleep: ○ Falls asleep quickly ○ Vivid dreams, with sound and color; recalls dreams ○ Sleeps deeply and uninterrupted for 9 h per night ● Diet: ○ Variable appetite in the morning ○ Vegetarian diet with organic fruits and vegetables ● Hobbies: ○ Plays princess, sings, draws, plays card games ○ Does not care to engage in physical activities ● Constipation (now resolved) ● In-toeing (pigeon-toed) ● Benign heart murmur ●

Past Medical History Conception Intentional pregnancy to a 43-year-old mother, Gravida 2, pregnancy 1, intact family Pregnancy Complicated by maternal HELPP syndrome (hemolysis, elevated liver enzymes, thrombocytopenia) in the late third trimester Birth Scheduled cesarean section due to HELLP syndrome Apgar score 8/9 Birth weight: 2.76 kg; birth length: 53 cm Infancy Easy baby, slept well 0–3 months: Exclusively breastfed 4–7 months: Mixed breast milk and formula 8–12 months: Formula and solid foods Normal development, met all milestones at appropriate age All vaccinations up to date and received in a timely fashion Temperament Infancy: Easy baby, slept and fed well Toddler (current): Very creative, loves to sing and draw; very social and cheerful, emotional, cries easily Childhood Phase Subprogram: Thyroid metabolic: 1–3 3 years of age: ●

Patient had resentment of her father regarding her own birth

Subprogram: Thyroid tissular: 4–7 4 years of age: ●

Multiple changes in nannies, which was reported to be stressful to the patient

Experienced intense fear when she woke up in the car and found herself alone in the garage (having fallen asleep on the way back home) Patient diagnosed with an astrocytoma 3 months after the fear of having been abandoned in the car

Commentary. Brain tumors are particularly susceptible to the effects of TRH due to its neuromodulating effects.36a This is especially true in children, because TRH is so prominent in this phase of childhood (Table 13.12), where it acts as an accelerator of metabolic brain activity (Chapter  8). Elevated parasympathetic activity and liver congestion will play a role in the growth of tumors as well. Considering the strong role of para in childhood, it is not surprising to see that brain tumors are the most common solid tumor in children, accounting for 26% of all tumors in children.37 The thyrotropic axis is her autopathogenic axis. From the PMH we see a correlation in time between development of the tumor during the thyrotropic phase of childhood and the experience of an intense expression of fear related to a perception of abandonment. Throughout the rest of the history we find other evidence of the role of this activation, in particular TRH. It is not the fact that the show awoke terrified that “caused” her tumor growth. It was that it occurred in the thyrotropic phase of growth in a child who has an autopathogenic thyrotropic axis and other required elements of the precritical terrain. Elevated TRH activity: ●

Emotional stressors: o Existential issues with father o Change of nannies

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● ● ● ●

● ●

● ● ●

●

●

o Fear from waking up alone in the car after a nap— this is the most likely accelerator of the growth of the tumor to its liminal expression correlated in time with the onset of symptoms Vivid dreams Easily brought to tears Teeth grinding (with spasmophilia) No physical activity: Stationary activities of grand imagination Benign heart murmur Fasciculations (during tumor phase) Hyperparasympathetic state: Easy infant, good eater Sleeps quickly and deeply Stationary activity Liver congestion: Lack of appetite in the morning Hyperadaptive state: Third trimester stress from maternal HELLP syndrome

Commentary. As one can see, the excision of the tumor, while lifesaving, did not address the patient’s terrain. This patient will continue to be susceptible to various disorders related to TRH over activity. Both her physical examination and biology of functions further corroborated these observations and demonstrated that the tumorigenic terrain persisted in her.

Initiating factor of structure Some disorders are functional in nature, such as an infectious disease. The disorder arises due to the way in which the global response to an aggression is managed by the organism. Other disorders are structural in nature. The disorder arises due to the inability of the organism to maintain a given level of structural function within the cell or tissue relative to the demand. These disorders have an IFS. Inflammatory bowel disease (cf. The theory of Endobiogeny, Volume 3, Chapter 11), MS, and chronic heart failure are examples of

structural disorders with an IFS. The IFS entrains a series of neuroendocrine and emunctory compensatory mechanisms that allows a person to remain in a fragile precritical state. In the face of an aggression, the critical state is installed and disease is expressed.

Temperament, personality, and physiopsychology Temperament Temperament is the reactionary modality of the genetic heritage. In antiquity, temperament is referred to one’s natural disposition. In musical terminology, temperament refers to how well tuned a note is across various octaves. The Endobiogenic definition refers to both concepts. It is a natural disposition because it is rooted in the genetic heritage. It is reactionary because it is expressed in adaptation (structuro-functional and functional). The various levels of metabolism are like octaves on a scale. Notes may be played both at different octaves (intensity of physiologic activity) and at different scales (permutations of various neuroendocrine coupling based on the structural or functional demands). Consider the note “C.” It has a specific Hz value for its position at each point of the keyboard. If one were not “well-tempered” the note C would be played a few hertz off from the “perfect” C. As a single note, it may not be apparent that one is not well tempered. But applied to the many notes that make a chord, i.e., to many neuroendocrine factors, it becomes apparent how a person can appear “ill tempered” or “off key.” Temperament refers to innate tendencies, the elemental or foundational qualities of response related to basic neuroendocrine activities. Thus, one may express parasympathetic, alpha-sympathetic, beta-sympathetic, or spasmophilic qualities from infancy (Table  13.19), which is why a history of infancy and childhood is so beneficial in an adult history. The relative predominance of one aspect of the nervous system over the other may change in time but is generally fixed by completion of puberty. Consider a ­patient

TABLE 13.19  Temperament of the infant by autonomic tendencies Temperament Para

Alpha

Beta

Spasmophilic

Ease of care

Easy baby

Sensitive, demanding

Full of energy

Irritable, hard to console

Sleep architecture

Good and long sleeper

Hard to settle down, awakes frequently

Tosses and turns, kicks off covers

Irregular sleep patterns

Bowel pattern

Stools frequently, passes soft stools

Constipated, passes hard stools

Frequent or rapid passage of stool

Colicky, irregular consistency or frequency of stool

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who was a good sleeper as an infant and young child. We would say that their temperament was vagotonic. As an adolescent, they experience difficulty in falling asleep. This is an alpha tendency. This does not contradict the conclusion that their temperament is vagotonic. It remains fundamentally vagotonic because it is a genetically determined tendency. What did occur is the expression of a disadapted alpha-sympathetic activity that predominated over para but only as a reactive element, and only with respect to sleep (in this case). The alpha may have been elevated as a reaction to a hyperpara state during pubertal growth. Or, it could have been solicited to relaunch endocrine activity to help complete growth and then was entrained. Thus, determination of temperament should be accomplished by investigating multiple areas of physiologic expression and reaction in childhood as well as adulthood. Let us consider an example where memory is represented by the note “C.” The temperament of a person can be such that they have a clear and accurate memory under basal conditions, i.e., middle C played in the key of C-major (C-D-E-F-G-A-B). However, under a certain level of adaptative demand, say, at work, their memory is highly detailed, clear, and accurate, to the degree that it is painful to recall certain events. This would be like C played 1 octave higher, but still in the key of C-major. It is a suboptimal or “higher” or more intense expression of the optimal pattern. Under duress, say, a violent motor vehicle accident, they have no recollection of the event at all. We would say that the reactionary modality of their genetic heritage played in A-mixolydian (A-B-C#-D-E-F#-G-A), and two octaves below the basal scale. This key is melancholic in nature, not bright and cheerful like the key of C. Furthermore, and it is two octaves lower, so feels “heavy.” In addition, the C note is no longer C major, but C sharp (C#). Thus, the organism plays a completely different physiologic pattern or tune that reflects a very different temperament in reaction to an aggression of certain intensity. In a clinical setting, one often encounters—if one inquires—adult woman report sexual abuse as a child which is not recalled until gonadopause. That is to say, the physiologic intensity of premenopause evoked a similar intensity experienced during the molestation and thus brought out the suppressed memories. The interest of the Endobiogenist is to determine how well tuned the temperament is in both quality and consistency. In other words, does the organism play the right tune (physiologic activity) at the right time in the right octave (intensity of activity) and the right progression of notes (entrainment of the endocrine loops)? Temperament is based on the genotype but is expressed as phenotype, which is why it is reactive in nature. For example, gamma-aminobutyric acid (GABA) is a calmative neurotransmitter. The GABA-A receptor is composed of 2-alpha, 2-beta, and 1-gamma subunits. The composition of the subunits affects responsiveness to GABA and

benzodiazepines. There is a genetic basis to anxiety and panic disorders correlated with polymorphisms in receptor subtypes, isoforms, density, and distribution of the GABA ­receptor.38, 39 However, there are a number of factors within the genetic programming, and thus within the terrain, that code for the expression of various other neurocalmative (e.g., endorphins) and neuromodulating (e.g., TRH, glutamic acid) factors, as well as neurosteroids (e.g., cortisol, testosterone, estrogens) that can aggravate or compensate for this basic genetic polymorphism. Thus, an assessment of the genetically derived temperament still requires an assessment of the terrain and the neuroendocrine factors that manage it.

Personality and physiopsychology Whereas temperament is inherited, personality represents acquired traits. Traits are constellations of qualities based on inherited temperament, inherited neuroendocrine factors, and reactive expression of both these factors. Personality is not fixed like temperament but does tend to be durable unless a person consciously attempts to alter it. A link between neuroendocrine function and personality has long been recognized. In the literature it is referred to as “psychobiology.” We propose a new term we find to be more accurate: physiopsychology. First, it is not cellular biology as a singular and isolated phenomenon that generates a psychological trait in a human being. It is the physiology of the system that does this. Second, it is the physiology that creates the organic parameters of psychological characteristics, not the psychology that creates a biologic characteristic. Of course, in function, there is an intertwined cycle of one affecting the other. For example, an accumulation of a biologic product such as glutamate or ammonia affects cognition and personality, but this accumulation of biologic products is itself the result of a disadapted physiology of the global system. Consider the neuroendocrine basis of introversion. Introversion is a personality trait that refers to a tendency to have a predominant interior life, such as a desire for reflection. It is related to a relative insufficiency of ACTH and cortisol with a delayed beta sympathetic activity. However, the quality of the introversion will be influenced by other factors of the terrain, such as temperament. For example, if introverted patients have a vagotonic temperament, they may be introverted and shy—this is a personality trait based on temperament. Even then, vagal tone can be modified through diet and medicinal plants, thus an introvert can develop a personality that is no longer typified by shyness but will likely remain an introvert. For example, a pancreas-sparing diet (low glycemic, no animal fats or fried foods) and the use of plants such as thyme (Thymus vulgaris) can reduce parasympathetic tone such that over time, even without c­ ognitive-behavioral modification, the shy person will no longer be shy, but will likely remain introverted and introspective.

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A number of studies have linked changes in serum levels of corticotropic hormones and various psychological states of both positive and negative valence—especially after stressful life events. With respect to cortisol, studies have found bimodal values of cortisol (elevated and diminished) as well as the relative degree of reactivity of the corticotropic axis to be associated with depression.40–46 These findings support the specific Endobiogenic theory of depression as well as the general concept of physiopsychology. According to our theory, there is a dysadaptation of the adrenal cortex in the face of an aggression that results in either excessive cortisol (most common) or insufficient cortisol. This occurs within a terrain of low self-esteem, blocked or delayed adrenaline response, and pre-critical factors related to vagotonia and exocrine pancreas dysfunction. Low central (brain) serotonin is the downstream consequence of the dysadaptation, not the cause of depression. Hormones can relate to negative psychopathology. For example, low cortisol is related to depression, disruptive behavior, and suicidal tendencies. Elevated serum cortisol is related to depression, disruptive behavior, schizophrenia, and borderline personality disorder. With respect to positive traits, serum levels of DHEA have been inversely correlated with creativity and social rejection. In other words, the lower the levels of DHEA, the greater the tendency toward creativity but also social rejection.47 Other influencers of creativity include cognitive flexibility, receptivity to new ideas, ­positive hedonic states (happiness, melancholy), and emotionally activating states (fear, happiness and melancholy).48, 49 Again this implicates that multiple neuroendocrine factors typically converge to create a specific aspect of a person’s temperament and personality. In the case of creativity, cortisol, global adrenal function, and TRH play key roles.

Traumatic events Physical and physiologic aggressions on the organism, such as temperature, infections, starvation, etc. demand a change in the equilibrium of the terrain. However, as demonstrated in Chapter 12, events that are merely perceived as traumatic or adverse provoke similar changes through the limbic area. Based on the pioneering work of Vincent Felitti, MD and colleagues, adverse childhood events (ACE) are highly correlated with long-term mental and physical health ­issues.50–53 According to their work, the following constitute ACE (listed in decreasing order of impact on health)50, 51: 1. Physical abuse 2. Alcoholism of parent(s) 3. Sexual abuse 4. Death of a parent 5. Abandonment by a parent 6. Divorce of parents 7. Depression in a primary caregiver

8. Emotional neglect 9. Being treated violently by mother 10. Physical neglect The concepts of terrain, autopathogenicity, endocrine timelines, and initiating factors of structure help explain how such a wide range of events can cause a wide range of disorders. The correlation is not in a specific physiologic mechanism, but in the general adaptation demand that it solicits in a chronic and durable fashion. Women report a higher number of ACE than men.50, 51 This corroborates with our empirical observations. In our referral-based practice in Endobiogenic medicine, approximately 60%–70% of adult woman have one or more ACE. Compared to patients who have had no ACE, those with multiple ACE have a significantly higher incidence in adulthood of. 1. Mental health: a. Depression b. Suicidal tendencies c. Addictions (alcoholism, smoking, and IV drug use) d. Earlier sexual experiences e. Multiple sexual partners f. Abuse of others in the family: i. Men: Abusing wives ii. Women: Abusing their children50–61 2. Physical health: a. Psychosomatic disorders b. Idiopathic disorders c. Morbid obesity d. Cardiovascular disorders e. Pulmonary disorders These results remain robust even when excluding for confounding factors such as smoking and diabetes as risk factors for disease.50, 51, 62–68 The Endobiogenist is encouraged to do three things when encountering ACE: (1) Ask the patient how they were affected by the event(s) at the time and how they are currently affected (2) Evaluate the prior and current physiologic impact of the events on the terrain (3) Determine if professional intervention may be needed to support the amelioration of the adaptative terrain Numerous studies have demonstrated that the maternofetal dyad has a strong level of what we refer to as entanglement (“emotional contagion” in the psychobiology literature). In other words, the terrain and temperament of the mother both during pregnancy and postpartum affect the child’s endocrine activity and thus temperament.69, 70 The same holds true among adults, including feelings of empathy, stress, and suicidal ideation.70–72 This reinforces the importance of evaluating the interpersonal ecology of the patient. Traumatic and adverse events, as well as a s­ tressful

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environment all constitute sufficient or sometimes significant sources of adaptative physiologic states. They can permanently alter the trajectory of neuroendocrine development and affect the efficiency of function of the organism.

The concept of trajectories A trajectory in physics can be defined as “the path followed by an object moving under the action of various given internal and forces.” The organism moves through both space and time and remains constantly under the action of external forces. There is, theoretically speaking, an ideal trajectory of development. It is the one that demonstrates the most optimal function and greatest degrees of resilience and adaptability given the genetic potential. However, long before conception, epigenetic changes start to alter this potential. As we have discussed above, the exposure of the organism to aggressions, ACE, social, cultural, environmental, and geographic factors can all alter the trajectory of development of the organism’s physiology, temperament, and personality (Fig. 13.11).

Four cases of trajectory Fig. 13.12 schematically represents the neuroendocrine trajectory of four patients. Case 1 (black line) represents the “ideal” progression of terrain through each phase of development, which include in utero. One notes some natural variation in adulthood during a genital pause phase in which the patient has a brief period hypofunctioning of her terrain, followed by a gradual correction over the next few years. An example would be a period of menorrhagia from 27 to 30 years

of age. Case 2 (orange line) is a case of ­hyperadaptation of the terrain due to an ACE that started in utero. In this case, the mother contemplated elective termination of the pregnancy. However, she feared rejection by her spouse. She kept the pregnancy but suffered from perinatal and postnatal depression Note how the prenatal terrain is already elevated above the optimal line. This patient’s terrain continued to have a hyperfunctioning terrain until his early 20s when he experienced a decline in functioning resulting in a type of “burnout” falling below the optimal function, followed by an improvement in function at a later age of adulthood. Case 3 (green line) is an expression of a hypoadaptation response to an ACE starting postpartum. The father abandoned the family. The stress brought about fibromyalgia in the mother with chronic fatigue, impairing her role as caregiver. In early adolescence, the patient experienced an increase in the functioning of her terrain. While she was able to sustain a higher level of function, it never reached her optimal state of function. Case 4 (red line) is an example of a patient who had a generally optimal development in childhood. He did not experience any ACE, but did experience a physiological blockage of adaptation at the onset of adolescence. This disadaptation resulted in adolescent-onset depression despite the absence of a family history of mental health illness. It took the patient another 15 years to recover a certain level of function but never returned to their optimal trajectory.

Conclusions When evaluating the total medical history of the patient, the Endobiogenist is evaluating the trajectory of the patient’s

FIG. 13.12  Trajectories of terrain development. See text for details. (© 2014 Systems Biology Research Group.)

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reactive elements: temperament and personality as well as the various factors, internal and external, intrapersonal and interpersonal, intragenerational and intergenerational, cultural, environmental, and geographic which serve as inductive elements to which the terrain responds. Each element of the history: present illness, past history and review of systems adds breadth and depth to the analysis of terrain. A competent history provides the basis for a focuses and productive physical examination. In turn, a proper Endobiogenic history and physical examination allows for the most thorough evaluation of the biology of functions and development of the most targeted treatment plan.

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Chapter 12

Adaptation syndromes The science of adaptation is beginning to develop into a separate branch of medicine…we will need specialist in stress and adaptation…the stress specialist will have to devote a good deal of his time to the study of internal medicine, experimental physiology and pathology, allergy, neurology, endocrinology, and so forth. Nevertheless, the immensity of the subject matter related to stress problems will undoubtedly require the training of specialists who may be consulted in connection with diseases. Hans Selye, Stress and the general adaptation syndrome, 1950.1

Introduction The only constant in life is change. The origin of all illness is resistance to what is and the corresponding responses of implosion, stagnation, or explosion. The capacity to adapt, and the ability to select the appropriate adaptation response are the fundamental principles of every system. The ability to utilize the adaptation response in the optimal degree of intensity and duration is essential for all organisms to maximize their survival and propagation. The organism is constantly engaged in some type of adaptation response in order to maintain a homeostasis. The Endobiogenist must be able to distinguish the various adaptation states in which the patient is in. This will determine the choice, intensity, and duration of therapy, as well as the anticipated results. Adaptation refers to the process of altering the level of functioning of the internal equilibrium. The demands for adaptation arise for three places. The first is the interior milieu: the general requirements for survival and optimal functioning in space and time. The second is the exterior milieu: the response of the organism to their environment and the demands it places on the individual based on factors of space, time, gravity, etc. The third is the central nervous system (CNS), which creates a valuated hierarchy of responses between the requirements of the interior and the demands from the exterior. There are four general types of adaptation responses for biological organisms of higher organization. The first responses are instantaneous reflexes. The second are adaptation syndromes. There are immediate, short-term, and chronic, and the general adaptation syndrome (GAS) of Endobiogeny. The third are the chronobiologic adaptation The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00012-4 © 2019 Elsevier Inc. All rights reserved.

syndromes (CASs). This include circadian, seasonal, and evolutionary changes, which includes certain circannual adaptations of endocrine function. The four is adaptative states (Fig. 12.1). The general interior milieu is the functioning of the body as physiologic automaton, like an anencephalic, but including the general structural metabolic functioning of the brain and the brainstem. The general interior milieu has variability in its metabolism due to two reasons: the natural course of growth and senescence, and the processing of nutrients and their waste products. These events alone necessitate a constant adaptation of the state of internal equilibrium. Thus, if an otherwise healthy person were to be placed in a hermetically sealed chamber, sedated and intubated but provided food through a nasogastric tube, they would still undergo a series of regular and repetitive adjustments to their internal equilibrium. The second demand for adaptation arises from the external milieu. The external milieu presents three types of demands on the organism: entrainment, engagement, and entry (Fig. 12.2). The first is the demand for entrainment of the rhythms of all entities and processes within the construct of what we call “nature.” There is a false sense—­perhaps seen only among humans—that we are neither of nor from nature, but merely in nature. Thus, there is a mental construct of battling against nature and the collective sense of entrainment that the rest of the entities and processes in Nature instinctively adhere to. We prefer to use the capitalized term Nature to refer to the sum of all living communities of the Earth, including humans. Life in the universal sense has its own periodicity and rhythmicity. The most frequent type of external demand on the organism is one of adaptation to the external rhythms in which we swim. Life expresses itself in hierarchical, multitiered nonuniform timescales.2 This is expressed within Life unfolding, morphogenic fields, as well as within the intrinsic functioning of each crystallized unity of function. These timescales may be additive or competitive, sequential or simultaneous, or some combination of all four qualities. Thus, simply existing creates a demand for adaptation of our internal rhythms to those outside of us, be it by our own species, other species, terrestrial rhythms, celestial rhythms, etc. In the face of these demands, the organism faces a tripartite response pathway: entrain, tolerate, or hibernate, each of which requires its own type of adaptation process. 157

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FIG. 12.1  Summary of types of adaptation according to the theory of Endobiogeny. See text for details. Σ, sympathetic; πΣ, parasympathetic; ANS, autonomic nervous system; Endo, endocrine. (© 2015 Systems Biology Research Group.)

FIG. 12.2  Adaptation demands placed on the organism from the exterior. (© 2015 Systems Biology Research Group.)

The second external threat is engagement. Each entity in its materialized state has a need for safety, food, and reproduction—and so does every other entity. Thus, in a world of restricted locations, resources, and mates, where timing, quantity, and quality are all determinates of value, it is inevitable that organisms, be it intra- or interspecies will engage each other for access to those resources. The anticipation, threat, or use of aggression requires ceaseless changes in

the state of the internal equilibrium both for the aggressor and for the aggressed. The third external threat is entry. The organism is a closed system open to the world around it. Every time we flare our nostrils to breath, open our mouth to eat, open our anus to defecate, open our urethras to urinate, or simply use our skin as the largest organ of metabolic exchange and detoxification, we expose ourselves to entry by microorganisms.

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FIG. 12.3  Parts of the limbic system are depicted in the lower central area of the cartoon: amygdaloid and hippocampus. (Source: Blausen.com staff (2014). Medical gallery of Blausen Medical 2014. WikiJ. Med. 2014;1(2). doi:10.15347/wjm/2014.010 [CC BY 3.0] From Wikimedia Commons.)

The challenge for all organisms is that the only way to survive is to risk death at every moment by opening ourselves up. Energy is derived from the external milieu. The processing of energy results in metabolic products that must be evacuated from our organism. It is a recapitulation of our concept of human-in-environment where we are the environment and the microorganism is the entity that perceives itself as merely being “in” an ecologic system that simultaneously supports and aggresses it. The third locus in adaptation demands of the internal equilibrium is the CNS. The CNS is the crossroads of three levels of awareness. It processes information from the internal milieu regarding the physiologic internal equilibrium and about the external milieu from its faculties of perception, information about the spatial location of the organism interacting with the external environment. Then, it processes information about the processing of information—a metastate of consciousness—be it in liminal, supraliminal, and subliminal states of awareness.

Limbic region The limbic region is the key to the integration of the adaptation syndromes and the functioning of the CNS, ANS, and endocrine systems (Fig. 12.3). It is referred to as “limbic” because the information exchanged and processed in this region represents the liminal threshold of awareness of all things cognitive, emotional, and physiologic, all things considered particularly human in its complexity and of ­incoherence. The limbic system is the point of evanescent consciousness and instincts, of endocrine and autonomic

function, of emotions and precognition, of perception and intuition, of memory and forgetting, of motivation and inhibition, of pleasure and pain (and when it is both), and of movement and stillness. At this crossroad, the experience of being, as Nietzsche wrote, “Menschliches, allzumenschliches” (“human, all too human”) manifests itself. The limbic system integrates the physiologic experience of life with the psychological perceptions of being alive to create hierarchical values that influence the adaptation syndromes in a way not originally considered by Bernard, Selye, and other early experimental physiologists. In summary, adaptation is the way in which the internal equilibrium is altered. That which solicits this change can be three in nature: the internal milieu itself, the external milieu and states of consciousness, and the attendant thoughts and emotions that develop from it (Fig. 12.4).

Buffering capacity Buffering capacity is the capacity in reserve. It allows adaptation responses to be more efficient so that the organism may return to its anterior state of function without a disruption of homeostasis. When the organism enters an adaptative state, where it enters a new state of equilibrium, the buffering capacity prolongs the organism’s ability to tolerate this state with minimal disruption of activity. When the buffering capacity becomes progressively diminished, the organism enters into precritical and then critical states of imbalance manifesting as disease (cf. Chapter 13). The buffering capacity consists of structural and functional elements (Fig. 12.5).

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FIG. 12.4  Interaction of the central nervous system (CNS) with the external milieu. The external milieu demands one of three types of responses: entrainment (of rhythms), engagement (cooperative or combative), and, entry (of nutrients, organisms, etc.). On the right, the CNS structure gives rise to the material elements of the ANS (autonomic nervous system), which solicits endocrine regulation of the terrain. The endocrine system, thanks to neurosteroid receptors, influences states of consciousness, which can be seen in changes in CNS function. At the crossroads of each modality is the limbic system, or, area, which both is influenced by and influences these three areas. (© 2014 Systems Biology Research Group.)

FIG. 12.5  Overview of buffering capacity. See text for details. (© 2015 Systems Biology Research Group.)

Structural reserve is the redundancy of structural elements. In mesoscopic terms, this refers to the duplication of organs. Most vital or key organs are paired, such as the kidneys, adrenals, lungs, and cerebral hemispheres. Even unpaired organs, such as the liver, have sequestered function, viz. lobes, with redundancy of action. At the cellular level, the number of mitochondria and storage vesicles are examples of redundancy. Unused structural elements can be recruited almost instantaneously, such as recruitment of alveoli. Functional elements of structure refer to elements required for cell function (cf. Chapter 2, section Terrain and Metabolism, and, Chapter 4, section A functional approach

to hormone activity: levels of metabolism). Examples include enzymes and ion channels. The rate of their function can be increased on demand thanks to other functional elements, e.g., intracellular calcium stores or recycling of ADP to ATP. The production and storage of hormones within endocrine glands is a type of functional element of structure. It allows for immediate release of stored hormones. In conclusion, tissues and organs have the capacity to instantaneously augment capacity of function several fold without soliciting genomic mechanisms which take hours to days to create new tissues or augment the size of an organ or its elements.

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FIG.  12.6  Stages of buffering capacity. The organism can engage instantaneous reflexes (left). If that is not sufficient, elements of immediate adaptation can be engaged (bottom center). Catalytic elements can then be engaged. If needed, the short-term adaptation sequence can be engaged, followed if required by chronic adaptation responses. (© 2015 Systems Biology Research Group.)

Functional elements of the buffering capacity are the reserve of quantitative material. There are two types: reserve of metabolites and regulators of metabolism. The second is the reserve of elements of immunity regulated by the endocrine system. Circulating hormones are a functional capacity of function. They function with 3%–8% bioavailability; the remaining 92%–97% are inactive through carrier protein binding (cf. Chapter 10). Each of the three prominent metabolites remain in reserve: glucose as glycogen, lipids as adipose tissue, and proteins as amyloid proteins and muscle. Finally, immune cells (leukocytes, platelets, and thrombocytes) are sequestered in the splanchnic vasculature and spleen. The expression of buffering occurs in two stages according to the theory of Endobiogeny (Fig. 12.6). The first stage is instantaneous reflexes or immediate responses. Examples include platelet-induced clotting, modification of the clotting cascade. The second stage relates to the elements of catalytic elements installed to pursue local defense through action-reaction dynamics. Enzyme catalysts and electrical gradients are two examples. In contrast, chronic mechanisms are installed when the buffering capacity has been exhausted. At each stage of response, if the current response is sufficient to assist in the return to the prior state of equilibrium, the subsequent stages are not required. The immediate and chronic adaptation syndromes are discussed later in the chapter.

Liver: Key to buffering capacity Among the organs of adaptation, the liver is perhaps the most important. It is the emunctory par excellence for both catabolic axes: corticotropic and thyrotropic. It provides buffering capacity for the organism by allowing acidic, inflammatory waste products of catabolism to be metabolized, to prevent degradation and fragilization of the terrain.

FIG.  12.7  Hepatobiliary unit’s role in buffering capacity. The liver and gallbladder together contribute numerous elements to the buffering capacity. Chief among them are glycogen, broken down to glucose. Glucose circulates and enters organs and tissues requiring this substrate for ATP production. Binding proteins allow hormones to circulate in reserve for immediate use whenever required. Bile binds lipophilic toxins. It also regulates cholesterol levels which are required for the production of various hormones (cf. text for details). The liver contributes to innate immunity through production of dendritic and Kupffer cells. They surveil all the blood that enters from portal and splanchnic circulation prior to returning to the heart for systemic distribution. (© 2015 Systems Biology Research Group.)

The liver plays a role in immediate adaptability (cf. below) in two ways. The first is storage of glucose as glycogen. Oxidation of glucose is the most efficient way of ATP production, and is required both for basal and adaptive metabolism. The second is production of hormone transport (binding) proteins. This allows hormones to circulate with a 10–100-fold surplus and instantaneously be mobilized. It also participates in innate immunity. Kupffer and dendritic cells surveil all blood from the portal vein related to exogenous intake of nutrients (cf. The Theory of Endobiogeny, Volume 2 Chapter 3). Liver produces bile, stored in the gallbladder. Bile binds lipophilic metabolites processed by the liver and allows them to be excreted in stool. Thus, we can speak of a hepatobiliary unit (Fig. 12.7). This unit also regulates cholesterol levels. Cholesterol ensures a sufficient base material for the production of the hormones of immediate adaptation through the corticotropic adrenal cortex. It is the base material for peripheral gonadotropic hormones of short-term adaptation. It is also the base material for vitamin D, which plays a role in immunity and regulation of the thyrotropic axis. The hepato-biliary unit is permanently submitted to control and regulation by the systems of adaptability of the organism during all durations of adaptation demand, be they of internal and external origin.

Adaptation syndromes The adaptation syndromes are a series of normal physiologic reactions of the organism that install a change in the functional equilibrium but which result in a return to the

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TABLE 12.1  A general summary of the adaptation syndromes and adaptability

prior state of function once the demand is discontinued. According to the theory of Endobiogeny, there are two types of adaptation: specific and general (cf. Table 12.1). The specific adaptation syndromes involve entrainment of particular groupings of autonomic, endocrine and organ function over various periods of time. Whatever be the type of adaptation response, there must be a buffering capacity that allows the organism to instantaneously respond to the aggression.

Immediate adaptation Immediate adaptation is the constant and acute adaptation of the internal equilibrium based on momentary demands of the organism. It primarily involves the sympathetic nervous system and the adrenal cortex with an appeal to the buffering system. It occurs in two phases: ANS-Buffering system, and Endocrine: 1. ANS: Sympathetic: αΣ, βΣ 2. Endocrine a. Adrenal cortex b. Thyroid c. Pancreas, endocrine (insulin) 3. Buffering system a. Splanchnic system b. Liver c. Innate immunity

Phase 1: Autonomic-buffering system Splanchnic system The splanchnic system includes the splanchnic bed, perihepatic, and perisplenic circulation. Approximately 30% of total circulating blood volume is distributed to the splanchnic system: 1500 L/min (Fig. 12.8). In comparison, vital organs such as the brain and kidney receive 14% and 22%, respectively. The splanchnic bed is an element of the functional reserve of buffering capacity. The splanchnic system is the single largest source of elements of adaptation. Within this system leukocytes, erythrocytes, and platelets are sequestered and available for immediate reentry into the general circulation. Both its content of blood and cellular elements from the bone marrow are a key part of the buffering capacity of the organism, particularly in immediate adaptation. The splanchnic system expresses a close integration of autonomic, vascular, emunctory, and annexal organs vital for the immediate survival of the organism (Figs. 12.9 and 12.10):

αΣ stimulates ● ● ●

Adrenal medulla: Adrenaline Splanchnic bed: Leukocytes Innate immunity

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100%

Lungs

100%

Right heart

Left heart

Heart

3% Celiac a.

Brain Skeletal muscle

V e i n s

Hepatic a.

14% Splenic a.

15%

Bone

5%

Gastrointestinal system, spleen

21%

Liver

6%

Kidney

A r t e r i e s

Stomach

Superior mesenteric a.

Liver Spleen Pancreas Small intestine

Inferior mesenteric a.

Total inflow 1500 mL/min pa = 90 mmHg

6% Other

Portal v. 6–12 mmHg

Large intestine

22%

Skin

Gastric a.

Total outflow 1500 mL/min pv = 3 mmHg

8%

FIG. 12.8  Splanchnic bed in immediate adaptation. The left portion shows the percent of absolute blood flow to various organs and tissues in the human body. The portion on the right shows the splanchnic circulation, which includes the blood flow to all digestive organs and annexal organs such as the liver. All venous drainage from the splanchnic bed—from all digestive organs—passes through the portal vein to the inferior vena cava and back into general circulation. (Modified and reproduced from Iaizzo PA. General features of the cardiovascular system. In: Handbook of Cardiac Anatomy, Physiology, and Devices. 2nd ed. Humana Press. © 2009.)

βΣ stimulates ●

●

●

Liver: Glycogenolysis: 2000-fold acceleration from basal rate managed by glycogen Pancreas: ● Glucagon: Glycogenolysis, neoglucogenesis ● Insulin: Glucose entry Cells: Augmentation of de novo ATP production

Leukocyte mobilization

Leukocytes Innate immunity

α∑ Hepatic veins

y

Hep at

700 mL/min Celiac artery

1300 mL/min

Glucose

Liver Spleen

Platelets Calcium clotting

β∑ Platelet mobilization

Pancreas Small intestine

Portal vein

Stomach

β∑ Aorta

Splanchnic SYSTEM

Cava

er ar t ic

ATP

Glucagon Insulin

Superior mesenteric artery

400 mL/min

FIG. 12.9  Drainage of all splanchnic circulation passes through the liver. (Reproduced from Pillai AK, et al. Portal hypertension: a review of portosystemic collateral pathways and endovascular interventions. Clin. Radiol. 2015;70(10):1047–1059. doi:https://doi.org/10.1016/j.crad.2015.06.077, Elsevier.)

Colon

Starter index

FIG.  12.10  Role of alpha (αΣ)- and beta (βΣ)-sympathetic on the splanchnic bed and annexal organs. See text for details. (Modified and reproduced from Koeppen B, Stanton B. Berne and Levy Physiology. 6th ed. El sevier © 2009.)

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Phase 2: Endocrine system αΣ stimulates the catabolic axes in order to liberate additional energetic material. This occurs through the yoking of both catabolic axes and the actions of their peripheral hormones (cf. Chapters 6, 8, and 10).

Short-term adaptation Short-term adaptation is a response to the continuation of immediate adaptation and offers the organism a (re-)constructive response to the catabolism of its predecessor. In order to not exhaust its buffering capacity, the organism must begin de novo fabrication of additional elements of response, be it immunoglobulins, enzymes, additional hormones, or hormone receptors. Thus, we see the reintroduction of the parasympathetic branch of the ANS into the adaptation response (Fig. 12.11): 1. ANS: πΣ 2. Endocrine: Hypothalamus, pituitary, gonads, parathyroid 3. Organs: Liver, exocrine pancreas, digestive tract, delayed (acquired) immunity There is a general solicitation of both the hypothalamic and pituitary hormones to manage the construction process.

Estrogen initiates metabolism, progesterone regulates it, and androgens complete it, thus the particular importance of the peripheral gonadotropic hormones. In addition, the GI tract and the annexal organs play a role in augmenting the absorption of nutrients from alimentation as well as the management of intermediate energy substrates such as amyloid proteins (cf. Chapters  2 and 7). The parathyroid contributes to the availability of calcium to augment the rate of metabolism (cf. Chapter 8).

Chronic adaptation Chronic adaptation occurs when an aggression does not cease, or when the organism’s perception of aggression does not. It requires a general solicitation of the entire neuroendocrine system as well as the thymus to manage the organism’s assessment of external vs. internal vs. auto-­ aggression. The liver continues to play a key role as does the digestive tract. 1. ANS: All branches 2. Endocrine: General elevation of hormone circulation + thymus 3. Organs: Liver, digestive tract 4. Immunity: Chronic immunity

Supraoptic nuclei

Hypothalamus

πΣ Mamillary body

Delayed immunity Supplies the paraumbilical varices

Median Eminence

Esophageal varices

Infundibulum

Gastric varices

Interior hypophyseal artery

Posterior Lobe Of Pituitary Gland Parastomal varices

Paraduodenal varices

Hypophyseal vein

FSH, LH

Rectal varices

Estrogens, progesterone, androgens

TSH

Parathyroid Calcium

FIG. 12.11  Schematic overview of the short-term adaptation syndrome according to the theory of Endobiogeny. See text for details. (© 2015 Systems Biology Research Group.)

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General adaptation syndrome (GAS) according to the theory of Endobiogeny Introduction The general adaptation syndrome (GAS) according to the theory of Endobiogeny differs from Hans Selye’s GAS (discussed below). Dr. Duraffourd, based on his comprehensive conceptualization of the neuroendocrine relationship, proposed a new type of adaptation syndrome. What Selye described as the GAS is only the immediate adaptation response according to the theory of Endobiogeny. This is not to diminish his meticulous experimental work. Selye was a visionary who sought to fundamentally reorganize our concept of homeostasis and disease, and redefine the role of the endocrine system in all maladies.

Definition The general adaptation syndrome according to the theory of Endobiogeny is a method of adaptation invoked during times of unknown aggressions. The GAS is programmed, sequential, systemic, and involves all four endocrine axes and related digestive organs and emunctories.

Characteristics Its programmed nature means that there are a series of stereotypic response every time the particular demand is invoked. It is sequential in the order of endocrine involvement and thus associated to glands and emunctories with respect to chronology and duration. The duration is not based on a chronologic time but qualitative biologic achievement. It is a “general” syndrome because it invokes systemic changes. In other words, not only does it invoke changes in the threshold and intensity of function of the endocrine system as manager of the terrain (though typically infra-liminal in nature), but also ensures that the endocrine system quantitatively and qualitatively alters the terrain both in its structure and in its function. Thus, it is called a syndrome because all three of these qualities run together.

Solicitation of the GAS The GAS is invoked by an unrecognized aggression that is existential and massive in nature. In this case, the programmed and sequential activity is the solicitation of all four endocrine axes in both loops of activity to alter the internal equilibrium of the entire organism. The GAS as a theoretical construct represents the totality of all neuroendocrine, digestive, and emunctory relationships at central and peripheral levels and at vertical, horizontal, and radial levels of management. All the adaptation syndromes, adaptative states, and basal functioning invoke particular and limited sequences and relationships may be found within the GAS.

The nature of this type of response to aggression must by necessity be acute and implies a necessary expenditure of supplementary energy to alter the internal equilibrium of the entire organism. The purpose of invoking the first loop is to mobilize elements of reserve in order to both furnish energy and augment the intensity of the response by the organism to the aggression. For example, when adrenaline is liberated, it increases the rate of glycolysis 2000-fold above the basal rate managed by glucagon. The structural elements of response, be they enzymes, muscles, or neurons, have calcium ratelimiting actions. Thus, in order for the organism to capitalize on the rapid increase in circulating glucose it must have sufficient calcium liberated from bones as well. Thus, buffering capacity is critical during the GAS. At the same time, the elements of anabolism are installed both in order to furnish new structural elements during the aggression, and also in preparation of an anticipated restructuring of the organism at of the end of the aggression. The purpose of the second loop is restitiuo ad integrum, the restitution of the organism to its prior state of structural capacity and functional dynamic prior to the aggression. If the aggression is of a low intensity but sufficiently repetitive, or, of a singular and intense nature but cannot be resolved, it must pass into a state of adaptability. Otherwise the organism will be submitted to a deinstallation of life and cease to exist due to auto-consumption.

Chronobiologic adaptation syndromes The CAS are a series of programmed adaptation responses to the demands placed on the organism based on internal and external chronobiologic requirements. They include short- and long-term time frames. The first and most frequent is circadian demands. The second is the change of seasons. The third is the biologic evolution of the organism throughout the seven phases of life (Chapter  13). In all these situations, the organism requires a particular and anticipated change in its equilibrium in order to harmonize its internal activity to the demands of exogenous rhythms. Inappropriate CAS adaptation plays a role in a wide range of disorders such as insomnia, hypersomnia, obesity, depression, chronic fatigue, immune dysregulation, and neuropsychiatric disorders, among others.

Circadian Circadian changes require a different predominance of metabolic activities: catabolic predominance during the day, and anabolic predominance during the night. Thus, the CAS installs a series of changes that alter the threshold of functioning of various axes. In this case, the programmed changes are not by axis, but by level of function: general pituitary (and emunctory) function at night, and a reinstallation of vertical corticotropic activity in the early morning.

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FIG. 12.12  Circadian adaptation. During the day, sympathetic, corticotropic, and thyrotropic axes are more predominant. During the night, parasympathetic and the anabolic axis (gonadotropic and somatotropic) are more predominant. See Chapters 4–6 and 9 for a discussion of each axis and its diurnal variations. (© 2015 Systems Biology Research Group.)

For example, in the evening, serotonin predominates over alpha-sympathetic function, allowing for an inhibition of CRH and a decrease in the level of functioning of the corticotropic axis, allowing for the installation of sleep and anabolic activity. In the early stages of the morning, melanocyte-stimulating hormone (MSH) lowers the threshold of stimulation of the adrenal gland thus relaunching catabolic activity for the morning. The CAS also adjusts the energy source from predominantly glucose to nonglucose substrates such as lipids and ketones (Fig. 12.12).

Seasonal The rotation of the Earth on its tilted axis, and, its revolution around the sun install variations of duration of light and darkness. From this organisms receive indications of a rhythmicity of life humans referred to as seasons. The

implication of rhythmicity is that the level of function of the organism, and hence its metabolism, must adapt itself to these external demands. The seasonal chronobiologic adaptation syndrome invokes changes in the level of functioning of the corticotropic and thyrotropic axes at all levels. This involves additional factors in a programmed and anticipated way, i.e., MSH and prolactin in the prespring, and serotonin and oxytocin in the preautumn. Dr. Duraffourd hypothesized that starting in the preseason, 3 weeks and 3 days before the solstices or equinoxes, the adrenal cortex and peripheral thyroid gland undergo certain changes (Fig. 12.13). The adrenal cortex shows four peaks. Each occurs during the preseason times in preparation for the general seasons as geomagnetic activity makes small adjustment (cf. discussion below). It has four plateaus which occur during the proper time of the seasons. Regarding the peripheral thyroid, we may make four observations: (1) it is inversely related to

FIG. 12.13  Seasonal chronobiologic adaptation syndrome according to Dr. Duraffourd, with geomagnetic data provided by and used with the permission of Professor Alfonsas Vainoras, MD, Habil. Dr., Lithuania State Medical University Institute of Cardiology, mean magnetometer readings from Lithuania, January–December 2015. Endocrine function is show in relative levels of fluctuation. Geomagnetic data is show in absolute value, in pico Teslas (pT). Dates are show in the US system where the month precedes the day of the month. Dates apply for the Northern hemisphere. From the left, geomagnetic activity is the highest line, followed by peripheral thyroid. The lowest line is the adrenal cortex. See text for details.

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mean geomagnetic power, (2) relative metabolic activity is less than adrenal cortex except in prespring and spring, (3) in prespring it has its greatest predominance over adrenal cortex to install a catabolic “spring cleaning” of accumulated waste products from the winter, and (4) in spring the thyroid shows reduced predominance. In general, one observes that the relative activity of both adrenal c­ ortex and thyroid glands are lowest in summer when mean geomagnetic power is greatest. Regardless, adrenal cortex activity continues to predominate over thyroid to prevent an explosive metabolic response. Biologic life on the Earth is developed in a geomagnetic field. The evolution of complexity of organisms occurred within the fields of geomagnetism (and gravity). Organisms are sensitive to their local magnetic environment.3 With respect to geomagnetism, we can make four general observations: (1) the mean power of geomagnetic output in picoTesla units inversely correlates with thyroid activity. This is the primary point of regulation of the rate of metabolism, (2) when a shift in geomagnetic output occurs during the month before the change of seasons, it solicits a brief and intense adrenal cortex response to adapt the functioning of the organism. Despite the fact that the most significant rate of change occurs at other times, it does not solicit an adrenal cortex response, (3) we hypothesize that the coexpression of hormones linked to the pineal gland regulate the adrenal sensitivity to geomagnetic changes, namely serotonin and MSH, and (4) the exception to these observations is the prespring period. It is unique in that in the first 2 weeks of March, both thyroid and geomagnetic activity rise. We hypothesize that this creates a period of extraordinary physiologic nourishment that supports the “spring cleaning” of the body: a catabolic predominance that helps expel accumulated biologically derived toxins during the winter months. In conclusion, the Earth’s magnetic output nourishes the human organism. The greater the nourishment from the Earth, the less cortico-thyrotropic activity is required. The less the nourishment on average from the Earth, the greater the cortico-thyrotropic response will be. Both fluctuations in geomagnetic activity and disruption of rhythmic living can adversely affect these processes.

Evolutionary biologic developments The human organism undergoes a number of major transformations from its initial materialization until the time of its dissolution. Each evolution is sequential and anticipated, preparing the organism for a subsequent phase of function. What is necessary in one phase can threaten the integrity of the organism in another phase. For example, the rapid rate of mass accumulation experienced in fetogenesis (Chapter 6) would be pro-carcinogenic in postuterine life. For example, cancer embryonic antigen (CEA) is elevated in embryogenesis. In postnatal life it is not, except in the case of chronic smokers and certain carcinogenic states.4, 5

There are seven stages of life: 1. Embryogenesis 2. Fetogenesis 3. Infancy 4. Toddlerhood 5. Puberty 6. Adulthood 7. Gonadopause The complexity of the human organism requires several timelines of development: structure, function, desire, will, movement, social intelligence, emotional intelligence, and intellect. Put another way: crystallization, organization, survival, reproduction, and de-installation of life. Thus, various evolutionary changes require a particular solicitation of the basic capabilities in varying proportions in order to establish each of the qualitative and quantitative changes required to be human. The first three evolutive changes are due to a complete reversal in the external milieu from aquatic to terrestrial (see Chapter 13 for a full discussion). Each phase installs a predominance of particular endocrine functions which must then undergo all the adaptation demands discussed in this chapter. Birth represents a major GAS response in the intralife transition between intrauterine and extrauterine existence. It invokes the GAS because it is an unknown and unanticipated aggression. The shock of rupture of materno-fetal symbiosis, and the inversion in the physiologic demands placed on the organism during the transition from interdependent marine life to independent terrestrial life constitutes a huge shock for the organism. For example, for the fetus, breathing is functionally redundant, but for the infant a necessary requirement of life; the fetus lives in silence, the infant will only live by making noise to indicate some basic need or emotional state. The fetus does not use its mouth for nourishment. The infant must use its mouth for nourishment or face starvation.

Adaptability and adaptative states Adaptability is the process of altering physiologic function to a level that is contrary to a person’s constitution in such a manner that it does not return spontaneously to its prior state of equilibrium. It can serve as a method of economizing adaptation syndromes by maintaining the minimum number of elements of terrain that must act in a dysfunctional state. The new state of equilibrium is an adaptative state. Adaptability is the process, and the adaptative state is the result. Fig.  12.14 presents the case of 48-year-old women who went through phases of basal and immediate adaptation, and chronic adaptation resulting in an adaptative state: Hashimoto’s thyroiditis. The upper of the two lines (red) is the thyrotropic axis. The lower of the two (black) represents the activity of the corticotropic axis. The graph depicts

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FIG. 12.14  Progression from immediate and short-term, to chronic adaptation to an adaptative state of Hashimoto’s thyroiditis. See text for details. (© 2015 Systems Biology Research Group.)

the history of adaptation demands placed on a patient over a 5-year (60 months) period of time. At time zero she was 43 years old. That year the patient faced typical demands for a working mother resulting in a series of repeated fluctuations in cortico-thyrotropic activity. As these changes were frequent but brief, it did not consume her buffering capacity. When she turned 44 years (month 12), her teenage son became addicted to prescription opioids. The emotional, financial, and physiologic stressors invoked the chronic adaptation syndrome. Due to its duration over 6 months, it consumed her buffering capacity, fragilizing her terrain. It resolved when her son entered treatment for his addiction. During months 18–26 (44.5–45 years) she was able to function in a manner similar to her prior state. Around 45 years (months 26–38) she was resubmitted to aggressions once again, invoking the chronic adaptation response. Her son relapsed and she had challenges at work. Around month 38 of her timeline, she entered into a premenopausal state. This installed a cortico-thyrotropic yoking to alpha in response to the change in gonadotropic activity. Due to the longer duration and greater number of aggressors (emotional, financial, social, and chronobiologic) her terrain entered in a state of adaptability. At that point (month 38) the aggression resolved. The corticotropic axis was able to return to its prior state of equilibrium, but the thyrotropic oversolicitation did not—it had become entrained. In order to economize the energy demand on the organism, the organism evolved the thyrotropic axis into an adaptative state and spared the oversolicitation of the other axes. Thyrotropic activity entered into a state of central hyperfunction and peripheral insufficiency resulting in Hashimoto’s thyroiditis. Two additional examples of adaptative states are presented. The first is Grave’s disease. In the theory of

Endobiogeny, we consider this to be a chronic ­oversolicitation of the thyrotropic axis initiated by the limbic system due to stressors. It moves the body into an adaptative state in order to economize the demands of hyperfunctioning to just the thyrotropic axis and not the entire organism per se. Another example is chronic bronchitis. During the preautumn or prewinter time, if the CAS activity is not sufficient to install the necessary adaptation of cortico-­ thyrotropic function, the organism invokes adaptability in order to install another physiologic level of function. One method would be an increase in πΣ to elicit a reactionary hyperalpha state to relaunch the adrenal cortex where MSH failed to do so. The prolonged activity of πΣ inadvertently oversolicits the exocrine and endocrine pancreas, which participates in the congestion of the lungs, and congestion and inflammation of the muscular lining of the airways. A secondary oversolicitation of TSH on the thyroid to readapt thyroid function will similarly participate in exocrine pancreatic oversolicitation and the formation of mucus, further congesting the airways. Thus, the precritical terrain for bronchitis is installed (Fig. 12.15). If there is insufficient exposure to infectious agent, the bronchitis will not occur. If there is exposure, the precritical state and compromised buffering capacity can allow for the bronchitis to develop and possibly progress into a chronic state (Fig. 12.16). In summary, there are six general groupings of adaptation responses: immediate, short-term, chronic, general, chronobiologic, and adaptability. Each solicits various ­aspects of the regulators of terrain: autonomic, endocrine, emunctory and digestive glands, and immunity (Table 12.1). Understanding the elements of terrain most implicated can help the clinical Endobiogenist to utilize a rational approach to the selection of interventions to assist the patient to be

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FIG. 12.15  The role of the pancreas in congesting the lungs and kidneys, created a fragilized terrain that favors a chronic bronchitis. See text for details. (© 2015 Systems Biology Research Group.)

FIG. 12.16  Installation of the critical terrain of chronic bronchitis. In the face of insufficient seasonal adaptation and the fragilized terrain shown in Fig. 12.15, the response to an aggression: cold air, infectious agent smoke, etc. sets off a response that installs the critical terrain of chronic bronchitis. See “A theory of Endobiogeny” Volume 2 Chapter 9 for details. (© 2015 Systems Biology Research group.)

more efficient in their response patterns and to end those that have entered into chronic or adaptative states.

5. Anticipate and prevent additional disorders that may develop from a disequilibrated terrain

Disadaptation states and their implications for treatment

Otherwise, the general approach to treatment will be to lessen or abrogate the offending agents and apply the following Endobiogenic treatments:

There are states of disadaptation so entrained by the organism, with a sufficient depletion of buffering capacity that a discontinuation of aggressing or nociceptive factors in the face of treatment does not result in cure. In these cases, the goal of therapy realistically will be to. 1. Restore buffering capacity 2. Reduce the intensity of symptoms 3. Support compensatory mechanisms 4. Utilize substitutive therapies where indicated

1. Restore buffering capacity 2. Reduce the intensity of symptoms 3. Support compensatory mechanisms 4. Anticipate and prevent additional disorders that may develop from a dysequilibrated terrain 5. Utilize substitutive therapies where indicated for the shortest time possible 6. Correct the terrain with anticipation of resolution of disorder

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Reflections on the general adaptation syndrome (GAS) of Selye Hans Selye, MD, PhD was a professor and director of the Institute of Experimental Medicine and Surgery, University of Montreal. He published his theory of the general ­adaptation syndrome in 1946 in the Journal of Clinical Endocrinology and Metabolism.6 However, as early as 1936 he published an article noting the significance of the adrenals in adaptation.7 Citations below are to his 1950 lecture in which he summarized the state of his experimental studies and conceptualization of the GAS according to his understanding at the time.

Nonspecificity of the stress response and its universality in all organisms According to Selye, all living organisms respond to stress, in which the “basic reaction pattern is always the same, irrespective of the agent used to produce the stress,” (p. 1383) hence it is a general syndrome and does not explain why an organisms expresses the signs and symptoms of stress in a particular way.

Role and types of stressors He considered stress to be both the cause and method of response to an aggression: both a provocateur and a conditioning factor. Thus, stress invokes the GAS. As a conditioning factor it has an intrinsic effect on the body according to its nature: “…the specific actions of the eliciting stressors modify the course of the resulting general adaptation syndrome (e.g., the glycemic curve will deviate from the characteristic pattern if insulin is used as the stressor agent)” (p. 1384). Selye explicitly recognized stressors as being physiologic, emotional, or psychosomatic in nature, although there was not sufficient experimental evidence for him to have a clear concept of how emotional or psychosomatic agents invoked the GAS.

The GAS according to Selye The GAS was thus divided into two general responses in an organism: 1. Passive nonspecific damage 2. Defensive (necrobiosis) Selye had a concept that the organism had a manager. Despite being familiar with the work of Claude Bernard and Bernard’s concept of the milieu intérieur, Selye did not elaborate on a theory of terrain to the best of our knowledge. Thus, he confounded the role of the ANS and the endocrine system stating the management of the organism involved the “two great integrating mechanisms, the nervous and endocrine system” (p. 1384). Selye saw

the sympathetic nervous system (not a term used by him) as functioning on two levels, but he did not appear to clearly differentiate between the effects of alpha- and beta-­ sympathetic activity. For Selye, at the endocrine level, the GAS only directly involved the pituitary-adrenal cortex: ACTH → Glucocorticoids, Mineralocorticoids ( + Factor “X” ) The GAS of Selye is essentially one portion of the immediate adaptation response according to the theory of Endobiogeny. He acknowledged that adaptability involved all “vital organs and functions,” including other endocrine activity. However, he did not believe them to be essential for the adaptation response: The principal endocrine response to stress is characterized by the so-called “shift in anterior-lobe hormone production.” This consists in a diminished secretion of somatotrophin [Growth Hormone], the gonadotrophins (F.S.H., L.H., prolactin) and thyrotrophin [TSH]-which are not essential for the maintenance of life during conditions of emergency-accompanied by an increase in the secretion of A.C.T.H. Apparently the anterior lobe is unable to produce all its hormones at an optimal rate if it is called upon to discharge extraordinarily large amounts of corticotrophin. (p. 1385).

Selye had a concept he referred to as “Adaptation energy” which includes part of what we would consider to be the buffering capacity of the organism. He referred to it as the magnitude of adaptability and considered it to be conditioned by hereditary factors. I have been intrigued by the fact that an already acquired adaptation to a certain stressor agent is gradually lost in the course of chronic exposure. This means that the ‘adaptation energy’ (or adaptability) of the organism is a finite amount. There is a singular similarity between the manifestations of the exhaustion stage, which ensues when adaptability is lost, and those of physiological senility. (p. 1390).

Selye faced criticism with respect to many different aspects of his theory of general adaptation. Perhaps the most vexing was the polymorphic response to distress. Physicians asked how a general response that was nonspecific and programmed could be responsible for so many different types of diseases. Again, he had a number of notions based on experimentation and reason, but no concept of or evidence for a theory of terrain. In his 1950 lecture, he cited six reasons for polymorphic response to stress: 1. The intrinsic effects of the stressor 2. The generalized and nonspecific nature of the response to stress

Adaptation syndromes Chapter | 12  171

3. Endogenous circumstantial and conditioning factors: a. Heredity b. Preexisting disease of certain organs c. Previous exposure to stress 4. Exogenous circumstantial and conditioning factors: a. External milieu b. Diet 5. Periodicity of exposure to aggressions 6. Peripheral conditioning factors: a. Upstream effects of stress b. Downstream effects of stress Selye’s conclusion was that the GAS is a general and nonspecific response. He believed that it helped explain why certain nonspecific therapies have helped in the past: fever therapy, electroshock, bloodletting and starvation. He concluded that their principle value was in stimulating ACTH and glucocorticoid production. Therefore, he concluded those therapies should be replaced by intravenous ACTH and glucocorticoid injections to treat a host of diseases from alcoholism to nasal polyps, from asthma to allergies, and from ulcerative colitis to rheumatoid arthritis.

Positive aspects of Selye’s research and conclusions Selye integrated numerous levels of biochemical, physiologic, and neuroendocrine observations into a systematic explanation of the response to stress. He recognized the importance of the corticotropic axis in adaptation and survival. He saw the axis as being more than just the pituitary and the adrenal cortex. He included the liver, the splanchnic bed, the spleen, and the kidney. Perhaps most importantly, he concluded that the concept of endocrinopathies need to be expanded beyond the concept of disorder of the endocrine glands. He concluded that majority of the diseases were the “by-product of faulty hormonal adaptative reactions to a variety of nonhormonal pathogenic agents.” Finally, Selye recognized the importance of training physicians in adaptability and the diseases of adaptation. He also foresaw the depth of training required for such physicians. In conclusion, the Selye’s meticulous experimentation, grand vision, and deep concern for both nosology and therapy laid the foundations for what we know today about stressors, stress, and adaptation.

References Shortcomings in Selye’s research and conclusions Selye’s contributions to medicine are monumental and neither can nor should be ignored, diminished, or overlooked. However, like all thinkers, he had certain constraints imposed on his conceptualizations, methodology, and conclusions by the rational reductionist experimental traditions of the day. He lacked a theory of terrain. Without a theory of terrain, he was not able to consider the role of other ­hormones outside the corticotropic axis in the GAS. He confused experimental research with supra physiologic doses of hormones with the effects of physiologic activity of hormones in fully intact organisms. Selye concluded that diseases of adaptation were all due to insufficient ACTH and/or glucocorticoids and advocated nonspecific substitutive therapy with corticotropic hormones.

1. Selye  H. Stress and the general adaptation syndrome. Br Med J. 1950;1(4667):1383–1392. 2. Chauvet G. Du développement á la conscience de l’individu á l’espèce Unpublished manuscript. n.d.. 3. McCraty  R, Atkinson  M, Stolc  V, Alabdulgader  AA, Vainoras  A, Ragulskis  M. Synchronization of human autonomic nervous system rhythms with geomagnetic activity in human subjects. Int J Environ Res Public Health. 2017;14(7):1–18. 4. Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer. 2012;76(2):138–143. 5. Kashiwabara K, Nakamura H, Yokoi T. Chronological change of serum carcinoembryonic antigen (CEA) concentrations and pulmonary function data after cessation of smoking in subjects with smokingassociated CEA abnormality. Clin Chim Acta. 2001;303(1–2):25–32. 6. Selye H. The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol Metab. 1946;6:117–230. 7. Selye  H. The significance of the adrenals for adaptation. Science. 1937;85(2201):247–248.

Chapter 14

Art of physical examination in Endobiogeny The problem is that very often it is not so easy to comprehend what the language of the body means. It is for this reason that one should not endeavor to explain the meaning of this language with a single sign. Jean-Claude Lapraz et Marie-Laure de Clermont-Tonnerre in “La médecine personnalisée: retrouver et garder la santé” (p. 111).

Introduction The relationship of the physician to the physical examination of the patient has been quite variable throughout history, affected by three issues: culture, time, and relevance. In many traditional cultures, touching of nonrelatives of the opposite sex was considered forbidden except in particular circumstances. For example, it was recorded that great Chinese physicians could read the pulse of female patient from behind a curtain with nothing but a string tied tightly around her wrist to transmit pulsations of the pulse. In other cases, an anatomical doll was used and the patient would point to locations of discomfort. Physical examination gained greater acceptability in places such as Europe and North America based on shifting attitudes regarding touching of the opposite sex. In addition, before the time of imaging studies, the astute physician relied on physical examination: inspection and palpation, then later auscultation to estimate the gross state of anatomical structures and their function. The rise of imaging studies, along with economic pressures on physicians for greater output has led to a decline in the perceived value or “luxury” of conducting a physical examination. Conversely, when physicians perform an examination, signs are missed or misinterpreted.1 When the physical examination is combined with imaging studies rates of accuracy of diagnosis increase.2–4 Ultimately, they are complimentary and not substitutive.5 The examination, along with history, allows for fact gathering, to build a hypothesis. Biomarkers and imaging studies are used to test that hypothesis.6 Part of the wasteful spending in the United States is utilizing imaging studies or biomarkers for hypothesis generation rather than evaluation. According to the theory of Endobiogeny, the physical examination remains a point of capital importance. The terrain is regulated by and formed under the direction of The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00014-8 © 2019 Elsevier Inc. All rights reserved.

n­ euroendocrine factors. Thus, in every aspect, every layer of the physical body represents a historical or current expression of the neuroendocrine regulatory factors. While there is overlap between findings by history and biology of functions, there are elements that can only be determined by physical examination, e.g., oversolicitation of the parotid gland due to exocrine pancreatic insufficiency of amylase production. Other factors can only be more precisely determined by physical examination. An example of this is hepatic congestion. There may be symptoms reported by the patient, but until the liver and related points are examined, one cannot determine what the level of congestion is: vascular, metabolic, hepato-splenic, hepato-splanchnic, etc. This chapter presents a survey of key elements of the physical examination according to the theory of Endobiogeny. While extensive, it is not comprehensive. It is to offer the clinician an idea of the wealth of information that can be obtained from a physical exam and to make an appeal for the reevaluation of its proper role in contemporary medicine. This chapter describes the approach to the exam and not the significance of its findings. That is discussed in The Theory of Endobiogeny, Volumes 2–4, where it is both catalogued by system and related to specific disorders.

Purpose of the physical examination The purpose of the physical examination is to evaluate the current and past indications of neuroendocrine management of the terrain. There are three levels of evaluation: exterior, middle, and interior. The exterior evaluation is that of the envelope of the organism: that which is apparent by observation and clarified by light palpation. The middle structures are below the level of the skin. They require auscultation and/or slightly deeper palpation. The interior structures are the visceral structures and their supporting tissues and structures. They typically require auscultation and/or deep palpation (unless they are protected by boney structures). These terms are not related to the embryologic structures of exoderm, mesoderm, or endoderm. Nor, do they refer to designations of body type such as ectomorphic (thin, rectangular torso, narrow waist in women), mesomorphic (medium build, inverted trapezoid), and endomorphic (stocky, square torso, fuller hips in women). These designations are the result 199

200  The Theory of Endobiogeny

of variable degrees of participation of numerous neuroendocrine and emunctory factors. In other words, two individuals may have an ectomorphic appearance for completely different reasons: one because of pituitary insufficiency, the other because of exocrine pancreatic insufficiency. Consider three women, each of whom has a different “-morphic” shape. One is ectomorphic (thin), another mesomorphic (medium build), and the third endomorphic (full figured). Despite this, the meso- and endomorphic women may both be estrogenic in their Endobiogenic body type. This would be determined by their smooth skin complexion, shiny hair, hips wider than their shoulders, and charm in their eyes. We can say that estrogens are relatively predominant in relationship to androgens. But what about the quantitative expression of estrogens? For this, we can evaluate density of bone and musculature. The mesomorphic women have a greater quantitative expression of estrogen activity and/or receptors because she has more tissue mass. The ectomorphic women would have a lower quantitative expression of estrogens. From the perspective of Endobiogeny, classification by external appearances is insufficient. It does not address quantitative and qualitative relationships simultaneously. Our designation is topographical. The advantage of this approach to the physical examination is that it allows for an

assessment of the relative distribution of metabolism between the interior and the exterior. For example, a person may have elevated growth factors that express themselves on the exterior, such as skin tags. However, their general ability to maintain and repair visceral organs in the interior may not be excessive. It may be optimal or deficient (Table 14.1). The neuroendocrine system manages metabolism, ergo, it manages the creation, adaptation, and evolution of structural elements based on the various internal and external demands, and those of space and time. Thus, the physical examination reveals aspects of phenotype. However, it should be cautioned that with respect to the exterior structures, one must learn to differentiate—to the degree ­possible—whether one’s findings are acute, chronic, acute on chronic, or past neuroendocrine activity (Fig. 14.1). It is a general truism in systems analysis that the significance of any single data point can only be determined by comparing it with one or more additional data points. With respect to the physical examination, no single physical exam finding is indicative of a single neuroendocrine ­activity. Furthermore, because systems are qualitative in their function, the analysis of two or more points favors the relative level of functioning of one neuroendocrine or emunctory factor in relationship to that of others.

TABLE 14.1  Determining the time scale of findings on the envelope Temporality

Description

Example

Acute

An acute change in the structure, structuro-functional or functional nature of the organism

1. Anterior abdominal findings

A chronic change in the structure, structuro-functional or functional nature of the organism

1. Signs of abdominal solicitation on the back

An acute change to a chronic adaptative change in the structure, structuro-functional or functional nature of the organism

1. New skin tags in a person with a history of skin tags

Chronic

Acute on chronic

Discussion

2. Musical respiration from bronchus

2. Bulbous appearance to nose

1. Nose: findings favors chronic growth hormone activity when there are other signs of elevated growth hormone found on exam; as an isolated finding, it may reflect a past event

2. Enlargement of a subcutaneous lipoma 3. Further bulbosity of a bulbous nose

Past

A prior neuroendocrine management of terrain

1. Leathery appearance of skin 2. Cleft chin 3. Cleft nose

1. Skin: hyperinsulinism for a period of time; even if insulin activity reduces, the changes may persist 2. Cleft: surge in gonadal androgens prematurely closes the growth plate, not necessarily indicative of current gonadal androgen activity

Art of physical examination in Endobiogeny Chapter | 14  201

was evoked because of intrauterine stress, as c­ ortisol activity diminishes postpartum, the lips may become fuller. This would be a structural change due to a return to the genetically programmed cortisol state in structure. An example of a permanent adaptative change would be an adolescent with a very full lower lip that had a lower lip of average density throughout childhood. Visceral congestion, especially on the pancreas, installed during puberty to aid the general somatotropic plan of pubertal growth would be considered the most likely reason for this event. One can explore this by asking about other signs of pancreatic oversolicitation: anal itch, hemorrhoids, and tonsillitis. FIG.  14.1  Long, slightly curved eyelashes in an adult caucasian female. Note the wide spacing between the eyelashes, the cloudy appearance of her iris, and dark blue ring on its periphery. Note also her white sclera, and freckles on her face. Each of these findings has significance in Endobiogeny. (Image: Shutterstock.)

Exterior structures The exterior expressions of metabolism are those in the envelope of the organism. The human being is a visual animal by nature, even in fetal life before faces have been viewed.7 The survival and adaptation values of this cannot be underestimated. We are oriented through subconscious assessments to evaluate the exterior features of other human beings, favoring symmetry as a sign of beauty.8 They are perceived in traditional cultures to, and, physiologically in fact do relate to fertility and strength, 9, 10 and are evanescent windows into the psychic experiences of joy, anger, aggression, etc.11 Thus, it should be no surprise that the envelope—the skin, hair, shape and size of breasts, etc.—contain such a complex interaction of neuroendocrine factors and expresses through the face and body postures a range of emotional valences and mental states. Skin and hair have a high rate of turnover; thus, they are most likely to reflect acute and subacute changes in nutrition and metabolism and thus of neuroendocrine management of the terrain. A note of caution is offered regarding the immediate subcutaneous structures, such as the fine osseous and cartilaginous structures of the face, hands, and feet. Before puberty, changes to these structures typically reflect a programmed, evolutionary chronobiologic development of structure, and may also reflect adaptative changes. Changes to the postpubertal structure will always be adaptative in nature. Two examples are given below.

Example of changes in the structure during childhood The evolution of the lips of infants serves as a good example. Thin lips favor elevated cortisol in structure. If this ­cortisol

Example of changes in the structure in adulthood A 25-year-old woman with severe dysmenorrhea once remarked to us how every month in the week of her premenstrual syndrome, her eyelashes would grow longer and more curved (Fig. 14.1). Once menstruation began, her eyelashes returned to being straight and of moderate length. The lengthening of the eyelashes occurs under the influence of FSH and the curl reflects an appeal to the thyrotropic axis for a relative augmentation of peripheral function. Thus, this is a temporary, adaptive change in the structure.

Middle structures The middle structures are those below the dermis and above the viscera. They include subcutaneous tissues, musculature, and associated blood vessels and lymphatics.

Interior structures Interior structures are the visceral organs and their related connective tissues, blood, lymphatic vessels, and bones. They are organs and structures that are either inaccessible to direct manual palpation (i.e., brain, lungs, heart, kidney, and adrenals) or covered by numerous layers of dense tissue (i.e., digestive organs, bones, etc.) requiring deep palpation.

General considerations regarding the physical examination The remainder of the chapter is not exhaustive, merely demonstrative. It is not implied that each physical examination will have the same level of attention to detail. The less time the practitioner has, the less complaints by the patient and the more focal those complaints, the more targeted the examination may be. However, according to the theory of Endobiogeny, there are two points to consider with respect to this statement: (1): the examination is careful and with purpose, (2) a focused exam is not limited to the area of physical abnormality or discomfort, but to the primary

202  The Theory of Endobiogeny

e­ lements of the critical terrain. We will illustrate them with the example of a child who presents with a complaint of ear pain and fever suggestive of otitis media. The Endobiogenist is not like a fisherman casting a wide net hoping to catch something worth keeping. She is more like an archeologist on an “expedition.” The history focuses on the considerations of the Endobiogenist toward the aspects of the terrain most implicated in the functioning of the organism. This approach to terrain implicates that nonlocal structures are interrelated by functionality, not space. In the case of an otitis media, the adrenal cortex, autonomic nervous system, and pancreas are implicated. Thus, a “targeted” exam is not limited to the ear canal. A “quick and targeted” Endobiogenic examination of this child in this case will include an evaluation of the following: (1) Local: a. External ear: Erythema, temperature b. Cerumen: Abundance, thickness, moisture c. Tympanic membrane: Color, mobility, visualization of bones (2) Regional a. Lymph nodes b. Parotid glands (3) Distal: a. Adrenals (deep palpation on the flank) b. Pancreas c. Alpha-sympathetic activity, e.g., hippus, temperature of hands and feet, brittleness of cerumen, etc.

Methods of evaluation There are four methods of evaluation in the physical examination: (1) (2) (3) (4)

Inspection Auscultation Percussion Palpation

Generally speaking, they should be performed in that order, from least to most noxious. This is especially true in infants and children. To palpate or to approach the child aggressively in a manner that causes them to cry and scream obviates any further evaluation except for inspection of the oral cavity and auscultation of the lungs.

Inspection Inspection involves observing or viewing an element of structure or function in a discerning manner. During inspection one should note qualitative and quantitative features such as size, color, and symmetry compared to other structures on the contralateral side of the body.

Auscultation Auscultation involves listening to hollow or cavitated structures and that which moves through them. The following structures can be auscultated (Table 14.2).

Percussion Percussion involves placing a finger over a solid organ such as the liver or lung and tapping it with a finger from the contralateral hand in order to determine the density of the organ.

Palpation There are two types of palpation: pressing into a structure and rolling skin over a structure. The pressing can be of a light, moderate, or deep pressure, depending on how close the structure is to the interior and how much connective ­tissue acts as a barrier. In Endobiogeny, pressure is applied to two types of structures. One is an anatomic organ proper. In this case, the purpose of application of pressure is to evaluate size, contour, and mobility of the organ. The second is a projection of a structure. A projection is a point unrelated to the anatomical location of the organ, but which corresponds to certain structuro-functional or functional states (Fig. 14.2). For example, we find that a general congestion of the gallbladder can be determined by deep palpation of the arch of the right foot. The second method is palper rouler, literally the rolling palpation. It is a type of rolling manipulation of the skin over glands, organs, or their projections. This method is based on a few considerations, key among them are embryologic unfolding and endocrine receptor density in the skin. We theorize that the skin, as a fractal expression of

TABLE 14.2  Auscultation of viscera Structure

Movement

Quality

Hollow viscera, e.g., small intestines

Digestive juices

Tinkling, gurgling

Vasculature, e.g., arteries

Blood

Bruits

Heart, e.g., atria, ventricles

Blood, valves

Murmurs, rubs, clicks

Airway, e.g., trachea

Air

Musicality, stridor, sturdor

Lungs, e.g., lung parenchyma

Air

Distribution of air on inspiration, expiration

Art of physical examination in Endobiogeny Chapter | 14  203

the cell membrane in complex organisms, is really the first brain, the enteric nervous system the second brain, and the brain in the cranium is the third brain.12 Thus, we find receptors for the CRH13 and the melanocortin family, which includes ACTH, in the skin.14 According to Dr. Duraffourd, a rolling palpation witnesses the general current level of ACTH solicitation of the adrenal cortex. The areas on the back (Fig.  14.2) not related to retroperitoneal or thoracic structures are evaluated by rolling palpation (i.e., right thoraco-lumbar: liver congestion). For example, a rolling palpation of the skin starting at the left inferior scapula tip towards the head that evokes pain suggests a chronic congestion of the pancreas. If the same procedure evokes pain over the right scapula, it indicates a chronic congestion of the liver. Horizontal rolling of the skin over the anatomical site of the adrenals indicated over-solicitation of the adrenals. Horizontal rolling of the skin over the superior aspect of the scapula indicates chronic congestion of the thyroid. In order to perform this correctly, it is important to grab the full thickness of skin and roll it with firm support from the thumbs, pushing along the fascia, like a Zamboni machine upon the ice. The importance of using different methods of evaluation of palpation is that a patient—especially androgenic patients—may not express any discomfort on evaluation of the physical organs but may do so on the evaluation of projections—especially under rolling palpation.

Keys aspects of the physical examination by system or location Musculoskeletal A patient’s posture, their physique, and the general articulation of the osteomuscular structures can be observed at ­various points of the consultation, both during the history, as well as during the physical examination. Other parts, such as muscle texture and architecture, will need to be evaluated once the patient is lying down. Most of the osseous structures are sufficiently clothed in muscle and are inaccessible or partially accessible by moderate or deep palpation except for those of the extremities, face, and cranium.

Musculoskeletal: Medio-interior ● ●

Posture Symmetry of structures (Fig. 14.3) ● Sagittal plane: Relative hypertrophy of bilateral structures ● Transverse plane: - Relative tonus of musculature, bone length, symmetry of shoulders - Relative relationship of distant structural elements to each, e.g., right shoulder to right hip, left shoulder to left hip

FIG. 14.2  Palpation of organs and projections of organs and glands. (© 2014 Systems Biology Research Group based on an image by Duraffourd and Lapraz, unpublished.)

204  The Theory of Endobiogeny

Superior Frontal plane

Right

Left

Cranial Medial

Lateral Proximal

Proximal

Transverse plane

Caudal

Distal

Dorsal or posterior Sagittal plane Distal Ventral or anterior

Inferior

FIG. 14.3  Sagittal/transverse, anterior/posterior, inferior/superior planes of evaluation of the human body. (Source: Netter medical illustration used with permission of Elsevier. All rights reserved.)

●

Body morphology, e.g., rectangular vs ovoid, size of head relative to body, length, and width of hands, or feet relative to other structures (Fig. 14.4).

Muscle: Middle ● ● ● ●

Density Tonus Texture Architecture

Consider the volume-to-density ratio of an infant’s thighs to that of a postmenopausal woman (right) vs a sporty young man (middle) (Fig. 14.5).

Integument: Exterior par excellence The integument in humans consists of the envelope of the organism: skin, hair, and nails. They are all exclusively exomorphic structures. However, they rely on middle and interior structures for their nourishment and integrity. This observation is quite relevant when considering disorders such as psoriasis or acne.

Skin ●

●

Bone: Interior ●

Contour: Smooth, flat, knobby

● ● ●

Pigmentation: General coloration, areas of hypo- and hyperpigmentation and the origin of the pigmentation (skin vs subcutaneous vessels) Texture Temperature Moisture Sebum

Art of physical examination in Endobiogeny Chapter | 14  205

FIG. 14.4  Body morphology by relationship of hips to waist to shoulders. Various configurations of these relationships related to various endocrine influences. For example, curvaceous hips relate to increased FSH in structure. Broad shoulders relate to androgens in structure. (Image: Shutterstock.)

FIG. 14.5  Texture and architecture of muscles throughout life. The infant (left) has large thighs relative to her upper body. On palpation, one will find that most of that mass is infiltrated fat, not muscle. The toned adult male (middle) as excellent structure and architecture of his muscles: they are very well defined and dense on palpation. The adult female (right) may have quadriceps that are palpable and defined, but the architecture is lacking: the muscle is soft and there is cellulite. (Images: Shutterstock.)

● ● ●

●

Pilosity Presence of furuncles, boils, etc. Note differences in the qualities of the skin in different parts of the body Dermatographia: Onset, duration, and intensity of blanching vs hyperemia

gender differentiation, status, values, etc.15–18 In addition to considering these factors with respect to personality, there are basic qualities to consider with respect to physiology (Fig. 14.6). ● ● ●

Hair Hair is an externalized structure that reflects a myriad of factors related to fertility, in particular gonado-thyrotropic integrity of function and nutritional status. Thus, in most cultures, hair plays an important semiologic role in fertility,

● ● ●

Length Integrity (i.e., are there split ends) Strength Sheen Color Color variance in various: ● Parts of the body ● Seasons ● Stages of development

206  The Theory of Endobiogeny

FIG. 14.6  Qualities of hair. The woman on the left has hair that is dry, straight, and with split ends. The girl in the middle has hair that is dark black with dense curls. The woman on the right has shiny, lustrous, long, and straight hair. (Images: Shutterstock and Pixabay.) ● ●

●

Distribution Density: Note how it varies between the head, eyebrows, arms vs legs, proximal vs distal extremities, anterior vs posterior portions of the body Texture: Coarse vs fine

Nails The nails reflect subacute and chronic changes in local and global physiology. They reflect nutritional, basal, adaptive, and adaptative changes (Fig. 14.7).

Visualization ● ● ● ●

Nail plate: Length, sheen, color Cuticle Lunula: Size, color Peri-cuticle lesions

Palpation ●

NB: Clubbing is a sign relating to a middle structure and should be investigated during the examination of the nails.

Face The face has the greatest number of muscles per square inch. It is the façade that the organism presents to the world. The face contains a high degree of gross and micro expressions. Thus, the physical examination of the face begins when the Endobiogenist first views the patient. The face is quite unique as it is the only structure in the body that contains direct access to endomorphic structures through visualization: eyes (an extroversion of cerebral tissue), oral cavity (orifice of the canal of Stensen), lymphoid tissue (tonsils, adenoids—with some visual aid), and osseous structures (teeth). During physical examination, one should be sure to evaluate the following features (with some redundancy from other systems.

Nail plate: Strength, texture, i.e., coarse vs fine

Exterior ●

●

●

●

●

● ●

FIG. 14.7  Evaluations of nails. This patient appears to have firm nails but with white spots on several nails, suggesting a zinc deficiency with intestinal inflammation. (Reproduced from Shah KN. Nail disorders as signs of pediatric systemic disease. Curr Probl Pediatr Adolesc Health Care 2012; 42(8):204–211. https://doi.org/10.1016/j.cppeds.2012.02.004, Elsevier.)

●

●

Forehead: Shape, height, length, presence of blemishes Eyebrows: Color compared to hair on head, length (toward the midline and distal ends), density, and distribution of hair (Fig. 14.8). Eyes: Eyelashes, eyelid texture, color, vascularity, blemishes Orbit: Periorbital coloration (general skin tone, black, blue, red) Nose: Shape (tapered, curved, bulbous, etc.), length, width, density of nostril hairs Philtrum: Length (Fig. 14.9) Lips: Length, width, fullness, color, vertical lines, vermillion border Chin: Contour, length, width, degree of cartilaginous vs osseous structure Cheeks: Prominence of zygomatic arch, color of arch, color of cheeks, presence of blemishes or vascularity

Art of physical examination in Endobiogeny Chapter | 14  207

FIG.  14.8  Evaluation of eyebrows. The woman on the left has eyebrows that lose density of hair in the periphery. She should be evaluated for a thyroid insufficiency or deficiency. The man on the right has eyebrows that are still black beyond his 60s and quite dense and bushy with hair. He has elevated ACTH (bushy) and DHEA (darkness of hair). (Image on the left reproduced from Itin PH et al. Superciliary upsweep or tented eyebrows a distinct mendelian trait. J Am Acad Dermatol 1997;37(2):295–297. https://doi.org/10.1016/S0190-9622(97)80373-8, Elsevier; Image on the right: By Papik/Shutterstock.com.)

FIG. 14.9  Philtrum evaluation. Child on the left and middle have long philtrum. Note the difference in the bulbous nature of the nose, and thickness of the lips. The man on the right has a philtrum of normal length for a Caucasian, but quite different lips. (Courtesy of NIH public domain.)

●

●

Sides of the face and jaw line: Presence of hair, quality of hair (downy, coarse, color, etc.), blemishes Ears: Color of the helix, hair in the orifice, size of ears

Middle ● ● ● ●

Forehead: Subcutaneous masses Eyes: Eyelid subcutaneous masses Ears: Subcutaneous masses fleshiness of ear lobe, etc. Oral cavity: Sublingual: Vasculature: Size, tortuosity, color (Fig. 14.10).

Interior ●

●

●

Eyes: Size, shape, sclera color (white, blue), sclera vascularity, color(s) of iris, dilation of pupil (Fig. 14.11) Nose: Color of mucosa, secretions (amount, density), turbinates, hair distribution Oral cavity

Tongue: Length, width, color, lesions, fissures, dental impressions ● Teeth: Number, color, history of dental work ● Gums: Color, integrity ● Palate: Color, vascularity ● Posterior pharynx: Color, prominence of lymphoid tissue ● Tonsils: Color, consistency, size ● Salivary glands - Parotids: Size, density, tenderness, size of orifice of canal of Stensen - Submandibular: Size, density, tenderness, size of orifice of canal of Wharton Ear: Canal, tympanum, otic bones ●

●

Thorax The chest holds classic expressions of sexual dimorphism in the breast examination. The breast in general, and in women

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FIG.  14.10  Examples of variations in sublingual vein congestion, an indirect expression of hepatic congestion with upstream hydrostatic pressure delaying drainage from the structures of the head. Sublingual congestion is determined by three factors regarding the veins: (1) prominence, (2) depth of color, (3) deformity. The more factors present and the more advanced they are, the greater the hepatic congestion can be assumed to be. From least to most congested: (D) Unremarkable: veins barely visible and lighter blue, (B): slight congestion: veins visible, light blue and largely straight, (C): mild congestion: veins slightly darker than (B), more prominent, and knotted in appearance, (F), moderate congestion: veins darker and easily visible but no deformities, (A): advanced congestion: veins dark and prominent with numerous deformities on right side of image, (E): more advanced congestion: veins are dark blue with numerous deformities and edema of surrounding tissue. (Reproduced from Tanaka T. Tongue diagnosis: relationship between sublingual tongue morphology in three tongue protrusion angles and menstrual clinical symptoms. J Integr Med 2015;13(4):248–256. https://doi.org/10.1016/ S2095-4964(15)60180-7. © 2015 Journal of Integrative Medicine Editorial Office, Published by Elsevier.)

FIG. 14.11  Exploded rosette, melanic spots, and injected sclera on examination of the eye. One may also note the wide spacing of the eyelashes, and their slight curl at the end. (Image: sruilk/Shutterstock.com.)

Art of physical examination in Endobiogeny Chapter | 14  209

in particular, is the crossroad of expression of all four axes and emunctory function. If local medicolegal and cultural considerations allow it, a breast examination should be performed during a general physical examination or for specific gynecologic complaints. One must not forget that the thoracic structures include the bones and muscles as well as the lungs, and are anterior and posterior structures.

Exterior ● ● ● ● ● ● ●

Thorax: Length, breadth, anterior-posterior shape Sternum shape: Concavity, convexity, etc. (Fig. 14.12). Hair distribution: Midline vs lateral areas Blemishes Breasts: Size, color Nipples: Size, color and width Areola: Size, color, width and nodularity

Middle ● ● ●

Ribs: Number, contour, tenderness Musculature: Intercostalis muscles Breasts: Vascularity

Interior ●

Lungs: Respiration: air flow, musicality, length of inspiration relative to expiration, use of accessory muscles,

● ●

●

airflow over larynx, trachea and bronchus; be sure to auscultate anterior, axillary, and posterior aspects of the lungs Breasts: Density, masses, tenderness by quadrant Nipples: Spontaneous or induced expression of liquid, liquid color, and consistency Xiphoid process: Width, length, degree of extroversion, tenderness on palpation (Fig. 14.13).

Cardiovascular The cardiovascular system, by its nature, is diffuse and will be found in all areas of the body. The cardiovascular examination can be done in toto as a discrete system, or in the process of evaluation of distinct regions of the body, i.e., the heart during the thoracic examination, the abdominal aorta during the abdominal examination, etc.

Middle A mesomorphic evaluation of the cardiovascular system is that of the superficial vasculature, i.e., the subcutaneous vasculature. ●

●

Inspection: ● Veins: Prominence and integrity, congestion ● Arteries: Prominence, pulsation Palpation: ● Pulse width, amplitude, strength, and symmetry (left vs right): radial, carotid, and femoral arteries

FIG. 14.12  Pectus excavatum in an adult male. (Reproduced from Sarwar ZU. Pectus excavatum: current imaging techniques and opportunities for dose reduction. Semin Ultrasound CT MR 2014;35(4):374–381. https://doi.org/10.1053/j.sult.2014.05.003, Elsevier.)

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Abdomen Unlike the thoracic cage, the abdomen contains vital organs that can be directly palpated because they are not protected by osseous structures. Because it contains the emunctories and the majority of digestive organs and annexal structures, the abdominal examination allows for a quick assessment of the digestive and buffering capabilities of the organisms. Due to the particular embryologic process of formation, the posterior aspect of the organism (i.e., the back) offers additional evaluation of chronic oversolicitation of the abdominal viscera (Fig. 14.2).

Exterior ●

●

●

Shape of abdomen and distribution of subcutaneous fat: Upper, mid, lower abdomen, sides, etc. Regional temperature of abdomen in the above noted areas Distribution of hair

Middle ● ● ●

FIG. 14.13  Palpation of xyphoid process. The xyphoid process, located at the distal tip of the sternum (shown highlighted in red) may be pressed with firmness. Its location (anterior with protruding tip), planar to chest or posterior (found retrograde), and pain on palpation are all significant findings. (Reproduced from Anatomography [CC BY-SA 2.1] via Wikimedia Commons.)

Interior: Abdomen: Listing of structures ● ● ● ● ●

●

●

Auscultation: ● Bruits Temperature ● Distal extremities: Hands vs feet vs nose vs ears ● Core vs extremities ● Chest vs abdomen

Interior ●

●

Heart: ● Palpation: Apex and orientation in chest ● Auscultation: Systole and diastole, regularity of rhythm, murmurs Vasculature: Abdominal aorta ● Visualization: Pulsation ● Palpation: Pulse width, amplitude, strength, and symmetry ● Auscultation: Bruits

Quality of subcutaneous fat: Doughy, firm, loculated, etc. Musculature: Tone, integrity Fascia: Integrity, compliance

●

●

●

Stomach Pyloric sphincter Duodenum Distal small intestine Colon: ● Ileocecal junction ● Ascending ● Transverse ● Descending ● Rectosigmoid ● Anal sphincter Liver: ● Superiomedial aspect ● Inferiolateral aspect Pancreas: ● Exocrine ● Endocrine Spleen

Interior: Abdomen: Examination NB: (1) Some visceral structures (i.e., gallbladder) cannot be directly palpated, but projected points are accessible, allowing for an indirect assessment of their function. (2) The examination is best done in the order below so as not to

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i­rritate the viscera and alter the accuracy of the examination of the basal functioning of the organisms. Auscultation ● Tone, rhythm, prominence, frequency of visceral sounds Palpation ● ● ● ●

Size Firmness Tenderness Mobility of visceral structures

Percussion ●

Density

Middle Palpation ● ●

Interior Palpation ● ● ● ●

Interior: Back There are projection points on the back that reflect chronic solicitation of certain visceral structures (Fig. 14.2). These will be discussed further in The theory of Endobiogeny Volumes 2 and 3 in chapters relating to gastrointestinal health and pathology.

Pelvic basin: Genito-urinary The genito-urinary structures are perhaps the most challenging to evaluate. Like the heart, they are partially protected by osseous structures, but unlike the heart, cannot be auscultated. Unlike the lungs, they are not localized to a single anatomic area, but are spread across one-third of the cavitated compartments of the organism.1 Certain organs, such as the uterus, can only be palpated by external manual examination during pregnancy or in cases of development of pathologic structures (i.e., leiomyoma). However, there are structures that are either externalized or accessible by digital examination. It will not be a routine part of the general examination, but should be considered when appropriate based on the symptoms or age of the patient (i.e., puberty, gonadopause).

Vascularity around the testicular sac Integrity of inguinal fascia

●

●

Testicles: Size, tenderness, degree of descent Vaginal wall Cervix Ovaries: Size, position, consistency Uterus: Size, position, muscular density, consistency Prostate: size, position, density, and consistency

Extremities The extremities refer to the arms and legs. The general evaluation of the integument, muscle, and bone has been ­discussed in other sections. In addition, there are, once again, referred points on the distal extremities related to thyrotropic, gall bladder function, and pelvic circulation which will be discussed in the relevant chapters of the book.

Middle ●

● ● ●

Musculature: ● Diameter of thigh relative to calf ● Diameter of proximal arm relative to distal arm ● Muscle texture and architecture relative to subcutaneous fat Ligamentous insertion: Tone and tenderness Subcutaneous fat distribution: Thigh, medial knee Distal pedal edema

Exterior

Back

Visualization (skin of external genitalia):

Middle

● ● ● ● ●

Pigmentation Lesions Hair: Color, distribution, texture Men: Foreskin: presence, hygiene Women: Clitoris and vulva, hygiene

and

●

● ●

Musculature: Tonus, texture, architecture, contractual asymmetry Subcutaneous fat distribution Ligamentous insertion: Tone and tenderness

Neurologic 1. In an adult of 1.8 m height, 0.6 m is cavitated: pelvis, abdomen, chest, and cranium. Of this space, approximately 0.2 m (33%) is the pelvis, abdomen and retro-abdominal structures: kidneys, ureters, bladder, gonads, uterus and/or prostate.

The nervous system: central, autonomic, peripheral, and visceral are all endomorphic structures. However, there are particular parts of the organism where the nervous system is superficial and easily accessible. As noted earlier, the eyes

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are a projection of brain tissue. A number of cranial nerves can be assessed around the head, ear, nose, and throat. Finally, reflexes in the distal extremities can be used to assess spinal neurologic integrity.

Interior Observation ● Orientation of patient to interaction, space, and time ● Posture ● Gait ● Rhomberg test Percussion ● Glabellar tap: Observe the rate of response of the upper and lower eyelids, and flutter posttap ● Deep tendon reflexes ● Chvostek Palpation or manual interaction Muscle tonus Hand-Chin: Palmo-mental reflex ● Legs: Oppenheim test ● Feet: ● Clonus ● Babinski test ● Sensory discrimination of skin: Pressure, temperature, sharpness Light ● Pupillary light examination: Observe hippus ● ●

Conclusions The history allows for the cataloging of symptoms—the subjective perception of events or feelings presented by the patient. The physical examination allows for the determination of signs—the objective analysis of structural and functional elements of the terrain. As with the history, the physical examination offers a wealth of information regarding the neuroendocrine management of terrain and the efficiency of the visceral organs and emunctories. Because there are multiple factors that influence structure, the Endobiogenist gathers multiple points of data from the examination and compares them with each other and against the historical findings for corroboration. The greater the number of data points, and the greater the number of methods of assessment, the greater the degree of confidence of the examiner that any particular finding favors or is associated with particular neuroendocrine elements. With this level of integration of data, the Endobiogenist may draw conclusions about the terrain of the patient, the axis of origin of the global or local imbalance, and the axes of compensation and implicated organs. At this point, a treatment plan may also be formulated.

However, a higher degree of assessment of objective, qualitative information regarding the structural, structurofunctional, and functional aspects of the terrain may be assessed with the biology of functions (BoF). The BoF, the subject of the following chapter, allows for another level of assessment that follows the same principles of analysis as the history and physical examination.

References 1. Verghese  A, Charlton  B, Kassirer  JP, Ramsey  M, Ioannidis  JP. Inadequacies of physical examination as a cause of medical errors and adverse events: a collection of vignettes. Am J Med. 2015;128(12):1322–1324. e1323. 2. Chen M, Zhan WW, Han BS, et al. Accuracy of physical examination, ultrasonography, and magnetic resonance imaging in predicting response to neo-adjuvant chemotherapy for breast cancer. Chin Med J. 2012;125(11):1862–1866. 3. Vainionpaa  MH, Raekallio  MR, Junnila  JJ, Hielm-Bjorkman  AK, Snellman  MP, Vainio  OM. A comparison of thermographic imaging, physical examination and modified questionnaire as an instrument to assess painful conditions in cats. J Feline Med Surg. 2013;15(2):124–131. 4. Valente SA, Levine GM, Silverstein MJ, et al. Accuracy of predicting axillary lymph node positivity by physical examination, mammography, ultrasonography, and magnetic resonance imaging. Ann Surg Oncol. 2012;19(6):1825–1830. 5. Haslam RH. Why perform a history and physical examination when we have magnetic resonance imaging? Paediatr Child Health. 2010;15(8):495–496. 6. Sapira JD. Why perform a routine history and physical examination? South Med J. 1989;82(3):364–365. 7. Reid VM, Dunn K, Young RJ, Amu J, Donovan T, Reissland N. The human fetus preferentially engages with face-like visual stimuli. Curr Biol. 2018;28(5):824. 8. Tovee  MJ, Tasker  K, Benson  PJ. Is symmetry a visual cue to attractiveness in the human female body? Evol Hum Behav. 2000;21(3):191–200. 9. Lewis  MB. Fertility affects asymmetry detection not symmetry preference in assessments of 3D facial attractiveness. Cognition. 2017;166:130–138. 10. Schacht R, Grote M. Partner choice decision making and the integration of multiple cues. Evol Hum Behav. 2015;36(6):456–466. 11. Wang Y, Zhang D, Zou F, et al. Gender differences in emotion experience perception under different facial muscle manipulations. Conscious Cogn. 2016;41:24–30. 12. Slominski A, Wortsman J. Neuroendocrinology of the skin. Endocr Rev. 2000;21(5):457–487. 13. Theoharides TC, Stewart JM, Taracanova A, Conti P, Zouboulis CC. Neuroendocrinology of the skin. Rev Endocr Metab Disord. 2016;17(3):287–294. 14. Catania A, Lonati C, Sordi A, Carlin A, Leonardi P, Gatti S. The melanocortin system in control of inflammation. ScientificWorldJournal. 2010;10:1840–1853. 15. Swami  V, Furnham  A, Joshi  K. The influence of skin tone, hair length, and hair colour on ratings of women's physical attractiveness, health and fertility. Scand J Psychol. 2008;49(5):429–437.

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16.

17.

Luong  MX, van der Meijden  CM, Xing  D, et  al. Genetic ablation of the CDP/Cux protein C terminus results in hair cycle defects and reduced male fertility. Mol Cell Biol. 2002;22(5):1424–1437. Jorizzo  JL, Atherton  DJ, Crounse  RG, Wells  RS. Ichthyosis, brittle hair, impaired intelligence, decreased fertility and short stature (IBIDS syndrome). Br J Dermatol. 1982;106(6):705–710.

18. Jackson  CE, Weiss  L, Watson  JH. "Brittle" hair with short stature, intellectual impairment and decreased fertility: an autosomal recessive syndrome in an amish kindred. Pediatrics. 1974;54(2):201–207.

Chapter 15

A new approach to biological modeling: Introduction to the biology of functions The complexity of physiologic phenomenon arises from fact that…biological system depends on the coordinated action of each of the constitutive elements. This is why the understanding of a biological system calls for an integrative approach, which ideally consists of the theoretical reconstruction of a given system from its elementary components. This raises a formidable experimental challenge that can only be met by the construction of new mathematical models allowing the numerical simulation of complex biological phenomena. Gilbert A. Chauvet, MD, PhD.1

Introduction In an aphorism, Hippocrates noted that “Life is short/And art long/Opportunity fleeting/Experimentations perilous/ And judgment difficult.”2 The life we perceive to be living is symbolic. All experiences are representational and evanescent. Recounting experiences, then, is a representation of a representation, two steps removed from an objective Truth. You hear the oboe in the opening bars of Mozart’s Requiem hovering above the stirring of cellos. The sound is gone. How can you express the sound of the oboe? You feel wistful and melancholic after listening to it, then the feeling is gone. How to describe it? A patient presents after a myocardial infarction to your office. The moment of ischemia, of neuroendocrine adaptation, of a psychological shift—how can one capture these events? It is only through some representational medium. When we think of symbols, we think of abstract visual representation: cross, peace sign, hand mirror of Venus, etc. In Asian languages, ideograms graphically represent ideas. In Indo-European languages, words have three levels of encoded symbolism. First, each letter represents a sound. Second, word represents a multisyllabic group of sounds. Third, the word-sound combination is arbitrarily associated with an idea. Ideas do not exist because of language. Language exists because of ideas. Symbols require a specific set of knowledge contextualized to space, time, and culture. It excludes more than it includes or communicates, The Theory of Endobiogeny. https://doi.org/10.1016/B978-0-12-816903-2.00015-X © 2019 Elsevier Inc. All rights reserved.

e.g., double entendres, contextual dependence of meaning, punctuation, not to mention tone, accompanying gestures, and facial expressions. It is also true of nonlanguage symbols, which requires induction into a set of shared beliefs and understandings in order to interpret their meaning. Despite the richness of their content, the transmission of ideas feels somewhat perilous as an enterprise of heuristic interpretation. Mathematics is the third type of symbolic representation of abstract concepts. What distinguishes it from the other two is that it is rational and discrete. There is no heuristic effort in understanding the concept of “nine” and presenting it as “9.” As a rational-symbolic language, it is ideal for expressing rational concepts that must be communicated to others by rational means (c.f. Chapter 1). Consider describing the area of two circles of varying radii. One could symbolically represent the circles, but one could not communicate their actual size—making it difficult to know what can fit inside of them. One could sing a song about circles or compose a jazz melody to convey the feeling of each circle, but it would remain highly heuristic. One could use words to describe one as larger than the other, and compare them to other objects, say, a medium-sized apple vs. a basketball, but it is not clear how large a medium-sized apple is, other than to say one knows it when one sees it. The genius of the formula of the A = πr2 where A is the area, π is pi, and r2 is the radius of the circle squared, is that it allows for the area of all possible circles to be described and compared to each other in a rational and clear way. For example, if the area of the first circle is 10 cm2 and that of the second 100 cm2, we all understand the absolute size of each and the relative difference between the first and the second circle. Thus, mathematics represents a clear, universal language offering quantitative and qualitative descriptions. Mathematics has long been applied to physical systems. It works well in part because physical systems are nonvolitional. Forces act on them and they in turn act on other objects. They are in a constant state of entropy with no mechanism of self-maintenance, self-preservation, or 215

216  The Theory of Endobiogeny

s­elf-propagation. Biological systems, while physical in foundation, possess emergent properties. They are selforganizing systems that express life through a process of consuming negentropy in order to resist entropy, a process we refer to as metabolism. They are scaled, multitiered hierarchical systems with levels of integration and interrelation within and across hierarchies. Finally, they have functional organization that is not seen in physical systems. The question arises as to whether one can or should describe biological systems using mathematics. To paraphrase the work of the late Gilbert A. Chauvet, mathematician, physicist, neurologist, and pioneer in mathematical integrative physiology:

a­ ctivities: subcellular, cellular, tissular, global, as well as structure vs function (Chapter 2). 3. Coupling of relative activity of one source (actor) on a sink (recipient) and multiples sources simultaneously on a sink (Chapters 5, 10, 11, and 12).

1. There are a huge number of data points in biology, now more than ever thanks to omics studies. 2. There is no general theory of interpretation for all these data points. 3. A method of integrating this information is required. 4. Most biologists do not know what “integrative” actually means. 5. Biologists and physicians state that there are too many variables in biology for it to be studied mathematically. 6. The study of biology must be done within the constraints of its own theory. 7. Therefore, a general theory of biology is necessary.

The need to use blood tests

In other words, the general theory of biology must attempt to describe biological events mathematically. We have made the argument that the theory of Endobiogeny is a general theory of biology and integrative physiology that creates a framework for explaining (verbally) the qualitative functioning of biological systems. The purpose of this chapter is to demonstrate how this can also be achieved mathematically. Chauvet notes, “Just as physics uses mathematics to provide a general view of the nonliving world, biology will have to rely on mathematical formalism to obtain an integrated vision of living organisms.”3 Dr. Duraffourd developed the biology of functions (BoFs) as an approach to characterizing the permanent dynamism of the organism according to the theory of Endobiogeny. Thus, the BoFs is not a mathematical theory of biology that uses philosophy or clinical empiricism for validation. It is the fruit of a theory of integrative physiology developed as a practical tool by and for clinicians to symbolically represent the most significant factors related to regulation of the terrain. The BoFs, as a series of mathematical formulas, meets Chauvet’s postulates for a biologic theory and addresses a number of concerns cited by researchers in the field: 1. Chosen factors are physiologically relevant upstream regulators of terrain. 2. It recognizes and distinguishes various levels of hierarchical biologic and physiologic organization and

In physics one breaks down complex objects to simpler forms to understand their functioning. In biology one must maintain the integrity of the whole if one is to understand the living system as it functions in and of itself. The question then arises, “How can one model complex physiologic behavior in living biological systems without killing them?” The answer is, “Through the medium of blood.”

From the earliest times of medical practice, physicians sought to look more deeply into the body without directly cutting it open. The goal was to confirm what was obtained by history and physical examination, and, to determine that which the first two could not determine. In the Hellenic tradition, the evaluation of bodily fluids has been the preferred method for over two millennia, primarily blood and urine. The analysis was qualitative in nature, based on the concept of the four humors. The shortcomings of this method include its subjectivity of analysis and lack of a precise assessment of specific neuroendocrine, cellular, and subcellular activities. Evaluation of blood continues to be an important diagnostic tool in modern medicine. The advantages of modern blood tests are many. They are objective, accurate, and reproducible. They are minimally invasive yet allow for the evaluation of complex physiology. They are easily repeated, offering longitudinal assessment of the evolution and devolution of physiologic processes and treatments. The shortcoming of modern lab studies is the binary nature of interpretation. Like the 0s and 1s of digital code, lab results are viewed as having two values and two interpretations: 0: lab test within normal range = no abnormality, ergo: no dysfunction 1: lab test outside the normal range = abnormality, ergo: dysfunction This algorithm is repeated for each individual lab value assuming, in the reductionist model, that each lab value can be viewed in isolation from other lab values. Routine lab testing creates a quandary for the clinician in two situations. The first is a symptomatic patient with normal lab values.4–9 The second is an asymptomatic patient with abnormal lab values.10–12 Both situations call into question the sufficiency of the reductionist model to explain the correlation between individual symptoms and individual biochemical data. This is typically the case for electrolytes, hepatic enzymes such as AST, ALT, and GGT,

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and other common tests. Such a binary system reads with an “error” message for both these situations. The clinician must either ignore abnormal values, ignore symptoms, do further testing without clear guidance of what or how to test, or empirically medicate the patient in hopes that the problem will go away. Other tests such as antibodies associated with autoimmune disease require more complex evaluation and ­decision-making, but pose problems themselves. They have a high degree of specificity but a low degree of sensitivity. Specificity is the percent of patients who have a negative test and do not have a disease. Sensitivity is the number of patients who have a positive test and have the disease.13 When evaluating a patient for lupus, e.g., anti-Smith antibodies (anti-Sm) have a sensitivity of 25%–30% but a high specificity.14 In other words, the presence of anti-Sm antibodies does not rule out disease, but their absence makes it less likely that lupus is present. If a patient is tested for anti-Sm in order to make a diagnosis of lupus in the presence of two clinical symptoms, and the patient is positive for anti-Sm, will they be denied treatment because a total of four criteria have not been met? Over 70% of patients with positive anti-Smith antibodies will not have lupus, but if they do not have lupus, what does it mean that the test was positive? A binary test cannot answer this question. If a patient meets four or more of the criteria associated with lupus, including anti-Smith antibodies, how does that advance an understanding of why they have lupus, or how they will be treated? Regardless of the test results, they will be treated symptomatically based on the organ(s) involved, and the intensity of inflammatory or autoimmune manifestations.15 In that case, what benefit did evaluation of biomarkers bring to the selection of treatment for the patient? Because the human body operates as a system, a method of evaluation is needed that can reflect this complexity while still using serum values as the foundation of its assessment. Such a method should reflect all the properties of a system. The method should be dynamic and individualized, characterizing the function of a single unit of activity in and of itself, relative to other units and relative to the global functioning of the organism in a quantitative and qualitative fashion. If the object of study and method of interpretation are based in a systems approach, serum lab values can be viewed in a nonbinary format, reclaiming their key role in analytical and objective medical practice.

The necessity of using serum biomarkers and their shortcomings The biology of functions] must allow for a synthetic study of the ensemble of functions—specific to the level of activity of each person—separately and in their relative ­interaction

(with each other). Metabolic fluctuations result from the complex fitting of the functionality (or the organism). The blood elements fluctuate unceasingly according to adapted reactions of our bodies to each endogenous and exogenous solicitation. Christian Duraffourd and Jean-Claude Lapraz.16

A biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”17 Biomarkers are used to screen, diagnose, and prognosticate.18 All blood analytes are biomarkers in that they are markers of some biologic process. However, the ability to “screen, diagnose, or prognosticate” arises from a proper analysis of biomarkers that is accurate, valid, and clinically relevant. Numerous biomarkers have been proposed over the years only to be discredited or discarded later. The fundamental shortcoming of these biomarkers is that they continue to be based on reductionist biology rather than systems biology. With respect to the selection and use of biomarkers, there are four common errors that have limited their clinical utility: (1) selection based on an animal model that does not realistically replicate human illness, (2) selection based on taking a clinical problem a priori and using statistical pooling to find an a posteriori correlative relationship, (3) use of biomarkers that are specific but not sensitive, and (4) mistaking downstream effects of pathology to be upstream causes. We will examine each error separately.

Selection based on an animal model of disease Animal models for human illness have long been used to determine single-causative agents of disease. Creating disease in a previously healthy animal is not always a realistic assessment of how the disease develops over time in humans because it fails to replicate the multiple factors within the terrain that are involved. Hepatic encephalopathy and the role of ammonia is a good example. Ammonia was long considered to be the direct cause of hepatic encephalopathy because (a) hepatic injury reduced the metabolic conversion of ammonia to urea, (b) humans with hepatic encephalopathy often had elevated serum ammonia, and (c) ammonia was shown to cause encephalopathy when infused in large amounts in otherwise healthy primates.19, 20 Clinical studies have demonstrated that neither the presence nor the severity of encephalopathy could be predicted solely by the serum ammonia level, nor was the improvement in encephalopathy proportional to the reduction in ammonia levels. Currently, most experts agree that there are multiple variables that play a role in the development of hepatic encephalopathy, of which ammonia is but one.21, 22

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Selection based on statistical pooling Another common method of selecting a biomarker is through epidemiologic studies. In these studies, a clinical condition is selected a priori and numerous biomarkers and epidemiologic data are collected. Patterns of abnormalities in biomarkers are then correlated with the specific condition. Gamma-glutamyl transferase (GGT) is a good example of this with dozens of epidemiologic studies showing strong correlation with various clinical conditions. The GGT is an enzyme that transfers glutamyl residues. An elevation in serum GGT above the norm is seen in hepatobiliary disease, biliary obstruction, and intrahepatic cholestatic disorders. The GGT also plays a key role in glutathione recycling most notably in the liver, but also in bile ducts, small bowel, kidney, brain, pancreas, spleen, and breast. Retrospective analysis of epidemiological studies have associated normal GGT in the upper quartile of normal (40–60; normal = 0–60 IU/L), with the bioaccumulation of heavy metals,23 persistent organic pollutants,24–27 dementia,28–30 hepatic insulin resistance,31 type 2 diabetes mellitus,26, 27, 32–40 hypertension,33, 35, 38, 40–51 and dyslipidemia40 independent of body mass index, lifestyle risk factors, or gender. While GGT has been noted to be elevated in a wide variety of disorders, all these disorders could be best described as having a component of oxidative stress, which would explain the elevation of GGT (even within the upper quartile of the normal range). Oxidation of glucose to make ATP is fundamental to human physiology. A disturbance in oxidation will be implicated in so many disorders that we wonder how it could be predictive of a specific disease state prospectively. If one finds a GGT in the upper range of normal, can one determine from this alone which patient has or will develop diabetes vs. hypertension vs. hyperlipidemia or a combination of these disorders? In a patient with hepatobiliary disease, with a GGT many fold above the norm, GGT can no longer be used to predict the presence of the disorders noted above. How can the risk of these various disorders be evaluated in such patients? There are numerous steps in the oxidation of glucose and in cellular respiration. How does a GGT in the upper quartile of normal guide the clinician in choosing the point of intervention, say, between insulin sensitization vs. oxidants vs. antioxidants vs. the Krebs cycle vs. mitochondrial support with l-carnitine, CoQ10, d-ribose, etc.? All it says is that somewhere in the body, there is or may be an insufficiency of glutathione, without clarifying if it is due to a deficiency in glutathione production, an insufficiency in glutathione recycling, or an excess of glutathione consumption.

Application of a biomarker with high specificity when it has a low sensitivity Prostate-specific antigen (PSA) is the most widely used screening test for prostate cancer in the United States and

Europe. In the United States alone, over 3 billion dollars is spent annually on the test. Discovered in 1970, it was approved by the US food and drug administration (FDA) in 1994 to detect cancer even though its success rate is only 3.8%.52 The PSA is a good screening tool in evaluating the efficacy of treatment of known prostate cancer, and in the surveillance of men with a history of prostate cancer posttreatment.53 In other words, the PSA test is specific for known, active prostate cancer, but not sensitive for cancer, much less predictive of cancer risk. It distinguishes neither benign nor malignant growth. It simply implicates dysregulated growth.54 Dysregulated prostate growth is seen not only in prostate cancer but also in noncancer-related events, such as benign prostatic hypertrophy, injury, use of certain medications, and infection. The PSA levels are low in some men with malignant cancer, and elevated in other men without cancer. Thus, PSA alone is not a good biomarker in screening for prostate cancer. This is not a purely academic discussion because with an abnormal PSA the number-needed-to-treat is 48:1, meaning that in order to save 1 man’s life, 47 men will undergo unnecessary biopsies with loss of sexual and urinary function, based on a test that is being used as an indicator of a specific pathology when it is simply a nonspecific indicator of a disturbed pathophysiologic state within the prostate.55

Studies that mistake the result of a pathologic event as the cause of that event Dysregulation of the immune system is implicated in chronic, low-grade microbial infection, and in altered inflammation/antiinflammation pathways. There was a large body of evidence in the 1980s and 1990s that strongly associated titers of Chlamydia pneumoniae with myocardial infarction.56–65 It was observed that patients who had myocardial infarction had a greater incidence of Chlamydial infection compared to those who did not. Chlamydia was found in biopsies of atherosclerotic tissue, and Chlamydia was found to be atherogenic in vitro. It was hypothesized that treating Chlamydia with the antibiotic Clarithromycin would lower the risk of myocardial infarction. Smaller studies supported this hypothesis66 but larger studies and metaanalysis found no benefit.67, 68 Both Chlamydial infections and arterial disease occur in an environment of immune dysregulation. Thus, they both are downstream effects of altered immunity (Fig.  15.1). The error here was to consider the downstream effects to be sequential, where Chlamydia caused arterial disease, or, contributed in a significant way that it warranted treating with antibiotics. Later studies found that Chlamydia titers and arterial disease also correlated with an elevation of creactive protein, a nonspecific indicator of acute inflammation.69 Thus, it is more accurate to conclude that while all

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FIG.  15.1  Relationship of chlamydia to atherosclerosis according to a global systems approach. Patients who suffer from chronic chlamydial infections and atherosclerosis share a common imbalance in cortico-­ thyrotropic activity. There is a disorganized immune response and chronic inflammation. The immune dysfunction allows for chlamydia to live in the body. The inflammation injures the arterial wall. Chlamydia has a tropism for the nutrients in the fatty plaque. Its presence in the plaque is opportunistic not causative. (© 2015 Systems Biology Research Group.)

these elements are downstream events of altered immunity, they are neither sequentially nor causally related (Fig 15.1). That is to say, the same dysregulation in immune activity that favors inflammation creates a terrain that also favors the installation of chronic, low-grade infections. The greater the inflammatory milieu, the greater the risk of atherosclerotic disease will be. The same type of error was made with respect to vitamin D and heart disease. Low vitamin D levels have been associated with an increased incidence of cardiovascular disease70–72 due to its association with a pro-inflammatory state. However, normalizing vitamin D levels does not change the clinical outcome of patients with CVD even when it improves the inflammatory terrain.73 Because diseases are multifactorial, altering one factor does not necessarily reverse the course of disease. In general, most biomarkers are single variables used to evaluate complex, multisystem disorders. From the Endobiogenic perspective, there are very few cases of “single variable disorders” because the body is a system containing many variables that affect each other’s function. Relying on single biomarkers to screen or diagnose or prognosticate ultimately has limited benefit for the clinician and the patient. Most often, it results in indiscriminate treatment, as in the case of PSA, where men receive potentially harmful biopsies and are prescribed the use of 5α-reductase inhibitors “just to be safe.” Or, it results in excessive treatment because a single biomarker does not allow for the pathophysiologic individuality of the patient (i.e., the terrain) to be determined. For example, in cardiovascular disease, there is a trend to use vitamin D (for low vitamin D), aspirin and fish oil (for elevated CRP), and a statin (for hyperlipidemia) because it is not possible from the current methods of evaluation to determine which aspect(s) of dysregulation is most responsible for the current state of disease.

An exception to the trend of using single biomarkers has been the use of multiple markers simultaneously in critical illness, such as septic shock or multisystem organ failure. Some examples include the Pediatric Risk of Mortality and the Acute Physiology, Age, Chronic Health Evaluation (APACHE).74, 75 These scores use dozens of serum biomarkers and vital signs, such as serum glucose, respiratory rate, heart rate, etc. as well as clinical classifiers, such as surgical status, use of mechanical ventilation on admission, etc. There are two key shortcomings of these multifactor tests with respect to clinical applicability. First, and most fundamentally, these evaluations represent retrospective attempts to find variables that predict mortality in order to stratify patients in research studies. Even within this narrow focus of interest, there is not an attempt to integrate these various factors into a coherent understanding of illness. These scores do not truly integrate physiologic abnormalities in a way that reflects the patient’s terrain. Even if the scores are valid, they do not provide clinical guidance on determining which system(s) is most responsible for the current disorder, to what degree, or in what order interventions should be administered, i.e., cortisol, vasopressors, ventilation, dialysis, etc. In summary, biomarkers are indicators of normal or pathologic activity. Biomarkers are commonly used in medicine and can be useful, but their ability to describe why an abnormality occurred or predict future imbalances is limited by the binary nature of the test. The ideal use of biomarkers would be based on a systems biology approach. In such a system, multiple factors are evaluated simultaneously, relative to each other, describing human physiology in a dynamic fashion. Such an approach can offer specific areas and methods of intervention tailored to the terrain of each individual patient. Endobiogeny offers such a system: the BoFs.

The biology of functions (BoF): A biological modeling system The purpose of the Biology of Functions is to quantify the functional abilities of the organism, before and after the effects of adaptation [to stressors]. Because [the terrain] is in permanent movement, functionality can only be measured by a dynamic, integrated and evolutionary methodology. C. Duraffourd, MD and JC Lapraz, MD.76

The BoFs is a biological modeling system developed by Dr. Duraffourd, based on the theory of Endobiogeny. As with other biological models, it simulates biological activity based on variables assumed to be most representative of the system, and is not a measurement of actual function. It differs from other biological models in three key ways. First, it simulates biological activity using biomarkers related to the direct and indirect effects of neuroendocrine

220  The Theory of Endobiogeny

a­ ctivity. Second, it evaluates quantitative as well as qualitative ­function. Finally, it evaluates both the potential and functional achievements of the organism. Current research in systems biology is focused on genomic and cellular activity. Many of these mathematical methods have proven to be robust, accurate, and predicative in examining narrow areas of physiologic activity.77–79 However, due to conceptual limitations, they can neither describe the terrain that brought about disease nor suggest the optimal treatment within the context of the global functioning of the individual organism and serve largely as research tools. As a model of the global functioning of the organism, the BoFs evaluates factors both in and of themselves, in relationship to other units of activity and in relationship to the system as a whole. There are numerous indexes evaluating neuroendocrine activity in the BoF. They are derived from 17 serum biomarkers that are linked to the various aspects of this activity, without directly measuring serum hormone levels except for thyroid-stimulating hormone (TSH) (Table 15.1). The biomarker norms are the normative data of the adult, premenopausal female, which is considered to be the null state of human physiology in Endobiogeny. The values of postmenopausal women, of men, and of children

are compared against this normative data. Some exceptions include particular indexes that have grossly different values in various phases of childhood (unpublished data), and well-characterized sexual dimorphisms noted between men and women, and their corresponding variations in serum biomarker values.80 A current shortcoming of the algorithm is the exclusive reliance on normative data from a Western European population. This will need to be addressed to broaden the applicability of the BoFs vis-à-vis men and women,80, 81 non-European populations82, 83 and children.84 Four biomarkers have a high degree of variability in their normative values from lab to lab and during particular phases of life: osteocalcin, total serum alkaline phosphatase, lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). The normative values determined by each lab are standardized to an internal consistency. The indexes evaluate relative neuroendocrine functionality and are derived from 16 direct ratios of the 17 biomarkers. The remaining indexes are indirect ratios: indexes of indexes. Nearly 90% of the indexes describe relative and qualitative function. In other words, they describe the physiologic capability of the organism in a contextual manner. The relativity of the indexes ensures global internal consistency and reproducibility across patients and diseases

TABLE 15.1  Biomarkers used in the biology of functions Origin

Biomarker

Value

Conversion

Bone marrow cellular products

Red blood cell

per μL

÷106

White blood cell, total

per μL

÷103

Neutrophil

%

None

Hemoglobin

g/dL

None

Platelets

per μL

÷103

Bone marrow-serum interaction

Erythrocyte sedimentation rate

mm/h

None

Bone stroma enzymes

Osteocalcin

ng/mL

Proprietary

Alkaline phosphatase bone isoenzyme

%

Proprietary

Lactate dehydrogenase

IU/L

Proprietary

Lymphocytes Eosinophils Monocytes Basophils

General enzymes

Creatine phosphokinase Endocrine

Thyroid stimulating hormone

μIU/mL

None

Electrolytes

Potassium

mmol/L

None

Calcium, total serum

mmol/L

÷2

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with reliable norms. The normal range of each index is determined by two methods. First, the general range is determined from high and low values of each biomarker of which an index is composed. The specific normative range is based on retrospective analysis of unpublished data from clinical practice. The use of such a limited number of biomarkers to derive a large amount of information about human physiology can only be achieved under two conditions. The first is if the body functions as a system and the effects of one event affect other events. The second is if the level of evaluation is sufficiently upstream that a small number of factors are linked to a wide variety of downstream events, having a profound effect on multiple lines of biologic activity. Hormones are secreted in extremely low concentrations (10−9–10−12 g/dL) yet have a profound impact on global physiology at the nuclear, cytoplasmic, cellular, tissue, organ, and system levels. Each subsystem of activity that the endocrine system manages is amplified at the level below it because each system manages or influences increasingly complex subsystems of activity. Thus, small changes at the endocrine level can have a profound and wide-ranging impact on the ensemble of metabolic processes. This is why we believe that such a small number of biomarkers can be used to generate such a large number of indexes.

The logic behind biology of functions indexes Three basic observations are the foundation of this elegant and simple biologic model: (1) the endocrine system is the manager of the terrain, of the biologic system, (2) certain biomarkers are produced as a result of this endocrine management, and (3) the true functionality of any system is based on the relative activity of one factor to another. Because these biomarkers are an indicator of endocrine management, indexing biomarker values as ratios provides an assessment of relative functionality of the endocrine management of the terrain.

Endocrine management We have established that the endocrine system is the true manager of the terrain, and that the effects of endocrine activity cannot be accurately evaluated by direct serum measurement.

Biomarkers and the endocrine system It has been known for nearly 100 years that changes in common biomarkers were associated with specific endocrinopathies.85–88 Through elegant experiments, it has been clarified that the changes in these biomarkers are the result of endocrine management of metabolism. For example, it was observed in the 1950s that androgens cause a proliferation of red blood cells (RBCs).89–95 Thus, RBC levels in the serum are a marker of a certain aspect of androgen function.

It was also observed that estrogens cause a proliferation of white blood cells (WBCs) and the same can be said about WBCs and estrogen activity (cf. discussion below).96, 97

Systems analysis and relative relationships As noted above, newer evidence suggests that the body is a true system, composed of various subsystems that act independently of each other, but in coordination with each other. Because the functioning of each unit is integrated and interrelated to the functioning of the others units and to the whole, it is the relative activity of one unit to another that determines the true state of functionality. The appreciation of relative changes in biomarkers has been present for nearly 100 years and is gaining increasing appreciation once again.86–88, 98–100 The value of relative changes of biomarkers in and of themselves and with respect to other markers is paramount in a systems approach. For example, in and of themselves, normal RBC and WBC counts do not offer actionable information about the state of androgens or estrogens. However, if you relate one to the other, you have a general evaluation of the global activity of androgens relative to estrogens regardless of the absolute value of RBCor WBCs, or the quantitative serum level of androgens or estrogens. The relative imbalance of androgens and estrogens can be clinically significant. Numerous studies have shown that even with normal serum levels of androgens and estrogens, one can develop fibroids, polycystic ovarian disease, infertility, or hair loss.98–103 The ratio of RBC to WBCs, called the “Genital ratio” (cf. below) is a necessary but not sufficient for the evaluation of gonadotropic activity. However, it lays the foundation for increasingly complex evaluations with respect these and other disorders. Normally, the diagnosis of and decision to treat “endocrine” disorders is based solely on quantitative serum concentrations of hormones. If levels are normal, there will be no justifiable basis for treatment, and the patient is condemned to suffer. If an empirical treatment is started out of compassion, there rests no objective reason for the choice of treatment, or a manner in which to understand why the treatment failed if it does not work. In such cases, the patient is considered to have an “idiopathic” disorder, often deemed untreatable. We believe that using ratios of biomarkers may be a more accurate and valid method of determining physiologic functionality, not only in cases of idiopathic disorders, but more broadly when evaluating various disorders, even common ones with atypical courses or unexpected response to treatment.

Precedence of using ratios in clinical medicine The practice of relating biomarker to each other is not new in medicine and there are many examples used on a daily basis (Table 15.2).

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TABLE 15.2  Ratios in medicine System

Ratio

Composition

Indication

Shortcoming

Renal

BUN/creatinine

Blood urea nitrogen/ creatinine

Evaluates the rate of renal perfusion relative to renal clearance

Does not indicate why perfusion or clearance is impaired, if it is due to structural or functional impairments, or both

Microalbumin/ creatinine

Microalbumin/creatinine

Evaluates resorptive integrity of kidney relative to its clearance ability

Does not indicate functional reasons for disruption in renal tubule integrity

A/G ratio

Albumin/globulin

Evaluates the risk of autoimmunity vs. cancer vs. liver failure

Does not evaluate endocrine, GI factors related to protein uptake, distribution or utilization

CD4+/CD8+

Subsets of lymphocytes based on specific cell determinates (CD)

Used to assess relative strength of immune system in HIV seropositive patients; CD4 counts vary day to day, so they are indexed relative to the CD8 count

Does not evaluate the factors related to generation, mobilization and regulation of immune cells

Hematocrit

Red blood cells/whole blood volume

Evaluates the density of blood relative to intravascular volume by indexing the amount of red blood cells produces relative to the total blood volume

Does not evaluate the factors influencing red blood cell production or demargination from the spleen

Immune

Hemato-logic

While these tests are dynamic—they are derived from circulating blood analytes—they do not indicate the relationship of individual units to each other or to the whole system, which is why we do not consider them to be candidates for use in a systems approach to biology. The BoFs is composed of a series of direct and indirect indexes. Direct indexes are composed of individual biomarkers directly related to each by various mathematical relationships. Indirect indexes are composed of direct indexes, indirect indexes, and/or individual biomarkers in various permutations that can contain up to six levels of indexes within indexes. An example of a direct index is the genital ratio, which looks at the impact of androgens relative to estrogens at the tissue level. It is a ratio of 2 of the 17 biomarkers: RBCs and WBCs. Genital ratio = Red blood cells / White blood cells = Androgen tissular activity relative to Estrogen tissular activity An example of an indirect index is the thrombotic index which expresses the risk of sudden thromboembolic phenomenon:

  Thrombogenic index      Thrombotic index =   × Evoked histamine index  / 10     ×Genital ratio     Indirect indexes are complex metaindexes composed of several other indexes. For example, we can open up the thrombogenic index and replace the basic equation with key factors related to thromboembolism:    Bone remodeling     ×Apoptosis × Necrosis  / 10  Thrombotic index =      ×Evoked histamine          × Genital ratio Acute ischemic events that result in sudden cardiac death occur in arteries that often have mild coronary artery luminal occlusion and minimal plaque calcification. Neither calcium score by CT scan nor angiography will be able to identify patients most at risk. Typically these events occur in patients under the age of 60, with minimal classical risk factors, thus general screening factors will not identify them either.104 The ability to aggregate the known factors related to thrombus formation and plaque rupture may help

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i­dentify patients most at risk for sudden cardiac death or acute ischemia based on functional factors rather than structural factors. The mathematical relationships in the index express that the risk of thromboembolism is the result of a triad of factors which are necessary but not sufficient on their own: (1) risk of thrombus formation, which can occur due to necrosis105–107 or apoptosis,104 (2) histamine activity,108–110 and (3) elevated androgens111–119 represented by the Genital ratio (androgens/estrogens) in the numerator, which is consistent with known pathophysiologic mechanisms of thromboembolic phenomenon. In summary, evaluating biologic activity relative to each other has precedence in medicine. It helps contextualize the relevance of one finding to another. The BoFs is composed of direct indexes where individual biomarkers are related to each other, and indirect indexes, where direct indexes and various biomarkers are indexed against each other to express increasingly complex biological activity that is multifactorial in nature. The majority of indexes in the BOFs are indirect indexes that evaluate the function of units of activity relative to other units of activity.

i­nformation, a delivery system of nutrients, and a remover of metabolic waste, but it is the cellular elements: WBCs, RBCs, and platelets that serve to delivery oxygen, defend, heal, and protect the body. The endocrine system as the manager of metabolism determines the rate of production of cellular elements from the bone marrow. Thus, blood is the foundation of life, and the endocrine system, as the manager of blood, is the manager of this foundation. The evaluation of blood cells reveals how the endocrine system manages life. In the BOFs, over 60% of biomarkers used are derived just from the cellular elements of blood, made in the bone marrow (Table  15.1). The complete blood count (CBC), then, is the basis of the BOFs. Androgens and estrogens stimulate the proliferation of RBC and WBCs, respectively. Thus, sex hormones are the foundation of the CBC—hence of life—and the initial point of study in the BOFs. (The bone stroma, discussed below, plays three key roles: protection and nourishment the marrow, regulation and assistance in global energy management, and communication of the state of the peripheral terrain to the central nervous system.)120–122 The roles of androgens, and then later estrogens, as the basis of life are evident from the time of conception. For Experimental and clinical basis for the first 17 days, it is the mother’s hormones that the emthe biomarkers used in the biology of bryo shares. At day 18 of life, the yolk sac becomes the first functions endogenous source of RBCs.123, 124 Rich in androgen recepwhich itself Endobiogeny and the BOFs are based on four scientific con- tors, the yolk sack stimulates erythropoietin, 124 plays a role in yolk sac maturation of RBCs, establishing cepts that are known and generally accepted: (1) human physthe key role of androgens in the foundation of structure.125 iology is complex, multifactorial, and exhibits the properties of RBCs,123 it also of a system, (2) the endocrine system manages metabolism, While the liver is an intermediate source 126 which is the basis of the continuity of life, (3) the metabolic under the management of androgens. By 34 weeks of gesactivity managed by the endocrine system results in the out- tation and throughout the remainder of life, the bone marbecomes the put of biomarkers that reflect the functional achievement of row, stimulated by androgens and estrogens, 127 source of the majority of blood cells. specific aspects of metabolism, and (4) when biomarkers are In summary, the activity of androgens and estrogens is related to each other in ratios, it contextualizes one type of reflected in the production of output of RBC and WBCs function relative to another to which it is linked anatomically, by the bone marrow. The evaluation of this activity, called sequentially, chronologically, biochemically, etc. the Genital Ratio, is used in the majority of indexes of the As shown below, the relationship between various BOFs. To accept the hypothesis that RBCs are a biomarker hormones and particular biomarkers is a long and well-­ of androgen activity and that total WBC count is a biomarker established fact based on modern physiology and the scienof estrogen activity at the level of the tissues, is to accept the tific method. The indexes composed from these biomarkers foundation of the majority of indexes of the BOFs. have been derived through inductive reasoning, and confirmed by over 30 years of clinical practice. The indexes have not been individually validated in peer-reviewed literature. Red blood cells (RBC) However, it stands to reason that if the correlation of each biomarker to endocrine activity is sufficiently demonstrated, Introduction then it is possible that such a biological modeling system Based on studies over the last 50 years, we concluded that RBCs reflect the tissular level activity of androgens. Here, may be a more valid assessment of biological activity. the bone as the site of production of RBCs represents the general assumed level of activity of androgens on other Bone marrow: Complete blood count tissues. This assumption is further refined with complex Life is permanent dynamism and the circulation of blood indexes to account for other factors. Studies have demensures this dynamism. Blood plasma is a conduit of onstrated that the administration of androgens stimulate

224  The Theory of Endobiogeny

erythropoiesis.89, 93–95, 128–130 Using RBCs as a marker of the functionality of androgens may prove to be more clinically relevant than quantitative measurements for four reasons: contradictory studies regarding serum levels of androgens and clinical effects, the complimentary nature of estrogens, the role of genomic vs. nongenomic effects, and genetic variations in intracellular (IC) conversion of androgens (cf. Chapter 7).

Limits of quantitative measurements of androgens Multiple studies have positively associated elevated levels of serum androgens, RBCs, or both in hypertension,131–134 thrombus formation,111–119 impaired insulin sensitivity,135, 136 and insulin resistance.137 However, low serum levels of androgens have also been positively associated with the same disorders.138–141 For example, while androgens are positively associated with dyslipidemia, they have also been associated with a reduction in triglycerides and LDL.112 Thus, evaluating serum androgen levels may be misleading.

Protective role of estrogens For years, it was believed without strong evidence that delayed cardiovascular mortality in women was due to a protective effect of estrogens. Prospective studies of estrogen supplementation demonstrated that not only supplemental estrogens offered no benefit, but they also elevated the risk of cardiovascular events.142–144 The lack of definitive protective effects of estrogens, and harmful effects of elevated and low serum levels of androgens in some men and not others suggests to us that it is the relative ratio of androgens to estrogens that is clinically relevant, not the absolute quantitative value of either in isolation.

Are androgens harmful in and of themselves? Studies suggest that androgens alone are not predictive of life span or risk of death from cardiovascular disease in men145–147 or women.148–151 Rather, androgens appear to be but one of many factors in a complex interplay of endocrine drivers of metabolism that influence the development, progression, and severity of a wide range of disorders from vascular disease131, 152 to Alzheimer’s disease.153 This may be one reason that assessments relying on serum androgens measurements alone have been inconsistent or contradictory.

Determining androgen function: Genomic and nongenomic effects Androgens, like most other steroidal hormones, have genomic and nongenomic effects.154 The ability to evaluate the relative impact of nongenomic vs. genomic affects in a particular individual may help solve the conundrum of whether high or low androgen activity is protective or harmful.

The genomic effects of androgens are what have been associated with serum levels of androgens. In contrast to the nongenomic effects, these effects take hours to occur, and are linked to many of the classic effects associated with androgens deemed to be harmful when dysregulated. These effects include smooth muscle proliferation, migration and vasorelaxation, increased monocyte migration and foam cell production, and increased apoptosis.154 Nongenomic effects occur within seconds. Mechanisms of action are believed to include a novel membrane-bound receptor, second messenger activation, and sex-hormone binding globulin receptors. Many of the nongenomic effects of androgens are physiologically beneficial and explain the protective effects of androgens observed in studies. They include relaxation of smooth muscle, increased neuromuscular signal transmission by calcium regulation, improved neuroplasticity, cellular proliferation and migration, and modulation of the transcriptional effects of classical androgen receptors.155, 156 What is clinically relevant is that these nongenomic effects cannot be blocked by drugs that block androgen receptor activity. This may explain two observations: (1) the variability of responsiveness to androgen blockers, (2) factors of risk and protection from disease cannot be reliably assessed by quantitative measurement of serum androgens, sex hormone-binding globulin (SHBG), or free androgen levels—because their effects do not rely solely on receptor activity.

Determining androgen function: Metabolic pathways There are a number of other factors adding to the difficulty of equating quantitative levels of testosterone (free or total) with androgen functionality. Recent studies have demonstrated in vitro and in vivo sex-based variability in androgen receptor sensitivity and concentration in various tissues.157 Approximately 5% of testosterone is converted within the cell to either dihydrotestosterone (DHT) or estrogens. In summary, the individual effects of testosterone on the body can vary based on: (1) genomic effects, (2) nongenomic effects, (3) receptor concentration, and (4) IC conversion tendency between DHT and estradiol. The net effect can be an amplification of genomic or nongenomic effects (DHT), or a counterbalancing effect (estrogens). Therefore, we believe that RBCs may be a useful biomarker reflecting the global degree of tissue functionality of androgens, when evaluated relative to other factors (discussed below).

White blood cells (WBC) Introduction The WBCs, also known as leukocytes, are blood elements that mature in the bone marrow then enter the circulation. Leukocytes consist of five types of cells that arise from a

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common hematopoietic precursor. White cells differentiate into neutrophils, monocytes, eosinophils, basophils, and lymphocytes. Estrogen stimulates a proliferation of leukocytes in the bone marrow. 54 Leukocytosis is associated with high estrogen states such as pregnancy158 and autoimmunity,159 as well as during the acute phase of infections. Thus, we believe that total WBC count can be considered to reflect the basic tissue effect of estrogens throughout the body.

Limits of quantitative measurements of estrogens The challenges of evaluating the role of estrogens in human physiology are far greater than for androgens, which is why specific aspects of estrogen activity requires more than a single biomarker (discussed below). Estrogen activity is complex, varied, and fundamental to human life. It involves endocrine and metabolic functions, both genomic and nongenomic in nature. Of all sex steroids, metabolically estrogens require the greatest number of metabolic conversions, being derived as such: Cholesterol à Progesterone à Androgens à Estrogens. Estrogens can be produced in the ovaries, in the adrenals, and by peripheral conversions in various tissues.160, 161 The pattern of estrogen production (central vs peripheral, adrenal vs gonadic vs hepatic) varies based on hereditary factors, age, and parturition status, and is affected by endocrine disrupters.160–163 There are multiple active forms of estrogens (estrone, estradiol, and estriol) as well as varying degrees of activity of estrogen metabolites. There are two types of estrogen receptors (alpha, beta), which have opposing activity with respect to cellular proliferation and various metabolic function. There are genetic polymorphisms in p450 metabolism of estrogens and polymorphisms with respect to receptor sensitivity, concentration, and rate of aromatase activity as well as nongenomic effects, which in sum all impact the effects of estrogens.164–170 In their review of estrogen metabolism, Zhu and Connery conclude: Studies that identify genetic and environmental factors influencing estrogen metabolism at or near estrogen receptors in target cells may be of considerable importance since these factors could profoundly modify the biological effects of estrogens in complex manners depending on the pathways of metabolism that are affected and the biological activities of the metabolites that are formed. Such effects need not be associated with an altered profile of estrogen metabolites in the blood or urine. Ref. 167

Estrogens: Beneficial or harmful? As with androgens, clinical trials are conflicting with respect to the beneficial or harmful role of estrogens in the body. The protective role of estrogens in cardiovascular

disease has come under question, as we have discussed above (cf. androgens).142–144, 160 With respect to cancer, estrogens can promote or lower the risk for cancer in and of themselves and in conjunction with other hormones.171–174 The contradictory nature of estrogen’s effects on telomere length, and the role of telomere length in cancer serve as another good example of the limitations of both quantitative hormone measurement and single-cause theories of disease. Estrogens increase telomere length. Women have the longest telomere length when follicle stimulating hormone and estrogen peak during the menstrual cycle.175 Telomere length is positively correlated with the rate of apoptosis and inversely associated with the risk of cancer. However, estrogens also cause leukocytosis, which is associated with shorter telomere length, less apoptosis, and greater risk of cancer.175, 176 Telomere length alone, like quantitative levels of estrogens, does not appear to be sufficient indicators of the global effects of estrogens on the terrain.

The case for multiple biomarkers of estrogen In conclusion, estrogens have various sources of origin, various rates of metabolism, changing concentrations and receptor densities throughout life, and can be affected by and affect other hormones in the body, as well as being disrupted by endocrine disrupters. Mounting evidence suggests that serum and urinary levels of estrogen and their metabolites may not be sensitive or specific enough measures of the effects of estrogens. We hypothesize, based on experimental evidence and clinical studies, that specific functional effects of estrogens can be inferred through the evaluation of particular serum biomarkers in and of themselves, as well as in conjunction with other biomarkers in increasingly complex ratios. In the BOFs, this assessment of estrogen function is accomplished by evaluating six different biomarkers: (1) total WBC count, (2) percent neutrophil count, (3) percent monocyte count, (4) percent lymphocyte count, (5) thyrotropin-­stimulating hormone (TSH), and (6) serum osteocalcin. Of these, WBCs are used as a general marker of global estrogen effects on tissues, and are the most foundational. Through the use of the genital ratio or its variation, the corrected genital ratio (cf. indirect indexes), WBCs can be used to evaluate the structural, functional, and adaptive role of estrogens in the body.

Neutrophils Neutrophils are a type of leukocyte that arise from granulocytes in the bone marrow. While the total leukocyte count (WBC) reflects global tissue effects of estrogens, we hypothesize that neutrophils can be used to assess particular aspects of estrogen activity, namely immune regulation and anabolism of tissue.

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The role of neutrophils is to participate in the immunologic response of the organism to aggressors. This can occur through inflammation177 or phagocytosis of microbes and cellular debris.178 Neutrophilia, absolute or relative, is associated with the anabolism of tissue, such as during pregnancy,177 wound healing179 autoimmune disease,180–182 and cancer.183–187 Estrogens are associated with the same events: preeclampsia,177 autoimmune diseases,188 and cancer,166 as well as wound healing.189–194 The majority of patients suffering from autoimmune disease are women, which implies a role for estrogens in the etiology of these disorders. Newonset autoimmune disease is frequently diagnosed in the peripartum period, and flare ups of existing disease often occur during pregnancy as estrogen levels rise up to 100fold from nonpregnant levels.195, 196 Neutrophils ordinarily exhibit a short half-life of 3–6 h, requiring a constant production by bone marrow to maintain normal circulating levels. Estrogens affect neutrophil populations in two ways. They increase the total production of neutrophils in bone marrow,197 and they inhibit apoptosis of circulating neutrophils, which increases the relative percentage of neutrophils in the total leukocyte differential, even when the leukocyte count is within normal limits, i.e., in noninfectious states.81 Estrogens manage the production and maintenance of neutrophils, thus estrogens manage a particular aspect of immunity related to inflammation, hostdefense, auto-immunity, and cancer. Therefore, neutrophils may be considered as a biomarker of the role of estrogens in immunologic, inflammatory, and anabolic activity within the body.

Monocytes Monocytes are WBCs derived from monoblasts in the bone marrow. They play an important role in the immune system, combating foreign organisms in the blood through phagocytosis and the release of pro-inflammatory cytokines. They also produce growth factors that aid in fibroblast activity for wound healing. After 24–72 h of circulation, they migrate into extravascular tissue where they differentiate into macrophages or dendritic cells (histocytes). Typically, monocytes represent 3%–8% of the total leukocyte population. The FSH stimulates estrogen production and estrogens suppress monocyte production.198 In the time that FSH is waiting for an estrogen response, monocytes play a role in anabolism by stimulating wound healing by releasing human growth factors.199, 200 During adaptation, as FSH and estrogen levels rise, monocyte levels fall, indicating an anabolic response by estrogens commensurate to the initial antianabolic activity of cortisol, thus reducing the requirement for monocytes. The lower the monocyte count, the greater the influence of FSH and estrogen is on the adaptation response, but this needs to be evaluated relative to the eosinophil count, which reflects

the role of ACTH on adrenal stimulation, as well as other factors (cf. Adaptation index). Conversely, monocytosis is inversely related to the relative efficiency of FSH in stimulating estrogen production. In menopause, monocytosis is observed.201 Monocytosis also reflects a relative or absolute insufficiency of estrogen’s activity during adaptation202 and is associated with increased risk of mortality in multiple diseases marked by dysregulation of the immune system such as lupus,203 autism,204 asthma,205 sepsis,206 atherosclerosis,207 myocardial infarction,208 myeloproliferative disorders, and leukemia.209–214 Thus, monocytosis implicates a terrain that is more favorable to inflammation, and altered immune states; in other words, a terrain of disadaptation of estrogen activity. As the bioavailability of estrogens and androgens are inversely related to each other due to the activity of SHBG,215 and as monocytosis reflects a relative insufficiency of estrogens during adaptation, monocytosis also reflects a more predominant peripheral androgen activity relative to that of estrogens.216

Eosinophils Eosinophils are a subpopulation of WBCs. Fundamentally, the role of the eosinophil is to serve as an indirect method of adaptation and congestion when the adrenal cortical response is not sufficiently adapted to the needs of the organism. While estrogens, as noted above, have a general effect on the proliferation of all leukocytes within the bone marrow, it is ACTH and cortisol that affect the circulating levels of eosinophils. The degree and intensity of ACTH activity on the adrenal cortex is proportional to the level of circulating eosinophils. Thus, the greater the ACTH solicitation of adrenal activity is, the greater the rise in eosinophils.217, 218 Eosinophilia, relative or absolute, is proportional to the degree of adrenal insufficiency, which is proportional to the demand for ACTH and inversely proportional to the efficiency of cortisol.219, 220 On the other hand, cortisol is inversely related to the eosinophil count because it reduces circulating eosinophils in three ways: (1) suppression of eosinophil maturation, recruitment, and survival,221 (2) sequestration of mature eosinophils in lymphoid organs,222 and (3) stimulation of eosinophil apoptosis through transcriptional upregulation.108 The greater the degree of circulating cortisol, the lower the eosinophil count. The lower the circulating cortisol activity, the higher the eosinophil count. While eosinophils cannot replace the complex roles that cortisol plays in the body, they can compensate in part for some of the adaptive functions of cortisol with respect to immune modulation. Eosinophils have direct antimicrobial effects through the production of RNase enzymes223–232 and the generation of reactive oxygen species, and are immunomodulatory through antigen presentation to T-cells.233–239

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Indirectly, they are an indirect source of histamine, which modulates the immune system.240, 241 In summary, eosinophil count is used in the BOFs to assess the intensity of the ACTH solicitation of adrenal activity (positively correlated) and the relative efficiency of cortisol activity (inversely correlated). The less efficient the adaptation response is, the lower the circulating cortisol levels, the greater the role of ACTH in restimulating the adrenal cortex, the higher the circulating eosinophil count will be. Eosinophils also contribute to the evaluation of inflammation, thrombosis, immune, and other activities.

Basophils Basophils are the least populous of all white cells. Basophils have been likened to circulating mast cells and play a role in the innate immune response, particularly against allergens242 and parasites.243 Basophils share similar receptors to eosinophils, such as eotaxin, and may serve as a tertiary method of adapting the adrenal response to aggressors in the face of inadequate cortisol response and insufficient eosinophil response. They are found in high concentration in the circulation and extracellular (EC) spaces of the skin and lungs in patients with atopic disease.244 The percent basophil count on differential is used in only one index in the BOFs, but indirectly in all indexes in which the total WBC count is used.

Lymphocytes Lymphocytes are a subset of leukocytes that are the mediators of immunity. The lymphocytes count is the sum of all three subsets of lymphocytes: natural killer (NK), T, and B cells. The NK cells are part of the innate immune system. They survey and directly attack viruses and tumors. T and B cells comprise the adaptive immune system. T cells manage cell-mediated immunity through the secretion of cytokines, regulate the activity of other immune cells and lyse cells infected by viruses. T cells also play a role in immunoregulation. B cells form antibodies specific to a unique aggressor and retains a memory of the aggressor in case of future aggression. Lymphocytes play a role in cancer surveillance, immunity, and autoimmunity. The concentration of total circulating lymphocytes can be related to three factors: cortisol, estrogen, and TSH. Cortisol is inversely related to lymphocyte counts. It reduces the circulating concentration of all three subtypes of lymphocytes, and augments destruction of lymphocytes.245–248 Estrogens are also inversely related to lymphocytes. There are several lines of evidence and clinical observations related to this. Estrogens directly inhibit the proliferation of lymphocytes.249 In high-estrogen states, such as pregnancy, there is a relative suppression of lymphocyte proliferation in order to reduce the immune

a­ttack by the mother against the fetus.158 Autoimmune disorders occur disproportionally in females who tend to have higher levels of estrogen activity and estrogen variability.157 There is an additional risk of developing autoimmune disease in the peripartum state when there is a terrain of hyperestrogenism and thyroid overstimulation.250, 251 Estrogens augment the infiltration of lymphocytes into various tissues, reducing the level of circulating lymphocytes.157 The relationship between serum TSH and peripheral lymphocytes is positively correlated to the metabolic needs of the body and the degree to which TSH is used to modulate thyroid activity.252, 253 When the lymphocyte counts are elevated, serum TSH levels tend also to be elevated, and the body tends to be in a state of increased need of thyroid activity. For example, in subclinical hypothyroidism, there is an increased appeal to TSH to stimulate the thyroid. These patients have lymphocyte counts that are elevated relative to euthyroid patients and/or in an absolute sense. When the body’s demand for thyroid hormones have been met by exogenous administration of thyroxine, lymphocyte counts reduce from their preintervention levels.254 In disorders of thyroid overactivity, such as Grave’s disease or autoimmunity, there is diminished appeal by the thyroid to TSH for stimulation. One does find diminished peripheral blood lymphocytes in these patients, though not consistently.255 As demonstrated below, other assessments of thyroid function (cf. LDH and CPK) help further contextualize thyroid efficiency. In summary, lymphocytes are inversely related to the degree of cortisol and estrogen activity in adaptation and tissue anabolism. The greater the degree of cortisol expression, and/or the greater the predominance of estrogen activity, the lower the lymphocyte levels. Lymphocytes are directly related to the degree of appeal to TSH to regulate thyroid function. The higher the lymphocyte count, the greater the appeal to TSH is, and often the greater the degree of thyroid insufficiency. Conversely, the lower the lymphocyte count, the more successful TSH has been in modulating thyroid activity regardless of the serum TSH level.

Platelets Platelets are circulating blood cells that arise from megakaryocytes in the bone marrow. Platelets have four primary functions in the body: hemostasis, repair and growth of connective tissues, transport of various factors, and modulation of inflammation. The hemostatic function of platelets has been observed for over 120 years and is well characterized.256 Platelets secrete numerous growth factors for the regeneration of connective tissue once hemostasis has been achieved, including platelet-derived growth factor, insulinlike growth factor-1 (IGF-1), fibroblast growth factor, and others.257, 258

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In general, platelets are absorbers of numerous factors in the blood, such as clotting factors and calcium, which allows them to participate in immediate hemostatic activity.259 In addition, platelets serve as the primary transporter of serotonin from the enteric cells where they are produced. Serotonin aids in intestinal motility and carbohydrate absorption.260 Serotonin also plays constitutive roles in the regulation of bone density.120, 261–263 Thus, platelets contribute to these physiologic activities as a serotonin transporter. Platelets participate in pro-inflammatory activity, adapting innate and adaptive immune mechanisms through the expression of chemokines and cytokines, and receptor-­receptor interaction with leukocytes.264 Platelets also contain histamine, which is secreted before aggregation occurs.265 In the BOFs, after the total WBC and RBC count, platelets are the most important biomarker derived from the bone marrow. Through the Starter index (cf. below), it is used to correct the genital ratio (RBC/WBC) in order to evaluate the role of genital hormones during adaptation. The Genital ratio corrected is used in over 50% of the indexes of the BOFs. Platelets, along with other factors, are used to assess histamine activity, risk of thrombosis, thromboembolic phenomenon, adrenaline activity, and peripheral serotonin activity.

alpha-sympathetic activity regardless of the origin of the anemia (genetic, hemorrhagic, renal, acute, or chronic) resulting in cardiovascular diseases such as cardiac remodeling and coronary ischemia.266–271 Anemia appears to alter the normal adaptive response to stressors, resulting in overadaptation.272 Based on these observations, we have concluded that hemoglobin can be viewed as a marker of the degree of alpha-sympathetic activity in adaptation. Because the general adaptation syndrome is initiated by alpha-sympathetic discharge (i.e., noradrenaline), hemoglobin comes to play an important and pervasive role in the BOFs.

Bone stroma-derived enzymes Two key stroma-derived enzymes are osteocalcin and alkaline phosphatase bone isoenzyme (ALPBi). In addition to their bone-related activity, they have direct effects on nonbone metabolic activity. These biomarkers in particular and the skeletal system in general inform the central nervous system of the state of the internal milieu, helping it modulate basal and adaptive capacities to meet the needs of the organism.120–122

Osteocalcin Hemoglobin Hemoglobin is a metalloprotein found within RBCs. Each RBC contains four hemoglobin subunits with an iron molecule in the center of each hemoglobin subunit. The primary role of hemoglobin is to bind and deliver oxygen from the lungs to the tissues, and bind and deliver carbon dioxide from the tissues back to the lungs. Thus, hemoglobin plays a role in acid-base balance as well as oxygen delivery. Hemoglobin (Hg) is an important determinant of the oxygen content of arterial blood, based on the equation of the calculation of arterial oxygen content (CA). Hg ( g / dL ) × 1.34 × arterial  CA =   saturation of blood ( percent )  + 0.0032 × Partial pressure of oxygen ( torr )  For a given saturation of blood and rate of consumption of oxygen, the lower the hemoglobin content is, the lower the oxygen content will be. Thus, the greater the cardiac output rise must be in order to maintain an equivalent rate of oxygen delivery. This can be expressed in the following equation, based on a rearrangement the Fick equation: Q = (VO2/(CA – CV)) × 100, where Q = cardiac output, VO2 = oxygen consumption, CA = arterial oxygen content, and CV = venous oxygen content. In  vivo and clinical studies demonstrate that in both children and adults, iron-deficiency anemia upregulates

Osteocalcin is a noncollagenous protein. Within the skeletal metabolism, it plays an important role in osteoblasty, fixing ionized calcium to hydroxyapatite crystals. In its nonskeletal role, osteocalcin plays a key role in global energy regulation and adaptation in at least three ways: 1. Glucose regulation: It improves the production and secretion of, and cellular sensitivity to, insulin, as well as the rate of glucose metabolism.121, 122, 273–275 2. Fat regulation: It increases the metabolism of adipocytes.121, 122, 275 3. ATP production: It augments the number and efficiency of mitochondria both in part from its role in glucose regulation and independent of this role.121 Serum osteocalcin measures the inactive carboxylated form. When osteocalcin is decarboxylated to its active form, it enters the tissues. The less active osteocalcin is, the higher the serum levels. The more active a role it plays in global metabolism, the lower the serum level. Osteocalcin regulates and is subject to regulation by various anabolic hormones. Serum osteocalcin is inversely related to insulin-like growth factors (IGFs)276 and estrogen activity. Estrogens stimulate osteoblasts to fix calcium, which requires active, carboxylated osteocalcin, which results in a decrease in serum decarboxylated osteocalcin.277–279 The TSH levels vary inversely with serum osteocalcin levels.280–282 Serum osteocalcin is directly correlated with tumor growth in both hormone-independent and

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h­ ormone-dependent tumors.283, 284 The wide-ranging impact of osteocalcin on the structure (bones) and function (metabolism) of the body cannot be overstated, thus its key role in the BOFs, where it is involved in over 60% of the indices.

Alkaline phosphatase bone isoenzyme Alkaline phosphatases are hydrolytic enzymes that work in an alkaline environment. They hydrolyze phosphates to be (re)used in the formation of proteins and nucleotides, and in the mineralization of bone. Although present in all tissues, they are concentrated in the liver and bile ducts, bone, intestine, and placenta, for which isoenzymes have been identified.285 ALPBi is present in the plasma membrane of osteoblasts. It is an indicator of bone mineralization286 and bone turnover. ALPBi is influenced by thyrotropic hormones in managing bone density.281 ALPBi is inversely associated with the efficiency of IGFs,287, 288 but the strength of this association depends on other factors as well. ALPBi is relationship to IGFs implies a relationship between serum ALPBi and all the activities in which the IGF family plays a role, such as energy production through the regulation of glucose entry into the cell, membrane permeability, free radical production, ATP production, inflammation, etc. ALPBi is also an indicator of dysregulated growth and is associated with acute lymphocytic leukemia, Paget’s disease, and metastasis of cancer to the bone.285

Systemic enzymes Creatine phosphokinase (CPK) CPK is an enzyme that manages the ultra-acute energy needs of the body. It manages the homeostatic state between ATP and ADP and the reservoir of phosphate between creatine and phosphocreatine. Based on computer modeling paradigms and in  vitro experiments, phosphocreatine, not ATP, caries the majority of energy produced by oxidative phosphorylation out of the mitochondria into the cytoplasm.289 When the cell has sufficient ATP, it donates a phosphate to creatine, creating phosphocreatine and ADP. Phosphocreatine is a stable reservoir of phosphate. When the cell needs an immediate augmentation of ATP, phosphocreatine donates a phosphate to ADP, which then becomes ATP. During periods of sudden increases in metabolic demand throughout the body,290 and in tissues with chronically elevated energy requirements, there is increased demand for CPK to transfer phosphate from ADP back to ATP. This allows for instantaneous availability of energy without de novo ATP production.289 The enzyme CPK catalyzes both reactions (Fig. 15.2). Skeletal and cardiac muscles contain the greatest concentration of CPK as they have the greatest needs for ­ultra-acute adaptation of energy. In general, when there is

FIG. 15.2  Interconversion of ADP and ATP. The enzyme creatine kinase allows phosphocreatine to donate a phosphate molecule to ADP, quickly converting it into ATP. The reaction is reversible, allowing ATP to donate a phosphate to phosphocreatine to hold in reserve. (Illustration by Boghog2 [Public domain], from Wikimedia Commons.)

insufficient response to a metabolic demand cells die, either by apoptosis or necrosis,291 resulting, in either case, in elevated amounts of CPK in the serum. This is classically observed during exercise292 and rhabdomyolysis.293 Thus, serum CPK is proportional to the rate of muscle turnover and the metabolic role of androgens (which anabolize muscle), but not in a strictly linear way or as the sole determinant of these functions.294 Elevated CPK levels in the serum is also associated with myocardial infarction,295 but lacks sensitivity and specificity as a sole biomarker of acute myocardial infarction.296 Biomarkers such as total WBC count, total neutrophil count, and platelets increase the sensitivity of the diagnosis and risk of mortality, which is consistent with the Endobiogenic posit that multiple biomarkers are required to accurately assess complex physiologic events.297, 298 CPK levels correlate with the degree of ATP flux due to insufficiency of oxidative phosphorylation, i.e., mitochondrial strain, but again, not in a strictly linear way. As a method of assessing oxidative deficiencies, serum CPK levels alone are neither necessary nor sufficient, but one of many associated factors (cf. Redox index, below),291 as is evidenced in cases of chronic fatigue syndrome where patients have normal cytochrome enzyme activity.299 Subclinical thyroid dysfunction (SCTD) has been associated with elevated morbidity and mortality in diabetes and cardiovascular disease, both of which are disorders of deranged redox states.300–302 CPK is inversely related to thyroid metabolic ­activity303, 304 and may be elevated in hypothyroidism and SCTD. The CPK has been shown to be inversely related to free T3 and free T4 levels, both in the diagnosis and treatment of hypothyroidism.305, 306 However, in any particular patient, the correlation is not linear. This is one of a number of observations (cf. TSH, below) that lead us to conclude that quantitative expression of thyroid hormones is neither sufficiently precise nor reliable to determine the actual metabolic impact of thyroid hormones on cellular metabolism.

Lactate dehydrogenase (LDH) LDH is an enzyme that catalyzes the interconversion of pyruvate and lactate (cf. below). Aerobic respiration, using

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glucose as a substrate, is the most efficient way of ATP production in the cells. The preferential pathway in the cell is to metabolize glycogen to glucose to pyruvate. Pyruvate is then converted to acetyl-CoA, which enters the Krebs cycle. When there is an insufficiency of coenzymes in the Krebs cycle and/or oxidative stress, LDH activity increases in order to convert pyruvate to lactate. Lactate generates ATP by anaerobic metabolism, but at a much lower yield than is attained with aerobic metabolism of glucose. LDH also converts lactate back into pyruvate to produce glycogen as energy storage for future use (Fig. 15.3). LDH is present in large amounts in the liver (the direct storage site of glycogen) and cardiac muscle (a major consumer of glucose) as well as in certain tissues and RBCs, but is found in the serum at low levels. An elevation of LDH in the serum represents a state of impaired oxidation of glucose relative to demands of the organism, as seen in cardiac ischemia,307, 308 muscle turnover,291 rapid cell and tissue growth,309 hemolysis,310, 311 and cancer.312–314

Endocrine Thyroid-stimulating hormone (TSH) TSH is a glycoprotein created in and secreted from the anterior pituitary gland. In clinical medicine, TSH is considered strictly within its intra-thyroid activity of stimulation of thyroxine (T4) and triiodothyronine (T3), i.e., merely as a barometer of thyroid function. Based on more current studies and the Endobiogenic theory of terrain, serum TSH levels have key intra-and extra-thyroid implications that should also be considered if the clinical significance of a serum TSH level is to be properly contextualized. Euthyroidism is defined as normal thyroid function that occurs with normal serum levels of TSH and T4. It has been assumed that TSH and serum levels of T4 have an inverselinear relationship based on classical feedback loops, and that this relationship is a reliable indicator of the sufficiency of thyrotropic regulation of metabolism.

OH

O LDH CH3

C

There are a sufficient number of anomalies to this assumption that raise questions about its validity. For example, euthyroid sick syndrome is defined as a clinical condition with normal thyroid function with a normal TSH levels but low serum T4 and T3. Subclinical hypothyroidism is a condition in which there is a functional hypothyroid state based on an elevated serum TSH, but a normal serum T4. Subclinical hyperthyroidism is a functional hyperthyroid state based on a serum TSH value below the normal limit, but normal T4. Finally, patients with normal serum levels of TSH, T4, and T3 may presents with symptoms consistent with hypo- or hyperthyroidism. See Section “Creatine phosphokinase” for a further discussion of the functional evaluation of thyroid metabolic activity. More recent studies demonstrated that serum TSH lacks a log-linear relationship to thyroid output of free T4 (fT4) and free T3 (fT3) (Fig. 15.4). Hoermann et al. in their evaluation of 3223 untreated patients referred for thyroid testing found poor correlation (R2 = 0.236) between TSH and fT4. For example, a serum TSH of 1.0 mU/L (0.4–4.1 mU/L) was associated with an fT4 anywhere between 4 and 28 pmol/L (9.5–25 pmol/L). Conversely, a free T4 of 14.5 pmol/L was associated with TSH between 0.1 and 100 mU/L.253 In our opinion, the serum level of TSH only reflects the responsiveness of the thyroid to stimulation without determining the final degree of metabolic efficiency of T4 or T3 (cf. “CPK,” and “LDH” above) or the degree to which thyroid catabolic activity has been adapted to anabolic demands from estrogen (cf. Genito thyroid index, antigrowth index, and bone remodeling index, below). TSH has a number of extra-thyroid relationships and functions independent of T4 or T3. TSH receptors are found in divergent tissues throughout the body.315 TSH activity is augmented by estrogen.316–318 TSH is suppressed by somatostatin.319 TSH helps regulate bone density (cf. Estrogen index for a full discussion) as well.280, 281 In summary, in the theory of Endobiogeny, serum TSH is used to evaluate intra- and extra-thyroid activities. Serum TSH is not a sufficient indicator of the efficiency of thyroid regulation of metabolism, but can help contextualize thyroid function relative to the demands of the body.

COOH NADH

Pyruvate

CH3

CH

COOH

Electrolytes Potassium (K+) and calcium (Ca+) are the only two electrolytes used in the BOFs.

NAD+ Lactate

FIG. 15.3  Role of the enzyme lactate dehydrogenase (LDH). Pyruvate is the end-carbohydrate from metabolism of glucose in the cytoplasm. Pyruvate can enter the Krebs cycle. When the rate of pyruvate exceeds the efficiency of any process from the Krebs cycle to mitochondrial oxidative phosphorylation, pyruvate can be converted by LDH to lactate, which has various metabolic roles in the body. (Illustration by Jfdwolff [CC BY-SA 3.0] from Wikimedia Commons.)

Potassium Potassium (K+) is the primary intracellular (IC)IC ion in the body and serves to maintain the resting membrane potential. IC levels are around 140 mmol/L, and extracellular (EC)EC levels 4 mmol/L. It is not the quantitative concentration per

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100

n = 3223

TSH (mU/L)

10

1

0.1

00.1 4

8

12

20

16

24

28

fT4 (pmoI/L) FIG. 15.4  Relationship of TSH to free T4 (fT4). See text for details (Reproduced from Hoermann R, et al. Complex relationship between free thyroxine and TSH in the regulation of thyroid function. Eur. J. Endocrinol. 2010;162(6):1123–1129. https://doi.org/10.1530/EJE-10-0106, European Society of Endocrinology.)

se but the ratio of IC to EC potassium (35:1) that maintains the resting membrane potential and neuromuscular stability. Serum potassium levels are regulated closely in order to maintain neuromuscular stability. A quantitative increase in serum potassium of 1 mmol/L can have a significant impact on neuromuscular activity.320 One source of EC potassium augmentation is glutamate. The most prominent neurotransmitter in the brain, glutamate is involved in neural plasticity and augments neuronal excitability.320a The egress of potassium from the cell changes the resting membrane potential, allowing for neurons to be more excitable.

Calcium While potassium is the element of membrane and cell stability, calcium is the element of action, movement, and variability. Calcium is the most predominant element in the human body because of its role in skeletal formation. Of total body calcium, 99% is in bones and 1% is bioavailable. Of the 1% that is bioavailable, 99.99999% is in the EC space, maintaining an EC:IC ratio of 12,000:1. Calcium reserves are extremely important to ensuring the proper ­adaptability of the organism during aggressions and programmed changes. Approximately 50% of serum calcium is ionized and bioavailable, and 50% is bound to proteins remaining in reserve. While cytoplasmic calcium levels are kept low, the mitochondrion and endoplasmic reticulum store calcium and make it available to calibrate cell function. Within the blood, calcium is the essential cofactor in the coagulation cascade. Within the interstitium, it is essential as a second messenger in muscle contraction. Calcium augments the rate of neuronal signal transduction and

n­ eurotransmitter secretion through upregulation of vesicle fusion. Within the IC space, calcium serves as a key signal transducer. In summary, both potassium and calcium concentrations are finely regulated at the EC and IC levels. Potassium is the primary IC element and maintains membrane stability. Calcium is a key element of adaptation and stimulates excitation, movement, and activity, both extra- and intracellularly. These two elements have opposing actions and overlapping factors that raise or diminish their serum concentration. Our interest in these elements with respect to the BOFs is how they regulate or are regulated by the adaptation response.

Some examples of direct indices derived from biomarkers Each function is quantified by an index, specified by a level of activity and made precise by a normative range. An index expresses the resultant efficiency of its activity in and of itself and adapted to the metabolic or tissue requirements of the organism. Related to corresponding circulating m ­ etabolites, the indices demonstrate a significant divergence. This divergence allows one to comprehend that the biological constants testify only to themselves and not to their physiological reality. On the contrary, the indices make it possible to evaluate their true level of metabolic activity: that of their production, consumption, and elimination. Their ensemble gives a very precise evolutive evaluation of the functionality: system by system, organ by organ. Christian Duraffourd and Jean-Claude Lapraz.16

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Definition of a direct ratio A direct index is an index that is a direct multiplication (product) or division (ratio) of biomarkers measured in the blood. The direct indexes are the basis of all the indirect indexes, which are indexes of indexes, direct or indirect in nature. As the direct indexes form the foundation of the indirect ones, the genital ratio (RBC/WBC) is the starting point of the direct indexes.

Direct indices using red and white blood cells The case for ratios We believe that when the total RBC count is evaluated relative to other factors a more nuanced appreciation of androgens in the body can be obtained. Androgens and estrogens have counterbalancing roles (Chapter  7). The quantity and quality of action as well as the chronology of action is important with respect to various disorders. Furthermore, the bioavailability of estrogens and androgens are inversely related to each other due to the role of SHBG.215, 321 Quantitative levels can be high, low, or normal, but as circulating androgens increase, the relative proportion of bioavailable estrogens decline due to an increase in SHBG, which increases its binding capacity of estrogens. The opposite is true when bioavailable estrogen levels increase in the body. Thus, in the BOFs, WBC count is also used to evaluate (through an inverse relationship) the relative rate of production and efficacy of androgens.321 When evaluating the risk of cardiovascular events, if there is absolute androgen predominance, but estrogens are also elevated, the patient may benefit from a quantitative reduction in androgens and estrogens. If there is androgen predominance but quantitative levels are low, the patient may benefit from an increase in testosterone and estrogen as

a number of large clinical trials have suggested. Regardless of the condition, by evaluating the qualitative and quantitative relationship of gonadic hormones, the BOFs provides guidance as to which clinical intervention may be most beneficial. In summary, three observations create compelling arguments for reconsidering how androgens are evaluated. The first is the contradictory nature of clinical trials with respect to quantitative androgen levels and risk of disease. The second is the multifactorial nature of disease, requiring that androgen activity be evaluated relative to other factors. Finally, the nongenomic effects of androgens may play a larger role in health and disease than previously appreciated, and these effects cannot be reliably predicted by quantitative measurements. Genital Ratio: It expresses the level of activity of tissue androgens relative to tissue estrogens. = RBC / WBC Fig. 15.5 demonstrates the upstream role of androgens, released from the gonads, where they act on the bone. The bone, as a tissue, has a metabolic response to the demands of gonadal androgens, which is to increase the production of RBCs. The output of these erythrocytes is the downstream events. The BOFs measures the quantitative downstream output and uses it as a representation of how effective the upstream regulator was in regulating metabolism, regardless of its quantitative output. Fig. 15.6 demonstrates the role of estrogens in a similar fashion. By relating the effective activity of androgens in relationship to that of estrogens, one quickly obtains an idea of the relative or qualitative achievements of these two anabolic hormones in relationship to each other and the state of metabolism. The clinical advantage was noted earlier in the discussion on the relationship of androgens and estrogens to cardiovascular disease.

FIG. 15.5  Numerator of the genital ratio: Androgen actions on the bone marrow with a downstream output of red blood cells. See text for details. (© 2015 Systems Biology Research Group.)

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FIG. 15.6  Denominator of the genital ratio: Actions of estrogens on the bone marrow with a downstream output of white blood cells. See text for details. (© 2015 Systems Biology Research Group.)

Direct index using neutrophils and lymphocytes Genito-thyroid (GT) Index: The GT Index expresses the relative activity of the gonads in relationship to that of the thyroid. When elevated, it reflects an efficient thyroid activity. When low, it reflects an augmentation of TSH demand on the thyroid, regardless of absolute thyroid glandular activity. = Neutrophils / Lymphocytes Neutrophils are a biomarker of the direct role of estrogens in immunologic, inflammatory, and anabolic activity within the body.322 Lymphocyte levels are inversely related to the degree of estrogen activity in adaptation and tissue anabolism. Lymphocyte levels are directly related to the degree of appeal to TSH to regulate thyroid function. The higher the lymphocyte count, the greater the appeal to TSH is, and often the greater the degree of thyroid insufficiency. Conversely, the lower the lymphocyte count, the more successful TSH has been in modulating thyroid activity regardless of the serum TSH level.

Direct index using monocytes and eosinophils Adaptation ratio: The adaptation ratio reflects the relative activity of ACTH on cortisol in relationship to FSH’s ­activity on estrogen during the adaptation response. When the adaptation ratio is elevated, FSH activity is effectively predominant. When the adaptation ratio is low, ACTH activity is predominant. = Eosinophils / Monocytes Eosinophil count is used in the BOFs to assess the relative strength of ACTH stimulation on the adrenals (positively correlated) and the relative efficiency of cortisol

activity (inversely correlated). Eosinophilia, relative or absolute, is proportional to the degree of adrenal insufficiency in the adaptation response. The FSH stimulates estrogen production and estrogen suppresses monocyte production. The lower the monocyte count, the greater the influence of FSH and estrogen is on the adaptation response. Conversely, monocytosis reflects a relative or absolute insufficiency of estrogen’s activity during adaptation and the need for monocytes to play a role in anabolism (cf. discussion on monocytes, above).

Direct index using platelets Platelet mobilization: The platelet mobilization index expresses the adaptative liberating capacity of platelets sequestered in splanchnic vs splenic reservoirs. When the platelet mobilization index is elevated, the effects of adrenaline are augmented and favor splanchnic demargination, as the splanchnic vasculature has a greater surface area and platelet capacity than the spleen. When it is low, it reflects a relative insufficiency of adrenaline activity in adaptation. = Platelets / 60 ( RBC ) Of the total mature platelets, some are kept in reserve along the margins of the peripheral vasculature and some in the splenic sinusoids. Because of the role of platelets in serotonin transport and secretion, and the role of serotonin in gastrointestinal motility and digestion, platelets are ­ particularly concentrated in the splanchnic vasculature. During times of adaptation, adrenaline liberates, i.e., demarginates platelets in order to achieve an immediate augmentation of platelet activity without waiting for megakaryocytes to mature.322a–322h The RBCs are in the denominator of the index for a number of reasons. The RBCs, independent of adrenaline mobilization and platelet activation, stimulate the thrombosis process.322i In  vitro studies suggest adrenaline’s

234  The Theory of Endobiogeny

activation of platelets (as opposed to its mobilization) may be mediated in part by increasing the metabolic rate of RBCs, which allows them to increase the activation of platelets.323 Thus, RBCs are in the denominator because they are an activator of platelet activity but not the primary mobilizer. The greater the effects of adrenaline, the more diminished the role of RBCs are as an aid in the aggregation process. Conversely, in anemia, the lower the hematocrit (RBC ÷ whole blood volume), the greater the compensatory rise in platelets must be in order to maintain a normal rate of thrombosis. The greater the anemia, the greater the cardiac output (cf. Hemoglobin, below) to compensate for the diminished oxygen-carrying capacity.324

Direct indexes using osteocalcin, alkaline phosphatase bone isoenzyme, TSH Growth indexes In these indexes, osteocalcin is in the denominator to reflect the inverse relationship between inactive serum osteocalcin and growth. Because ALPBi is associated with growth, it is used in the numerator of indexes evaluating growth, and in the denominator of antigrowth indexes, in contrast to serum osteocalcin, which has an inverse correlation to growth, hence its role in the denominator. Estrogen index: It expresses the endocrinometabolic activity of estrogens, i.e., both the genomic activity of estrogens and the nongenomic metabolic activity within the cells. = TSH / Osteocalcin TSH levels vary inversely with serum osteocalcin ­levels.280–282 Together, they reflect the endocrinometabolic activity of estrogens. Estrogen activity is directly correlated to the serum level of TSH.316, 325–327 Estrogens relaunch TSH, so that the catabolic activity of thyroid hormones matches the anabolic activity of estrogens.316, 328 The greater the estrogen demand and the less responsive the thyroid, the greater the serum TSH level rises, hence the role of TSH in the numerator of the index. Estrogens increase the conversion of osteocalcin to its active form to increase bone density, thus serum osteocalcin levels are inversely related to estrogen activity, hence the role of osteocalcin in the denominator.277–279 Growth index: The growth index expresses the metabolic activity of growth hormone. = ALPBi / Osteocalcin Chronic growth hormone activity increases ALPBi and reduces serum osteocalcin.287 Turnover index: The turnover index expresses the speed of renewal of tissue; its elevation implies a slowing

down of this renewal; conversely, its reduction signifies the acceleration of tissue renewal. = TSH × ALPBi

Direct index using CPK and LDH Thyroid index: The thyroid index expresses the metabolic activity of the thyroid at the cellular level. = LDH / CPK When assessing the impact of altered CPK levels on cellular metabolism, it is important to relate it to the efficiency of long-term energy production, reflected in the serum level of lactate dehydrogenase (cf. LDH). LDH participates in the conversion of glycogen to glucose for de novo production of ATP (Fig. 15.7). When cells cannot keep up with chronic metabolic needs and necrose, the level of LDH rises in the blood. Thus, LDH can be viewed as a marker of chronic metabolic strain. A person with normal serum levels of LDH and CPK can be, functionally speaking, in one of three states: a relative state of balance between chronic and acute energy management (normal ratio of LDH to CPK), a relative state of metabolic insufficiency (relatively low LDH, relatively elevated CPK), or a relative state of metabolic excess (relatively high LDH, relatively low CPK). For example, in hypothyroidism, both LDH and CPK levels are elevated compared to normal controls, but the more severe the thyroid disease, the greater the rise in CPK relative to LDH (Fig. 15.8).328a Conversely, in hyperthyroid states, the ratio of LDH to CPK is increased, but the greater the degree of hyperthyroidism, the larger the ratio becomes. (Table 15.3). It is interesting to note that in McGrowder et al.’s study, the difference in LDH between subclinical and overt hypothyroidism was not found to be statistically significant, but the difference in CPK was. The significance of the difference is only evaluating the ratio of LDH to CPK, which decreased by 57% between the subclinical and overt hypothyroid states. Other studies have shown more dramatic differences in the ratio of LDH to CPK. For example, Burnett et  al. found LDH levels to be elevated 2 times above the normal serum values, but found CPK levels to be 10–15 times above the norm, reflecting from the Endobiogenic perspective, a greater insufficiency of acute vs. chronic metabolic ­activity.303 Again, in stable coronary artery disease LDH levels are elevated to a greater degree than CPK.308 During metastasis of cancer both LDH and CPK can be elevated 10-fold or more, indicating a significant, supraphysiologic demand on the body. The ratio may be normal, but the actual global metabolic demand is elevated. Thus, both the absolute value of LDH and CPK needs to be evaluated individually and in relationship to each other, as well as other

A new approach to biological modeling: Introduction to the biology of functions Chapter | 15  235

Upstream

Downstream

T4, T3

Increased oxidative demand

Cell

??

O CH3

C

Reduced oxidative demand

OH COOH

LDH

NADH Pyruvate

CH3

CH

COOH

NAD+ Lactate

LDH

LDH

FIG. 15.7  Role of lactate dehydrogenase (LDH) in the numerator of the thyroid index. Thyroid hormones are the upstream regulator that creates a demand for ATP for cellular activity. LDH is the downstream output from the cell. LDH is in the numerator because the more the efficient thyroid hormones are in regulating cell metabolism, the greater the amount of LDH enzyme transcribed and used by the cell. (© 2015 Systems Biology Research Group.)

FIG. 15.8  Role of creatine phosphokinase (CPK) in the denominator of the thyroid index. The less effective the response of the cell to thyroid hormones, the greater the requirement for CPK to recycle ADP to ATP through phosphorylation. (© 2015 Systems Biology Research Group.)

TABLE 15.3  Relationship of LDH and CPK to thyroid activity Condition

LDH

CPK

Ratio

Hyperthyroidism

233.80

88.37

2.65

Subclinical hyperthyroidism

227.81

105.98

2.15

Normal controls

202.85

102.19

1.99

Subclinical hypothyroidism

340.38

179.80

1.89

Hypothyroidism

421.00

389.90

1.08

CPK, creatine phosphokinase; LDH, lactate dehydrogenase. Modified from McGrowder DA, et al., Serum creatine kinase and lactate dehydrogenase activities in patients with thyroid disorders. Nig J Clin Pract. 2011:14(4).

236  The Theory of Endobiogeny

determinants of cellular energy production (cf. ALPBi, LDH, and osteocalcin). In summary, the enzyme CPK is directly related to the degree of insufficiency of thyroid activity, muscle turnover, the metabolic activity of androgens, and oxidative insufficiency/mitochondrial strain. The ratio of LDH/CPK evaluates the final functional achievement of thyroid hormones in regulating the metabolic activity of the cell.

Some examples of indirect indices derived from direct indices and biomarkers The new mathematics...is one of relationships and patterns. It is qualitative rather than quantitative and thus ­embodies the shift of emphasis that is characteristic of systems thinking—from objects to relationships, from quantity to quality, from substance to pattern. Fritjof Capra.

= Genital ratio × Starter index Genital ratio = RBC / WBC = RBC × Starter index / WBC Comment: The starter index looks at the starting energy for adaptation in the splanchnic bed (c.f. Chapter  9: Somatotropic Axis, Glucagon, and, The theory of Endobiogeny, volume 2, chapter 1: The Autonomic Nervous System, BoF Indexes) (The genital ratio is corrected for the role of androgens in the sequestration vs. mobilization of elements of adaptation. Musculotrope index: expresses the relative level of endocrine and metabolic (i.e., genomic and nongenomic) activity of androgen receptors according to the balance orientation of sex hormones in osteomuscular metabolism. = Genital ratio corrected × ( CPK / ALPBi )

329

Definition of an indirect index Direct indexes evaluate specific aspects of basic physiologic relationships, such as the genital ratio (RBC/WBC). Indirect indexes are metaindexes, composed of both direct indexes, and indirect indexes—in other words, indexes of indexes. By comparing the activity of numerous factors in relationship to others simultaneously, we find several advantages. It allows for a more sophisticated evaluation of an individual’s terrain. For example, through these indirect metaindexes, one can weigh both exacerbating and protective factors related to a disorder. By opening up the metaindex and evaluating the indexes from which it is composed, one can evaluate the particular variables most implicated in the abnormal activity. Finally, one can evaluate the cumulative effect of all variables in toto. Such an approach may allow for a more precise stratification of patients based not on clinical symptoms, but on pathophysiology. This allows for a more precise treatment to be devised based on the neuroendocrine factors most responsible for an individual’s symptoms as opposed to tissue pathology of clinical symptoms alone. In summary, indirect indexes allow one to model increasingly complex aspects of metabolism based on a systems analysis approach of the terrain.

Some indirect indexes using RBCs and other factors to evaluate androgens Genital ratio corrected: expresses the basic level of activity of tissue androgens relative to tissue estrogens during the phenomenon of acute adaptation.

Comment: CPK reflects testosterone’s role on muscle turnover.294 ALPBi reflects the rate of bone turnover.286 The greater the effects of androgens, the lower the rate of bone turnover, the lower the serum level of ALPBi, thus the greater the musculotropic index value will be.330, 331

Some indirect indexes using WBCs and other factors to evaluate estrogen activity Genital ratio corrected: expresses the basic level of activity of tissue androgens relative to tissue estrogens during the phenomenon of acute adaptation. = Genital ratio × Starter index. Refer to the discussion above. Aromatization of adrenal estrogens: expresses the relative part of aromatizing activity of adrenal cortex hormones into estrogens relative to the adrenal cortex’s other activities. = Permissive cortisol index / Genital ratio corrected Permissive cortisol index = 1 / Androgenic index = 1 / ( Genital ratio corrected × Androgenic index ) The formula states that the rate of aromatization of adrenal products to estrogens is inversely related to rate of production of androgens in the body. The adrenal gland produces androgens (i.e., 17-ketosteroids) that can be converted to testosterone, dihydrotestosterone, or estrogens. The adrenal cortex’s contribution to androgens and ­estrogens are inversely related to each other. The greater the rate of conversion of these products is to estrogens, the less the availability of precursors for peripheral androgen activity. Conversely, the greater the uptake of adrenal androgens is by androgen-sensitive tissues, the less the availability of adrenal androgens is to be converted to estrogens.169, 332–334

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Some indirect indexes using neutrophils and other factors to evaluate estrogen activity Throughout the various indexes, estrogen activity is evaluated in relationship to adrenal activity (discussed above; c.f. RBC, WBC, monocytes, and eosinophils), thyroid activity (cf. lymphocytes, TSH, LDH, CPK, and osteocalcin), as well as its competitive, cooperative, and additive function with respect to anabolic factors such as progesterone, androgens (cf. RBC, monocytes, CPK), and somatotropic growth factors (cf. TSH, osteocalcin, alkaline phosphatase). Cortisol index: expresses the functional activity of cortisol from the adrenal cortex and its excretion during syndromes of adaptation.

production, and adrenal androgen production.339, 340 Due to the extensive role of cortisol in human physiology, the eosinophil count contributes to the assessment of atopic disorders, various aspects of cellular metabolism such as apoptosis, necrosis, and membrane permeability, as well as histamine expression,108, 341–349 inflammation,350 coagulation,350 immune function, carcinogenesis, and cancer survival.351–364 As always, the role of eosinophils needs to be evaluated relative to other factors. Cortisol index: We have already discussed this index, but present it from a different perspective to reveal the role of eosinophils in the formula. = ( Catabolism / Anabolism index ) /

= ( Catabolism / Anabolism index ) / Adaptation index In the numerator is the catabolism/anabolism index which evaluates the relative rate of catabolic activity in relationship to that of anabolism. Cortisol primarily favors catabolism thus this index is in the numerator. In the denominator is the adaptation index, which is eosinophils/ monocytes (cf. adaptation index). Recall that cortisol stimulates the apoptosis of eosinophils. Thus, the lower the adaptation index, the greater the activity of cortisol is effectively, and the higher the index will be. Rate of anabolism: expresses the rate of anabolic activity of the body. = Catabolism index / ( Catabolism / Anabolism index ) Catabolism index = Thyroid index / Corticoadrenal index Comment: Recall how the catabolism/anabolism index evaluates the relative balance of metabolic activity. It is in the denominator because the smaller the index, the more it favors anabolism. However, in order for anabolism to occur, there must be some catabolism which provides material to “nourish anabolism” as we say in Endobiogeny. Thus, the numerator is the catabolism index. The catabolism index is itself composed of two indexes: thyroid and corticoadrenal index (i.e., index of global adrenal cortex function). The thyroid index was discussed earlier. The greater the activity of peripheral thyroid hormones are, the greater the provision of catabolic material for anabolism. However, this is truly only in the case that adrenal cortex activity is not too excessive. In this case, it blocks anabolism, which is reflected in a smaller value of the index.

Some indirect indexes using eosinophils and other factors Eosinophil count contributes to the evaluation of various aspects of adrenal physiology, such as circulating cortisol, permissive and adaptive cortisol activity,219, 335–338 DHEA

Adaptation index Adaptation = Eosinophils / Monocytes = ( Catabolism / Anabolism index ) /

( Eosinophils / Monocytes ) = ([ Catabolism / Anabolism index ] × Monocytes ) / Eosinophils Comment: The lower the eosinophil count is, the greater the role of cortisol secretion during adaptation, the more efficacious cortisol is in its antiinflammatory and antiallergic capacity, which is consistent with the clinical literature, as noted above, hence the placement of eosinophils in the denominator. Evoked histamine index: expresses the circulating rate of active histamine. = ( Eosinophils × Platelets × Adaptation index ) / Adrenal Cortex index Adaptation index = Eosinophils / Monocytes =  Eosinophils × Platelets × ( Eosinophils / Monocytes )  / Adrenal cortex index

(

)

= Eosinophils2 × Platelets /

( Adrenal cortex index × Monocytes ) Adrenal cortex index = Cortisol index / Androgenic index

(

= Eosinophils2 × Platelets × Androgenic

)

/ ( Cortisol index × Monocytes ) As noted above, eosinophils are an indirect source of histamine secretion; the greater the relative or absolute percent eosinophils, the lower the rate of circulating cortisol, the greater the rate of circulating histamine. As the formula suggests, other factors modulate the threshold of histamine

238  The Theory of Endobiogeny

production, thus eosinophilia alone is not sufficient to account for the total amount of circulating histamine. The greater the estrogen activity (low monocytes), the greater the release of histamine independent of the antihistaminic effects of cortisol.365 Neither estrogen nor testosterone alone have been sufficient to account for histamine secretion in human models, thus suggesting that a multifactorial assessment of factors related to histamine secretion will be more accurate in assessing the histamine burden in the body.366

Some indirect indexes using lymphocytes and other factors Catabolism/Anabolism index: It expresses the relative part of activity of catabolism of the organism in relationship to its anabolic activity. = Genito  thyroid index / Genital ratio corrected Genito  thyroid index = Neutrophils / Lymphocytes = Neutrophils / ( Genital ratio corrected × Lymphocytes ) Anabolism index: It expresses the level of anabolic activity of the organism. = Catabolism index / ( Catabolism / Anabolism index )  Catabolism index × Genital ratio corrected  =   ×Lymphocytes  / Neutrophils The anabolism index evaluates the absolute rate of anabolism as a result of corticotropic, gonadotropic, and thyrotropic considerations of relative and absolute activity. (cf. catabolism-anabolism index under “Indirect indexes using neutrophils” and the catabolism index under “Indirect indexes using LDH or CPK” for a further discussion). A low rate of catabolism in and of itself does not mean that the rate of anabolism is low. Each level of activity can be elevated, low, or normal. The anabolism index seeks to evaluate the quantitative rate of anabolisms. The catabolism index as a quantitative assessment of catabolism is in the numerator. The lower the absolute rate of catabolism, the greater the predominance of anabolism may be. However, the relative rate of catabolism to anabolism rate the greater the predominance of anabolism. As noted above, the higher the lymphocyte levels, the less well adapted the thyroid is in its catabolic activity, thus the lower the rate of catabolism will be. The greater the genital ratio corrected, the greater the predominance of ­androgens relative to estrogens in adaptation, which favors the completion of anabolism. Apoptosis index: It expresses the general level of apoptotic activity of the organism in its entirety.

= Structural expansion index / Membrane expansion index Structure expansion index = Anabolism index × Nucleomembrane activity index Membrane expansion = Catabolism index × Growth index corrected = ( Anabolism × Nucleomembrane activity index ) / ( Catabolism index × Growth index corrected ) Apoptosis was first described in 1847. For 140 years (1847–1987), the study of apoptosis was morphologic in nature. From 1988, with the discovery of bcl-2 protein, the genetic mechanisms of apoptosis have been the primary focus of study.367 From the Endobiogenic perspective, because the endocrine system manages the rate of metabolism of the cell, it mediates the life of the cell and the time of apoptosis or necrosis or lack thereof, such as with cancer cells. The plethora of pro- and antiapoptotic signaling factors are the means of regulating apoptosis and while interesting, are not the determinant of when and to what degree of intensity apoptosis occurs (or does not). The validity of such an index would allow for a global approach to managing apoptosis that is concordant with the general scheme of factors related to cancer growth, and away from the endless search for “silver bullets” in pharmacotherapy—natural or synthetic—that are highly target with respect to specific mechanisms of apoptosis, but carry the risk of potentially more serious side effects. The numerator is composed of the Anabolism index and the Nucleomembrane index. The greater the numerator, the greater the rate of apoptosis is. Cell growth occurs as a result of anabolism, which requires increased activity at the level of the nucleus with respect protein transcription (represented by the Nucleomembrane index) relative to membrane activity. The greater the anabolic activity of the cell, the sooner it will reach the end of its programmed number of division, and hence die by apoptosis. The denominator is composed of the membrane expansion index, which is itself composed of the product of the catabolism and the growth index corrected indices. When there is catabolic predominance,368, 369 and/or elevated IGF activity370, 371 the membrane expands.372 A greater rate of membrane expansion relative to that of structural activity implies that more energy is devoted to cellular hyperplasia than to cellular divisions, hence the longer it takes for the cell to die due to reaching its programmed time of death. In summary, the endocrine system is the regulator of apoptosis, while pro-apoptotic proteins are the mechanism of apoptotic cell death. From the Endobiogenic perspective, an endocrine approach to the evaluation of the global physiologic rate of apoptosis allows one to evaluate the reason for apoptosis (or its insufficiency) and to pinpoint the causative

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factors, and thus allows for a clinical plan to address these particular imbalances. In contrast, merely enumerating the number of pro- or anti-apoptosis factors active does not at this time offer a path of clinical intervention.

Some indirect indexes using platelets and other factors Evoked histamine index: We reproduce the formula again to discuss the role of platelets. = ( Eosinophils × Platelets × Adaptation index ) / Adrenal cortex index Adaptation index = Eosinophils / Monocytes = ( Eosinophils × Platelets × Eosinophils ) / ( Adrenal cortex × Monocytes )

(

)

= Eosinophils2 × Platelets / ( Adrenal cortex × Monocytes ) The quantitative amount of histamine in platelets is less than that found in leukocytes.373 However, because platelets activate neutrophils and monocytes on the endothelial surface of the vasculature, and due to their 25-fold numerical superiority to leukocytes, they play an amplifying role in inflammatory disorders374 well characterized by the actions of eosinophils and basophils.375 This is reflected in the formula of the histamine index. The greater the numerator is, the greater the numerical value of the index and thus the greater role of pro-histaminic elements relative to antihistaminic elements. In the numerator is the product of two factors: Eosinophils2 × Platelets The normal value of percent eosinophils is 0.1–7, square of the norm is 0.12–72, or 0.01–49. Conversely, the value of platelets is 100–400 (cf. Table 15.1 for conversion factor). Thus, mathematically, and it is proposed that biologically, the role of platelets in histamine expression is 2–10,000fold greater than that of eosinophils, balanced of course by the relative effects of antihistaminic factors expressed in the denominator.

Some indirect indexes using osteocalcin Antigrowth indexes In these indexes, osteocalcin is in the numerator to reflect the relationship between inactive serum osteocalcin and antigrowth activity. Pro-amyloid index: expresses the level of IC hypometabolism. By extension, it evaluates the degree of insufficiency of cellular respiration (i.e., mitochondrial efficiency in the production of ATP by oxidative phosphorylation).

By extension, it evaluates the degree of cellular nutritional insufficiency. = Index of reduction × Insulin resistance index Comment: Osteocalcin is in the denominator of the insulin resistance index, itself in the denominator of the formula, placing osteocalcin in the numerator of the global formula. Recall that serum osteocalcin is inactive osteocalcin, and that the greater the level of inactive osteocalcin, the less optimized mitochondrial function and insulin activity will be. With respect to the composition of the formula, the index of reduction is in the numerator. The greater the rate of reductive capacity, the less the relative potential of oxidation will be of carbohydrates or fats.376 The index of insulin resistance is in the denominator. The greater the degree of insulin resistance, the less glucose is available for oxidation.377 Thus, the pro-amyloid index evaluates the degree of cellular nutritional insufficiency (insulin resistance) and insufficiency of material for cellular respiration (index of reduction). It is called the pro-amyloid index because the greater the degree of mitochondrial insufficiency, the more likely the organism will be to rely on proteins such as amyloid proteins as an alternate form of energy.378 Antigrowth index: expresses the global level of activity of the ensemble of antigrowth factors (cf. TSH for a full discussion). = 1 / Growth index corrected Growth index corrected = Growth indeex / Turnover Growth index = Alk Phos bone isoenzyme [ ABPi ] / Osteocalcin Turnover = APBi × TSH = ( ABPi / Osteocalcin ) / ( APBi × TSH ) = Osteocalcin × TSH Comment: Osteocalcin is as a pro-growth factor at the tissue level. Serum osteocalcin is inversely related to its activity at the tissue level because it measures the inactive form of osteocalcin. The higher the serum osteocalcin level, the less pro-growth activity at the tissue level. Thyroid hormones favor growth by increasing the metabolic rate of the cell. The greater the serum TSH, the less responsive the thyroid is to stimulation thus the less well-calibrated growth activity is at the cellular level. While this index evaluates the relative insufficiency of pro-growth factors (it is the inverse of the growth index corrected), it can be considered as an indirect evaluation of antigrowth factors such as leptin, resistin, and other antigrowth factors that are known to directly oppose the effects of alkaline phosphatase and osteocalcin.379, 380

240  The Theory of Endobiogeny

Somatostatin index: expresses the level of activity of somatostatin; indirectly, it witnesses the relative level of activity of the exocrine pancreas. = Antigrowth index / Cortisol index Comment: Somatostatin inhibits growth hormone381–384 and cortisol inhibits somatostatin. This index is a good example of how one type of endocrine activity—in this cortisol—is contextualized and oriented toward a completely different hormonal activity—somatostatin—but its evaluation relative to another series of activities—antigrowth factors. The lower the degree of circulating cortisol in the face of antigrowth activity, the less inhibition of somatostatin there must be, and therefore the greater the relative predominance of somatostatin activity is presumed to be.385–388

An indirect indexes using CPK and LDH Catabolism index: This was discussed earlier under section “Anabolism index.” It expresses the level of catabolic activity of the organism. = Thyroid index / Adrenal cortex index Thyroid index = LDH / CPK = LDH / ( Adrenal cortex index × CPK )

Two indirect indexes using TSH and other biomarkers Thyroid yield: It expresses the relative part of thyroid metabolic activity in relation to its level of solicitation by the pituitary. By extension, it contributes to an evaluation of the threshold of response of the thyroid to pituitary solicitation. = Thyroid index / TSH Thyroid index = LDH / CPK = ( LDH / CPK ) / TSH = LDH / ( TSH × CPK ) Comment: The thyroid index evaluates the functional metabolic impact of thyroid hormones on the rate of cell metabolism, as discussed under section “Creatine Phosphokinase.” By assessing this activity relative to the serum TSH level, the thyroid yield index evaluates how readily the pituitary can adapt the thyroid. For example, a patient with a normal thyroid index (irrespective of serum fT4 and fT3) but a very low TSH (i.e., 0.1 mU/L) has a thyroid that is quickly regulated by the pituitary and is at risk of overadapting thyroid activity relative to the degree of solicitation. Consider a terrain in which the effects of thyroid hormone activity are 150% optimal. The thyroid index is 8.25 (3.5–5.5). When TSH stimulates the thyroid gland, the gland responds quickly resulting in a rapidly inhibited TSH

at 2 (0.5–4.5 μIU/mL). The thyroid yield is 8.25/2 = 4.125 (2–3). What is being evaluated is the functional IC yield of thyroid hormones relative to the efficiency of response to TSH. The interpretation is that thyroid activity is elevated and the gland is sensitive to stimulation and responds 2–3 times too quickly. In other words, the current TSH value is normal but too elevated for this patient. Despite having a normal serum TSH, a medicinal plant that slows down TSH stimulation of the thyroid, such as Lycopus europaeus (Gipsywort), would be recommended. Now consider a situation where the thyroid activity is 80% of optimal with a thyroid index value of 2.8. When TSH stimulates the thyroid gland, it also responds too quickly resulting in a rapidly inhibited TSH at 0.66. The thyroid yield is 2.8/0.678 = 4.125, the same elevated thyroid yield as in the first case. Here, the interpretation is that the thyroid gland responds quickly to stimulation but there is something at the peripheral level that impairs optimal regulation of cellular metabolism regardless of the quantitative output of thyroid hormones from the gland. In this case, while inhibition of TSH with Lycopus europaeus is recommended, so is improvement of peripheral sensitivity to thyroid hormones, such as Zingiber officinale (Ginger). The thyroid yield index can offer clinicians new insights into how to approach clinical symptoms and how to reconcile it with laboratory data. It relies not on serum levels of T4 and T3, but on this subtler functional assessment, regardless of the quantitative output of thyroid hormones. Bone remodeling index: It expresses the level of bone remodeling and the degree of alteration of bone and cartilage; it also testifies to the general level of metabolism and, in particular, its activity in adaptation. = Turnover index / Osteocalcin = ( TSH × ALPBi ) / Osteocalcin Comment: As discussed under section “Bone stromaderived enzymes,” the bone plays a significant role in energy regulation. The rate of bone turnover can be viewed, according to the theory of Endobiogeny, as a reflection of global rate of cell turnover. The higher the turnover index, the lower the rate of peripheral cell turnover is in the body. Elevated serum TSH implies a lack of thyroid activity at the tissue level, and may implicate inefficient thyroid regulation of the metabolic rate of the cell (cf. “thyroid yield,” above). Elevated ALPBi is directly related to the degree of bone turnover from osteoblastic activity.286 It indirectly implicates according to the theory of Endobiogeny, an increased demand on the bone stroma to assist in the regulation of global energetic requirements of the organism.120–122 Osteocalcin regulates mitochondrial activity, estrogen sensitivity, and insulin sensitivity,121, 122, 275 which can augment the energetic and anabolic capacity of the cells. Serum osteocalcin is inversely related to these effects of

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o­ steocalcin, hence its role in the denominator [cf. Estrogen index (Osteocalcin) for a full discussion).

Structure and function values Because the terrain operates under both basal and adaptive demands, Dr. Duraffourd developed a method for distinguishing the effects of function (adaptation) vs. structural (basal) metabolic activity. All lab values and initial results of indexes represent functional values. Using the starter index, which evaluates how the organism adapts to aggressions, the values of function can be extrapolated back into structure. Some indexes, such as the thyroid index, have only function values. Most, though, have structure and function values. This is valuable because it allows the Endobiogenist to evaluate the modalities of function and determine if the origin of the problem related to the maintenance of structure of functional adaptation demands. It can also help offer more precise recommendations for lifestyle modification, such as meditation vs. aerobic exercise. One may find indexes in which the structure value is absolutely high and function value absolutely low, or vice versa. From this, two questions often arise. First, “which value is ‘correct?,’” and “Which value should be treated? The elevated or diminished value?” Assuming that the data input is correct and within reasonable variation form the normal value (cf. below), both values are “correct.” They reflect serious discrepancies in the capabilities of the organism in structural and functional achievements. The area of emphasis in the evaluation and the choice of treatment will be based on an assessment of whether the disorder is one of a structural or functional disadaptation. When in doubt, use adaptogenic plants.

Comparison to historical and physical exam findings If the Endobiogenist has performed a detailed history and physical examination and has interpreted it correctly, their findings will correlate very well with the BOFs. However, it should be understood that each method of evaluation has different parameters and offers different levels of information. Therefore, discrepancies can be seen. For the novice Endobiogenist, whenever there is doubt between the conclusions derived from these three methods, treat based on the conclusions of the BoF. This maxim by no means contradicts or diminishes the value or necessity of history and physical exam. Ideally, vis-à-vis the BOF, they will contextualize the findings of the BoF and allow for a more precise selection of treatment. Recall that history and ­physical examination produce unique information that cannot be derived from the BoF, such as past history or emunctory function.

The optimal integration of history, physical examination, and BoF are illustrated in two cases of hypothyroidism. Two 48-year-old premenopausal women develop Hashimoto’s thyroiditis. The first woman developed it after a single, intense traumatic experience: the death of her beloved husband. The duration and intensity of treatment will be relatively shorter as long as she has worked through the grief of her husband’s death. The second woman developed her thyroiditis at the culmination of a divorce from her verbally abusive husband of 28 and 18 years of living with her verbally abusive father before that. In this case, thyroid oversolicitation is more entrained. The second patient will likely require a longer, more intensive treatment that addresses central and peripheral factors. The role of the BOFs is to determine precisely the therapies most targeted to the terrain. The role of the history and physical examination will be to determine the duration of treatment and buffering capacity of the organism.

Some words of caution about values of indices The BOFs is a modeling system that characterizes particular aspects of the management of the terrain—namely neuroendocrine management. It does not directly measure physiologic activity. There are many other aspects of biologic existence that it does not measure: electrochemical, electromagnetic, communication networks, van der Waal charge interaction, conformational binding efficiency of proteins, etc. What the BoF does do is evaluate and calculate neuroendocrine management based on three very particular assumptions: (1) The endocrine system is the true manager of the terrain and the autonomic nervous system modulates the endocrine system. (2) Biomarkers reflect the downstream metabolic output of upstream neuroendocrine management of terrain.1 (3) Biomarker values input into the system do not deviate significantly from their normative values. Stipulation 3 is most crucial when the patient has a TSH 5 μIU/mL. In these cases—often due to iatrogenic dosing of thyroid medication—a large percentage of indexes may be accurate in the general picture they present, but not precise with respect to their numerical value. For example, consider the estrogen index whose formula is TSH/osteocalcin (adult female 0.2–0.4). Note how as the TSH varies for the same osteocalcin,2 the results deviate from the normative value (Table 15.4). In the particular case of the estrogen index, there are compensatory formulas for calculating aspects of estrogen

1. The only exception to this point is serum TSH. It has both upstream and downstream activities.

242  The Theory of Endobiogeny

TABLE 15.4  Evaluation of the estrogen index with variable TSH values and stable osteocalcin value Estrogen index (0.2–0.4) TSH

Osteocalcin

High

7.5

5

1.5

3

5

0.6

1.5

5

0.5

5

0.1

0.1

5

0.02

activity that do not involve TSH or osteocalcin. Because the BOFs is composed of formulas, the output is only as accurate as the input data. ● ● ●

When TSH values are 5 μIU/mL enter a value of 5 On follow-up studies, for the prior evaluation, reenter the original measured TSH in order to evaluate the relative change in terrain. This is because numerous other biomarkers will also change as the TSH has changed.

Some advice on the interpretation of indices The BOFs is a tool to aid the physician in the assessment of the terrain and its evolution or devolution over time based on the effects of time itself, treatment, or both. It is not a stand-alone method of diagnosing or treating patients. It is not a binary system where it is sufficient to see how many results are high, low, or normal. When using the BOFs in the Endobiogenic evaluation remember two basic principles in order to do no harm: 1. Interpret a single index relative to one or more other indices. 2. When in doubt as to the root cause of illness, treat symptoms. With respect to point one, we will illustrate an evaluation of thyroid function. The thyroid metabolic index evaluates the metabolic impact of peripheral thyroid hormones (T4, T3). What does it mean if the value is within the normal range and what are the therapeutic implications? One must evaluate this level of peripheral thyroid hormone function relative to the thyroid yield, as we discussed above. Avena sativa (Wild oat) and Zingiber officinale (Ginger) are two possible plants that can improve the thyroid yield. But, which of these two is most targeted for this patient?

Normal

Low

0.3

One may expand the evaluation to look at genital function. If the GT index (neutrophil/lymphocytes) is low, Avena sativa is more targeted. If there are insufficient genital androgens, Zingiber officinale is more targeted. Let us say that the thyroid index is normal and you wish to contextualize its meaning to two other indexes: thyroid yield and Genitothyroid. There are 9 possible combinations of interpretations. Table 15.5 demonstrates an Endobiogenic method of analysis of three indexes, assuming that one is normal and the other two vary between elevated, normal or low. The evaluation can be further expanded to look at the role of the thyroid in general metabolic activity relative to the adrenal cortex. Based on this evaluation, further considerations can be made in the assessment of terrain and the choice of treatments. The algorithm will result in a different combination of therapeutic choices based on if the thyroid metabolic index is low or elevated. If we consider three possible values for each index (normal, high, low), then an evaluation of three indices vis-à-vis each other has 27 possible c­ ombinations: 9 for each permutation of the thyroid metabolic index TABLE 15.5  Evaluation of three indexes where one (Thyroid index) is normal Thyroid yield index

Genito-thyroid index High

Normal

Low

High

Lycopus europaeus

Lycopus europaeus

Zea mais

Normal

Depends on other factors

No treatment indicated

Vitex agnus castus

Low

Depends on other factors

Avena sativa Zingiber officinale

Avena sativa Zingiber officinale

2. The osteocalcin value is the adjusted value based on a proprietary formula that accounts for variations in the osteocalcin value between various laboratories.

A new approach to biological modeling: Introduction to the biology of functions Chapter | 15  243

(low, normal, or elevated). Because of the polyvalent action of medicinal plants, there are typically