Reproductive Endocrinology [1 ed.] 9784431402770, 4-431-40277-2

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LANDES BIOSCIENCE

V ad eme c um

LANDES BIOSCIENCE

V ad e me c u m

Reproductive Endocrinology and Infertility

Reproductive Endocrinology and Infertility

Lewis

Vivian Lewis

v a d e m e c u m

Reproductive Endocrinology and Infertility Vivian Lewis, M.D. Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Rochester School of Medicine and Dentistry Rochester, New York, U.S.A.

LANDES BIOSCIENCE

AUSTIN, TEXAS U.S.A.

VADEMECUM Reproductive Endocrinology and Infertility LANDES BIOSCIENCE Austin, Texas U.S.A. Copyright ©2007 Landes Bioscience All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the U.S.A. Please address all inquiries to the Publisher: Landes Bioscience, 1002 West Avenue, Austin, Texas 78701, U.S.A. Phone: 512/ 637 6050; FAX: 512/ 637 6079 ISBN: 978-1-57059-702-2 Cover artwork by Kristen Shumaker

Library of Congress Cataloging-in-Publication Data Reproductive endocrinology and infertility / [edited by] Vivian Lewis. p. ; cm. -- (Vademecum) Includes bibliographical references and index. ISBN-13: 978-1-57059-702-2 (alk. paper) 1. Endocrine gynecology . 2. Infertility, Female--Endocrine aspects. I. Lewis, Vivian, M.D. II. Series. [DNLM: 1. Genital Diseases, Female. 2. Endocrine System Diseases. 3. Infertility, Female. WP 140 R4247 2007] RG159.R452 2007 618.1--dc22 2007001376

While the authors, editors, sponsor and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein.

Dedication I would like dedicate this book to my family whose love, support and patience have made it possible for me to pursue a career in academic medicine. My parents, Oswald Lewis and Vivian Lewis, encouraged and nurtured a love of learning. My brothers and sister were crucial in providing an intellectually stimulating environment as I grew up. My husband, Rustam Tahir, and sons, Darius and Jason, have been understanding and supportive while I put in the long hours necessary to complete this project. I am grateful to you all.

Contents Preface ......................................................................... xv Acknowledgements ..................................................... xvi

Part I: Reproductive Endocrinology 1. The Menstrual Cycle ...................................................... 3 John T. Queenan, Jr. GnRH .................................................................................................... 3 Follicular Phase ....................................................................................... 4 Luteal Phase ............................................................................................ 7 The Endometrium: Proliferative and Secretory Phases ............................ 8

2. Puberty and Its Disorders ............................................ 10 Adelina M. Emmi and Lawrence C. Layman Normal Puberty Physiology .................................................................. 10 Somatic Changes ............................................................................. 10 Endocrinology of Puberty ................................................................ 10 Abnormalities of Puberty ...................................................................... 12 Precocious Puberty .......................................................................... 12 Delayed Puberty .............................................................................. 15

3. Amenorrhea ................................................................. 23 Michael Wittenberger and Alicia Armstrong Evaluation ............................................................................................. 23 Eugonadism, Uterus Present ............................................................ 25 Hypogonadism (Prior Estrogen Exposure), Uterus Present ......................................................................... 25 Eugonadism, Uterus Absent ............................................................ 28 Hypogonadism, Uterus Present ....................................................... 29 Diagnoses ............................................................................................. 29 Eugonadotropic Amenorrhea (Normal FSH and LH) ............................................................ 29 Hypogonadotropic Amenorrhea ...................................................... 32 Hypergonadotropic Amenorrhea ..................................................... 33 Treatment ............................................................................................. 34

4. Dysfunctional Uterine Bleeding ................................... 36 William R. Phipps Differential Diagnosis and Mechanisms of Bleeding ............................. 37 History ................................................................................................. 39 Physical Examination ............................................................................ 40 Laboratory, Imaging and Other Diagnostic Studies ............................... 40 Treatment ............................................................................................. 43

5. Diagnosis and Management of Polycystic Ovary Syndrome .......................................................... 47 Kathleen M. Hoeger Diagnosis .............................................................................................. 47 Epidemiology ........................................................................................ 47 Clinical Features ................................................................................... 47 Pathophysiology .................................................................................... 48 Endocrine Evaluation ............................................................................ 49 Impact of Obesity ................................................................................. 50 Metabolic Complications ...................................................................... 51 Treatment Options ............................................................................... 51 Oral Contraceptives and Progestins ................................................. 53 Anti-Androgens ............................................................................... 53 Insulin Sensitizing Agents ................................................................ 54 Lifestyle Modification ...................................................................... 54

6. Obesity: Recognition and Treatment in Women .......... 56 Erin E. Flaherty and Richard S. Legro Assessment ............................................................................................ 57 Metabolic Syndrome ....................................................................... 57 Treatment ............................................................................................. 58 Diet and Exercise ............................................................................. 58 Pharmacotherapy ............................................................................. 58 Categories of Weight Loss Drugs ..................................................... 59 Other Medications and Herbal Supplements ................................... 60 Surgery ................................................................................................. 61

7. Hormonal Contraception ............................................ 65 Sarah Prager and Jody Steinauer Background .......................................................................................... 65 Assessing Evidence about Contraception ............................................... 65 Combination Hormonal Contraception ............................................... 67 Combination Oral Contraception ................................................... 67 Extended Use Combined Oral Contraception ................................. 70 Transdermal Contraceptive System .................................................. 72 Combined Contraceptive Vaginal Ring ........................................... 73 Injectable Combined Hormonal Contraception .............................. 74 Progestin Only Contraceptive Methods ................................................ 74 Progestin Only Pills ......................................................................... 74 Progestin Only Intramuscular Injection ........................................... 76 Implantable Progestin Contraception .............................................. 77 Levonorgestrel Intrauterine System ....................................................... 78 Emergency Contraception .................................................................... 79

8. Endometriosis .............................................................. 84 Sireesha Reddy Definition and Epidemiology ............................................................... 84 Pathogenesis .......................................................................................... 84 Diagnosis .............................................................................................. 84 Medical Treatment ................................................................................ 85 Oral Contraceptives ......................................................................... 85 Progestins ........................................................................................ 86 Gonadotropin Releasing Hormone Analogs ..................................... 86 New Therapies ................................................................................ 87 Surgical Treatment ................................................................................ 87

9. Hyperprolactinemia ..................................................... 89 Ghassan Haddad and Michael A. Thomas Biochemistry ......................................................................................... 89 Etiology ................................................................................................ 89 Physiologic ...................................................................................... 89 Pharmacologic ................................................................................. 90 Pathologic ....................................................................................... 91 Prolactinomas ....................................................................................... 91 Evaluation ............................................................................................. 92 Galactorrhea ......................................................................................... 92 Treatment ............................................................................................. 93 Observation ..................................................................................... 93 Medical Treatment ........................................................................... 93 Surgery ............................................................................................ 94 Radiotherapy ................................................................................... 94 Pregnancy Considerations ..................................................................... 94

10. Premenstrual Syndrome ............................................... 96 Stephanie A.M. Giannandrea, Linda H. Chaudron and Tana A. Grady-Weliky Risk Factors .......................................................................................... 96 Clinical Symptoms and History ............................................................ 97 Differential Diagnosis ........................................................................... 98 Etiology ................................................................................................ 99 Treatment ............................................................................................. 99 Lifestyle Interventions ................................................................... 100 Nutritional, Vitamin and Alternative/Complementary Treatment Strategies .............................................................. 100 Psychoeducation ............................................................................ 101 Cognitive Behavioral Therapy (CBT) ............................................ 101 Pharmacologic Interventions ............................................................... 101 Antidepressants .............................................................................. 101 Anxiolytics ..................................................................................... 104 Hormonal Treatments ................................................................... 104

11. Treatment of the Menopausal Woman ....................... 107 Ghassan Haddad and Daniel B. Williams The Menopause .................................................................................. 107 The Transition ............................................................................... 107 Symptoms of Menopause .................................................................... 108 Vasomotor Symptoms ................................................................... 108 Regimens for Hormone Replacement ................................................. 109 Alternative Treatments for Hot Flashes .......................................... 110 Alternative Medicine ..................................................................... 111 Genitourinary ..................................................................................... 112 Local Therapy (Vaginal or Topical Administration) ....................... 112 Osteoporosis ....................................................................................... 113 Pathophysiology ............................................................................ 113 Risk Factors and Diagnosis ............................................................ 113 Cardiovascular Disease ........................................................................ 115 HERS Study and Secondary Prevention of Cardiovascular Disease ...................................................... 116 WHI Study and Primary Prevention of Cardiovascular Disease ..... 116 Alzheimer’s Disease ............................................................................. 116 Risks of Homone Replacement ........................................................... 117 Estrogen Replacement Therapy and Breast Cancer ........................ 117 Estrogen Replacement Therapy and Endometrial Cancer .............. 117 Venous Thromboembolic Events ................................................... 117 Benefits of Hormone Replacement ..................................................... 118

12. Reproductive Endocrinology Diagnostic Imaging ..... 120 Peter Klatsky and Victor Y. Fujimoto Principles of Ultrasound and Magnetic Resonance Imaging (MRI) ..... 120 Ambiguous Genitalia .......................................................................... 120 Amenorrhea ........................................................................................ 121 Secondary Amenorrhea .................................................................. 125 Infertility ............................................................................................ 126 Anatomic and Tubal Factor Infertility ............................................ 126 MR-Hysterosalpingography ........................................................... 135 Recurrent Pregnancy Loss ................................................................... 135 Ovulatory Disorders ...................................................................... 136 Diminished Ovarian Reserve ......................................................... 137 Endometriosis ..................................................................................... 139 Fibroids .............................................................................................. 141

Part II: Infertility 13. An Overview of Female Infertility .............................. 145 Sandra L. Torrente and Valerie Montgomery Rice Overview ............................................................................................ 145 Ovulatory Disorders ...................................................................... 146

Tubal Disorders .................................................................................. 149 Treatment ...................................................................................... 150 Endometriosis ............................................................................... 150 Uterine Disorders .......................................................................... 150 Cervical Disorders ......................................................................... 150 Unexplained Infertility .................................................................. 151

14. Surgical Treatment of Female Infertility .................... 153 Mohammed Al-Sunaidi and Togas Tulandi Diagnostic Laparoscopy ...................................................................... 153 Laparoscopy Promoting Fertility ......................................................... 154 Adhesiolysis ................................................................................... 154 Treatment of Endometriosis .......................................................... 154 Treatment of Distal Tubal Occlusion ............................................. 156 Treatment of Proximal Tubal Occlusion ......................................... 158 Treatment of Mid-Tubal Occlusion ............................................... 159 Laparoscopic Treatment of Polycystic Ovary Syndrome (PCOS) ... 159 Hysteroscopy in Infertility .................................................................. 161 Diagnostic Hysteroscopy ............................................................... 161 Operative Hysteroscopy ................................................................. 162

15. Ovulation Induction .................................................. 165 Jon C. Havelock and Karen D. Bradshaw Testing Prior to Ovulation Induction .................................................. 165 Ovulation Induction Monitoring ........................................................ 167 Complications of Ovulation Induction ............................................... 167 Multiple Pregnancy ....................................................................... 167 Ovarian Hyperstimulation Syndrome (OHSS) .............................. 168 Methods of Ovulation Induction ........................................................ 168 Weight Loss ................................................................................... 168 Clomiphene Citrate ....................................................................... 168 Metformin ..................................................................................... 170 Aromatase Inhibitors ..................................................................... 170 Laparoscopic Ovarian Diathermy .................................................. 171 Glucocorticoids ............................................................................. 171 Pulsatile Gonadotropin Releasing Hormone .................................. 171 Dopamine Agonists ....................................................................... 171 Gonadotropins for Ovulation Induction ............................................. 172 Background ................................................................................... 172 Follicular Maturation with hCG—The Terminal Act in Ovulation Induction ......................................................... 173 Gonadotropin Ovulation Induction in PCOS ............................... 174 Ovulation in Hypogonadotropic Hypogonadism ........................... 175 Gonadotropins in Controlled Ovarian Hyperstimulation (COH) ...................................................... 176 COH with Gonadotropins in in Vitro Fertilization (IVF) ............. 176

16. Assisted Reproductive Technology ............................. 178 Tiffany Von Wald and Kim Thornton Definitions ......................................................................................... 178 Infertility History and Evaluation ....................................................... 179 Indications for ART ............................................................................ 181 Tubal Disease ................................................................................ 182 Endometriosis ............................................................................... 182 Male Factor Infertility ................................................................... 183 Ovulatory Disorders ...................................................................... 183 Unexplained Infertility .................................................................. 184 Diminished Ovarian Reserve ......................................................... 184 Other Indications for ART ............................................................ 184 Success Rates ...................................................................................... 184 Complications .................................................................................... 185 Multiple Gestation ........................................................................ 185 Ovarian Hyperstimulation Syndrome (OHSS) .............................. 186 Ectopic Pregnancy ......................................................................... 186 Other Risks ................................................................................... 187 Fetal Risks ..................................................................................... 187

17. Alternative Medicine and Female Infertility ............... 189 Hey-Joo Kang, Pak Chung and Raymond Chang Acupuncture ....................................................................................... 189 Herbal Treatments .............................................................................. 191 Vitamins and Dietary Supplements ..................................................... 191 Mind/Body Techniques ....................................................................... 192

18. Male Infertility ........................................................... 194 Stephanya Shear and Jeanne O’Brien Epidemiology ...................................................................................... 194 Physiology .......................................................................................... 194 Differential Diagnosis ......................................................................... 195 Evaluation ........................................................................................... 196 History and Physical ...................................................................... 196 Laboratory Studies ......................................................................... 197 Radiologic Studies ......................................................................... 198 Management ....................................................................................... 199 Post Evaluation—Follow Up Care ................................................. 199 Other Surgical and Medical Treatments for Infertility .................... 200

19. Your Environment; Your Fertility—Is There a Link? .. 201 Shanna H. Swan The Environment and Reproductive Factors in the Male .................... 202 The Environment and Reproductive Factors in the Female ................. 203 Factors That May Alter a Couples’ Fertility ......................................... 208 Web-Based Resources .......................................................................... 209

Index .......................................................................... 213

Editor Vivian Lewis, M.D. Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Rochester School of Medicine and Dentistry Rochester, New York, U.S.A.

Contributors Mohammed Al-Sunaidi, M.D.

Linda H. Chaudron, M.D., M.S.

Department of Obstetrics and Gynecology McGill University Montreal, Quebec, Canada

Departments of Psychiatry, Pediatrics, and Obstetrics and Gynecology University of Rochester Medical Center Rochester, New York, U.S.A.

Chapter 14

Alicia Armstrong, M.D. Reproductive Biology and Medicine Branch National Institute of Child Health and Human Development Bethesda, Maryland, U.S.A. Chapter 3

Karen D. Bradshaw, M.D. Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Texas Southwestern Medical Center Dallas, Texas, U.S.A. Chapter 15

Raymond Chang, M.D. Department of Internal Medicine Institute of East-West Medicine New York, New York, U.S.A. Chapter 17

Chapter 10

Pak Chung, M.D. Department of Obstetrics and Gynecology Center for Reproductive Medicine and Fertility Weill Medical College of Cornell University New York, New York, U.S.A. Chapter 17

Adelina M. Emmi, M.D. Section of Reproductive Endocrinology, Infertility and Genetics Department of Obstetrics and Gynecology Medical College of Georgia Augusta, Georgia, U.S.A. Chapter 2

Erin E. Flaherty, D.O.

Kathleen M. Hoeger, M.D.

Department of Obstetrics and Gynecology Pennsylvania State University College of Medicine Hershey, Pennsylvania, U.S.A.

Department of Obstetrics and Gynecology University of Rochester Medical Center Rochester, New York, U.S.A.

Chapter 6

Chapter 5

Victor Y. Fujimoto, M.D.

Hey-Joo Kang, M.D.

Department of Obstetrics, Gynecology and Reproductive Sciences UCSF Women’s Health, Mount Zion San Francisco, California, U.S.A.

Center for Reproductive Medicine and Fertility Weill Medical College of Cornell University New York, New York, U.S.A.

Chapter 12

Stephanie A.M. Giannandrea, B.A. University of Rochester Medical Center Rochester, New York, U.S.A. Chapter 10

Tana A. Grady-Weliky, M.D. Department of Psychiatry University of Rochester School of Medicine and Dentistry Rochester, New York, U.S.A. Chapter 10

Ghassan Haddad, M.D. Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Cincinnati College of Medicine Cincinnati, Ohio, U.S.A. Chapters 9, 11

Jon C. Havelock, M.D. Pacific Centre for Reproductive Medicine

Burnaby, BC, Canada Chapter 15

Chapter 17

Peter Klatsky, M.D. Department of Obstetrics, Gynecology and Reproductive Sciences University of California, San Francisco San Francisco, California, U.S.A. Chapter 12

Lawrence C. Layman, M.D. Neurodevelopmental Biology Program Institute of Molecular Medicine and Genetics Medical College of Georgia Augusta, Georgia, U.S.A. Chapter 2

Richard S. Legro, M.D. Department of Obstetrics and Gynecology Pennsylvania State University College of Medicine Hershey, Pennsylvania, U.S.A. Chapter 6

Jeanne O’Brien, M.D.

Stephanya Shear, M.D.

Department of Urology University of Rochester Medical Center Rochester, New York, U.S.A.

Department of Urology University of Rochester Medical Center Rochester, New York, U.S.A.

Chapter 18

Chapter 18

William R. Phipps, M.D.

Jody Steinauer, M.D., M.A.S.

Department of Obstetrics and Gynecology University of Rochester Rochester, New York, U.S.A.

Department of Obstetrics, Gynecology and Reproductive Sciences University of California, San Francisco San Francisco, California, U.S.A.

Chapter 4

Sarah Prager, M.D. Department of Obstetrics and Gynecology University of Washington Seattle Washington, U.S.A. Chapter 7

John T. Queenan, Jr, M.D. Department of Obstetrics and Gynecology University of Rochester Medical Center Rochester, New York, U.S.A. Chapter 1

Sireesha Reddy, M.D. Department of Obstetrics and Gynecology University of Rochester Medical Center Rochester, New York, U.S.A. Chapter 8

Valerie Montgomery Rice, M.D. Department of Obstetrics and Gynecology School of Medicine Meharry Medical College Nashville, Tennessee, U.S.A. Chapter 13

Chapter 7

Shanna H. Swan, Ph.D. Department of Obstetrics and Gynecology University of Rochester School of Medicine and Dentistry Rochester, New York, U.S.A. Chapter 19

Michael A. Thomas, M.D. Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Cincinnati College of Medicine Cincinnati, Ohio, U.S.A. Chapter 9

Kim Thornton, M.D. Division of Reproductive Endocrinology and Infertility Beth Israel Deaconess Medical Center and Boston IVF Harvard Medical School Waltham, Massachusetts, U.S.A. Chapter 16

Sandra L. Torrente, M.D.

Daniel B. Williams, M.D.

Department of Obstetrics and Gynecology School of Medicine Meharry Medical College Nashville, Tennessee, U.S.A.

Department of Obstetrics and Gynecology Division of Reproductive Endocrinology University of Cincinnati College of Medicine Cincinnati, Ohio, U.S.A.

Chapter 13

Togas Tulandi, M.D. Department of Obstetrics and Gynecology McGill University Montreal, Quebec, Canada Chapter 14

Tiffany Von Wald, M.D. Division of Reproductive Endocrinology and Infertility Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts, U.S.A. Chapter 16

Chapter 11

Michael Wittenberger, M.D. National Institute of Child Health and Human Development Bethesda, Maryland, U.S.A. Chapter 3

Preface Reproductive Endocrinology and Infertility provides an overview of the most frequently encountered clinical challenges faced by medical students and residents. Part I begins with chapters on reproductive hormonal physiology and development to provide a basis for understanding the management of the most common reproductive clinical problems that confront obstetrician-gynecologists and other practitioners in women’s health. Several of the chapters, including obesity, premenstrual syndrome, menopause and imaging, provide a cross-disciplinary approach to endocrine related problems common among reproductive aged women. Part II includes chapters on the evaluation of infertility, as well as surgical and medical approaches to treating infertility in men and women. The chapter on alternative medicine provides a basis for understanding the increasingly popular use of therapies such as acupuncture and herbal treatments. The last chapter discusses the influence of environmental factors on fertility, an important field that is often ignored in the traditional approach to infertility. This text is meant to be used as a portable reference with readily accessible information including a summary of key points in each chapter. All of the contributors are involved in residency training programs and understand the kinds of patient management questions that are encountered in a busy practice. Our goal with this book is to provide information that will support solid patient management and hopefully pique the appetite to learn more. Vivian Lewis, M.D.

Acknowledgements I wish to extend many thanks to all of the contributors for their hard work. I am especially grateful to the authors who are current or recent trainees as their perspective is closest to the main target audience for this book. I would also like to thank Ron Landes and the staff at Landes Publication for their help and responsiveness. Finally, Anne Tedrow’s organizational skills were invaluable in helping to compile the submissions of the 33 authors featured in this volume.

Part I Reproductive Endocrinology

Chapter 1

The Menstrual Cycle John T. Queenan, Jr. Once a month the human endometrium exhibits a well-orchestrated, repeating cycle of proliferation, differentiation, death and renewal. Remarkably, the same cells programmed to slough within two weeks in the absence of a blastocyst are also able to nurture a gestation, if present, for 40 weeks. For implantation to occur, synchronization between the age of the embryo and the developmental stage of the endometrium is an absolute requirement. When functioning properly, the hypothalamic-pituitary-ovarian axis will coordinate the recruitment and selection of a dominant follicle while ordering endometrial preparation. Reproductive cycles begin at puberty as the hypothalamic pulse generator is activated and GnRH is secreted. Menstrual cycles are the most irregular during the 2 years after menarche and during the 3 years before menopause. Once a cyclic pattern is established, the menstrual cycle serves as a highly sensitive indicator of an intact hypothalamic pituitary ovarian (H-P-O) axis. To the clinician, the monthly cycle of endometrial degeneration and regeneration provides confirmation that the infertile patient has ovulatory cycles. Hypothalamic secretion of GnRH guides pituitary secretion of FSH and LH. The hypothalamus receives an enormous variety of signals and information. The interplay between the follicle and the CNS depends upon the ability of estrogen to transmit messages of positive and negative feedback. There are highly sensitive regions within the hypothalamus where estrogen can elicit feedback. Progesterone also exerts profound negative feedback on the hypothalamus. CNS neurotransmitters can exert their influence independent of sex steroids. Norepinephrine is stimulatory whereas dopamine, B-endorphins and other opioid peptides are inhibitory to the release of GnRH. The convergence of signals within the hypothalamus culminates in a pattern of pulsatile GnRH secretion.

GnRH Gonadotropin releasing hormone (GnRH) is a 10 amino acid peptide that is synthesized in the neuronal bodies of the arcuate nucleus of the medial basal hypothalamus and transported to the median eminence by neuroendocrine cell terminals. GnRH effluxes into capillaries and is transported from the hypothalamus to the pituitary through the portal circulation. GnRH binds to its receptor on the cell surface of the gonadotrophs. There, it activates adenylate cyclase and stimulates gonadotropin release. GnRH can stimulate the synthesis and release of both FSH and LH from the same cell. The variation in pulse frequency alters the ratio of FSH to LH. GnRH is secreted in a pulsatile manner; the amplitude and frequency of secretion vary throughout the cycle. In cell culture, pulsatile, rhythmic activity is an intrinsic property of individual GnRH neurons. A single or small group of GnRH Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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neurons may initiate a pulse and entrain other participating cells resulting in a neuroendocrine cascade. In the hypothalamus, the population of these neurons is termed 1 the GnRH pulse generator. If the frequency of GnRH pulses increases, there will be slight dominance of FSH over LH. This small, incremental FSH rise in the early follicular phase is sufficient to elicit follicular recruitment. One pulse every hour is typical of the follicular phase while one pulse every 2-3 hours is typical of the luteal phase. Normal gonadotropin secretion requires pulsatile GnRH discharge within a critical frequency and amplitude. Adequate FSH levels and LH pulses at approximately 60-90 minutes stimulate the normal growth of ovarian follicles. A slower frequency results in anovulation and amenorrhea. Follicles do not develop when the LH pulses decline to intervals of less than 2-3 hours. High, prolonged GnRH exposure saturates the GnRH receptors causing anovulation by down-regulation of the GnRH receptor and abolition of the gonadotropin response.

Follicular Phase Although the process of menstruation represents the endpoint of a previous cycle of endometrial changes, the first day of menstruation is the most recognizable point and is usually taken to mark the first day of an idealized 28 day menstrual cycle. On cycle day 1 menstruation arrives and a new cycle begins. During the follicular phase an orderly sequence of events takes place that ensures that the proper number of follicles is ready for ovulation. Folliculogenesis is a process that is initiated well prior to the arrival of menstruation. Once a primary follicle leaves the resting state it will take 85 days, or three complete menstrual cycles, to reach the point of ovulation. The follicle destined to ovulate is recruited in the first few days of the third cycle. It will measure 1-2 mm on cycle day 1. The first morphological evidence of maturation is differentiation of the granulosa cell layer and enlargement of the oocyte. Follicular recruitment will be driven by FSH secretion that started at the end of the luteal phase in the previous cycle. The demise of the corpus luteum at the end of the preceding cycle results in an abrupt decline in levels of progesterone, estrogen, and inhibin. FSH secretion is suppressed in the luteal phase by negative feedback from estrogen and progesterone. The sharp decline in these factors abolishes the negative feedback and allows FSH to rise shortly before and during menses. The increase in FSH at the luteal-follicular transition is responsible for follicle recruitment and initiation of steroidogenesis. Ovarian follicles may be found in four conditions: resting, growing, preovulatory or atretic. Once follicles leave the resting state, there are only two possible outcomes—ovulation or atresia—with atresia accounting for more than 99%. The primary oocyte, formed in fetal life, persists in prophase of the first meiotic division until the time of ovulation. Oocytes are stored in primordial follicles and protected for later use. This nongrowing group of follicles is termed the resting pool. Within the primordial follicle, the oocyte is sequestered in an immuno-privileged site. There are several layers of protection. Granulosa cells secrete the zona pellucida inward placing a mucopolysaccharide layer around the oocyte. Numerous cytoplasmic processes of the granulosa cells penetrate the zona pellucida presumably for respiration and nutrient exchange. A basal lamina separates the granulosa cells from the theca cells. Inflammatory cells are found within the ovarian cortex and stroma; however the oocyte is shielded from the influence of infection or hormones while it lies behind this barrier.

The Menstrual Cycle

5

Oocytes residing in the resting pool are probably under inhibitory control from autocrine factors. It is well documented that when oocytes are removed from resting follicles, they can spontaneously undergo nuclear maturation in vitro. This suggests 1 a release from local inhibitory factors. Such a strategy makes sense, as the limited supply of female gametes would be protected from influences that would render them unsuitable for future cycles. Folliculogenesis is continuous throughout life. Each day a cohort of follicles reaches 2-5 mm size and is either available to be further recruited by FSH or will undergo atresia. Thus, a cohort is always ready and continuously available for a response to FSH. Even without gonadotropin stimulation, some primordial follicles will leave the resting pool and develop into preantral follicles. This process occurs during times of anovulation (i.e., childhood, pregnancy, and OCP use) as well as during ovulatory cycles. The initial steps of follicular growth are independent of stimulation by pituitary hormones. Therefore the rate is unaffected by changes in the circulating gonadotropin or sex steroid hormone levels. The absence of gonadotropin stimulation will not prolong the total lifespan of oocytes, nor will excessive gonadotropin stimulation prematurely exhaust the oocyte supply. Primordial follicles are continuously undergoing an initial phase of growth and development that, in the vast majority of circumstances, will end in atresia. The gross wastage of follicles may be the necessary consequence of maintaining a constant supply of gonadotropin-sensitive follicles throughout each day of a woman’s reproductive life. This general pattern is interrupted when a group of follicles responds to a rise in FSH at cycle start and is propelled to further growth. Once they leave the resting pool they will establish contact with the circulatory system. Under the influence of FSH, the number of granulosa cells increases. As the FSH concentration rises there is a concomitant rise in estradiol receptors within the granulosa cells. Increasing estradiol levels within the follicle stimulate mitotic activity and increase the sensitivity to FSH. One of the major actions of FSH is the induction of granulosa cell aromatase activity. Little or no estrogen can be produced by FSH unprimed granulosa cells. FSH induces its own receptors and also increases activin, inhibin, and LH receptors. Activin is a potent FSH stimulator that will account for more FSH than does GnRH. Once the follicle acquires LH receptors and aromatase activity, ovarian androgens produced by the theca will be converted to estradiol. High local concentrations of estradiol enhance the follicular response to LH by working synergistically with FSH to induce LH receptors. Ovarian steroidogenesis is usually LH dependent. Folliculogenesis is thought to occur in four phases: recruitment, selection, dominance and ovulation. Recruitment takes place during cycle days 2, 3, and 4. The term recruitment indicates a cohort of quasi-synchronous follicles has entered a gonadotropin-dependent rapid growth phase. Overt connection of the follicular apparatus to the peripheral blood stream is coincident with onset of gonadotropindependent follicular growth. By cycle day 5 both menstrual flow and follicular recruitment end. In women, spontaneous multiple ovulation is atypical. Selection refers to the reduction of the cohort size down to the species-specific ovulatory quota. The dominant follicle is selected early when it develops LH receptors. LH stimulates androgen production in the theca. The dominant follicle uses androgen as a substrate and further accelerates estrogen output. Fluid accumulates amid the granulosa cell mass. The antrum is formed as the oocyte is displaced to one side by this process. Follicles

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at this stage measure 4-6 mm from the secretion of mucopolysaccharides by the granulosa layer, and the transudation of plasma proteins from the newly acquired 1 theca layer. By day 6 rising levels of estrogen in the bloodstream begin to cause peripheral effects. Estrogen first induces the lining of the uterus to proliferate and later promotes the secretion of thin, watery cervical mucus. The follicle destined to become dominant secretes the greatest amount of estradiol, which, in turn, increases the density of FSH receptors on the granulosa cell membrane. Rising peripheral estradiol levels result in negative feedback on FSH secretion. This withdraws the stimulus to the smaller follicles that have fewer FSH receptors. The nondominant follicles cease development and then become atretic. Selection marks the time when the influence of a single follicle creates an environment in which only it can adequately mature and reach ovulation. Peripheral levels of estradiol rise significantly by day 7 shortly after the process of selection of the dominant follicle has occurred. LH receptors are present on theca cells at all stages of the cycle and on granulosa cells after the follicle matures. While directing a decline in FSH levels the midfollicular rise in estradiol exerts a positive influence on LH. During the late follicular phase LH levels rise steadily stimulating androgen production in the theca. Usually one follicle reaches maturity and is ovulated while the remainder undergo atresia before the point of ovulation. The primary purpose of the other follicles is to deliver androgen substrate. Aromatase activity is highest in the preovulatory follicle thereby maintaining a high concentration of estradiol and a low concentration of androstenedione. In contrast the other follicles are FSH and aromatase deficient with a resultant predominance of androstenedione. After having served the purpose of acting as an endocrine gland, these follicles ultimately undergo atresia. By Day 8 selection ends and maturation begins. Normally, only one ovary sponsors recruitment. Once a dominant follicle is present, the opposite ovary could be removed without effect on the ensuing ovulation. This means that there is unambiguous ovarian asymmetry once the dominant follicle has been selected. The dominant ovarian follicle is the sole follicle destined to ovulate and somehow it continues to thrive in a milieu that it has helped to make inhospitable to others within its cohort. As the level of circulating estradiol rises, the plasma FSH falls back to basal levels (through negative feedback). The follicle reaches a state of gonadotropin independence. It is now self-sustaining and could continue to mature under the influence of only interfollicular FSH and estradiol. At this point in the cycle, rising levels of estradiol have induced endometrial proliferation. The lining which started at 1 mm will grow to a thickness of 8-10 mm. Ovarian hormones produce cyclic changes in all other parts of the female reproductive system. In the proliferative phase rising levels of estrogen promote secretion of thin watery mucus that permits the passage of spermatozoa into the uterus around the time of ovulation. By Day 11 estradiol is near its peak, and the lining has grown to maximal thickness. The follicle is near mature size at 16-20 mm. The final steps of oocyte maturation steps are completed on day 12. Having risen rapidly, estrogen levels reach a peak 24-36 hours before ovulation. The LH surge is preceded by an accelerated increase in serum estradiol levels. At nearly all times in the menstrual cycle, estradiol exerts a negative feedback effect. However, when estrogen levels exceed a critical threshold for a period of 2-3 days a change in the functional capacity of the gonadotrope occurs. There is a marked increase in sensitivity to GnRH and large amounts of gonadotropins are releasable

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from a reserve pool. Only at this time can an LH surge occur. The process of self-priming means the LH response to the second GnRH pulse is much greater than to the first. The rising progesterone levels seen at the late follicular phase fur- 1 ther augment the LH surge as well as initiating a small surge in FSH. The LH surge leads to resumption of oocyte maturation, luteinization of granulosa cells and the production of progesterone and prostaglandins. Shortly before ovulation the preovulatory follicle reaches a diameter of 20-25 mm. Elevation of a conical stigma on the surface of the protruding follicle precedes rupture. Proteolytic enzymes and prostaglandin participate in degradation of the follicular wall. The oocyte, zona pellucida and corona radiata will detach from the follicular wall and float in the antral fluid. As ovulation approaches, the blood supply to the ovary increases and the ligaments contract pulling the ovary closer to the fallopian tube. The late follicular increase in serum estradiol levels will elicit an abundance of clear fertile mucus secreted by the cervix. Prior to ovulation the oocyte enters telophase of the first meiotic division. Chromosomal reduction occurs by migration of one half of the oocyte chromosomes into the periphery of the cytoplasm. There the chromosomes are packaged into the first polar body and extruded from the cytoplasm. After expulsion of the first polar body the oocyte enters second meiotic division. It arrests at metaphase until fertilization occurs. Ovulation occurs 10-12 hours after the LH peak and 36 hours after the estradiol peak. The most reliable indicator for the timing of ovulation is the onset of the LH surge, which begins 28-32 hours before ovulation. When the mature follicle ruptures, the oocyte, zona pellucida, and corona radiata are expelled into the peritoneal cavity near the entrance to the tube. The second meiotic division of the oocyte is not completed until after penetration of the ovum by a spermatozoon.

Luteal Phase Fertilization takes place within the ampullary portion of the tube. Over the next two to three days the ovum remains unattached within the lumen as it is propelled toward the endometrial cavity by the ciliary action of the tubal epithelium. Movement of the ovum down the tube is aided by a current of fluid propelled by the action of the ciliated epithelium lining the tube. There is also propulsion from the gentle peristaltic action of the longitudinal and circular smooth muscle layers of the tube. The cervical mucus becomes highly viscid after ovulation and forms a plug that inhibits ascending entry of microorganisms from the vagina. The cervix functions to admit spermatozoa to the upper genital tract at a time when fertilization is opportune, but at other times, including pregnancy, to protect the normally sterile uterus and upper tract from bacterial invasion. These cyclic changes form the basis for the “natural’ forms of contraception that identify “the fertile period.” Immediately following ovulation, the ruptured follicle collapses, leaving behind a collapsed cyst lined by a thick layer of granulosa cells. It usually fills with a blood clot and redistends. With a sufficient number of LH receptors on the granulosa cells, LH acts directly on the granulosa cells to cause luteinization (formation of the corpus luteum) and the production of progesterone. The granulosa cells enlarge and increase their lipid content. Penetration of the basement membrane by blood vessels provides the LDL cholesterol that serves as the substrate for corpus luteum (CL) progesterone production. Large deposits of cholesterol arise from circulating lipoproteins (i.e., the yellow color) and support the high quantities of progesterone production. The blood clot and luteinized thecal and granulosa layers are invaded by capillaries to form a rich vascular network. The thecal layer acquires a blood supply that it did not contain

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during the entire follicular phase. This facilitates the massive progesterone secretion. The corpus luteum is the most active steroidogenic tissue in humans, but in the ab1 sence of pregnancy it has a finite lifespan of 12-16 days. After ovulation the GnRH pulse generator is slowed for the luteal phase. LH, FSH and estradiol levels fall but some LH is essential to maintain CL function. The accumulation of LH receptors during the follicular phase sets the stage for the extent of luteinization and the functional capacity of the corpus luteum. Normal luteal function requires optimal preovulatory follicular development and continued tonic LH stimulation. A defective luteal phase can contribute to infertility and early pregnancy wastage. Maintenance of the corpus luteum is normally dependent on pulsatile gonadotropin secretion, but endogenous (from a pregnancy) or exogenous hCG can serve the same purpose. The onset of the LH surge (28-32 h prior to ovulation) is the most reliable clinical indicator for the timing of ovulation. Progesterone is thermogenic so core body temperature rises by about 0.6˚F until 2 days before the next period in nonconception cycles. If implantation does not occur, LH and FSH return to basal levels and their receptor numbers are reduced leading to a marked decline in the progesterone and estradiol synthesis. Without the continued stimulus of LH, the corpus luteum cannot be maintained and 12-14 days after ovulation it regresses to form the functionless corpus albicans. Regression of the corpus luteum appears to involve the luteolytic action of its own estrogen production, mediated by an alteration in local prostaglandin production. Initiation of a new cycle is dependent on regression of the corpus luteum. Reactivation of the GnRH system results from the withdrawal of the inhibitory effects of corpus luteum steroids and inhibin. Released from the negative feedback effects, the GnRH pulses begin to accelerate leading to a rise in FSH levels that occurs two days before the onset of menses.

The Endometrium: Proliferative and Secretory Phases After menses the endometrium consists of simple tubular glands set within a vascular, cellular stroma. During the proliferative phase of the menstrual cycle, the glands are small, straight and round when seen in cross section. The endometrium is the primary target (organ) for ovarian steroids. Under the influence of estrogen, the glands multiply and their epithelium becomes taller and pseudostratified, during the follicular phase of the cycle. After ovulation, the onset of the secretory phase is signaled by the appearance of subnuclear vacuoles of glycogen which are evident in the endometrial glands by day 16. These start to migrate toward the lumen by day 17 although the majority are still subnuclear. By day 19 glycogen vacuoles are being extruded from the luminal edge of the cell. Meanwhile, after 2-3 days of tubal transport, the embryo enters the uterine cavity on day 17. It will not attach to the uterine epithelium for 2 to 3 days. On day 18-19, it hatches from the zona pellucida in preparation for attachment. There is a narrow window of receptivity to blastocyst implantation that corresponds to the period between cycle days 20 and 24 in a 28 day cycle. Peak levels of progesterone are seen at 8-9 days after ovulation, which approximates the time of implantation of the embryo. At that time, the endometrium has sufficient depth, vascularity, and nutritional richness to sustain placentation. While the endometrium is acquiring its receptivity, the embryo is acquiring its invasiveness. On day 21 the embryo attaches to the uterine epithelium. The peak of interglandular glycogen secretion coincides with the time of implantation of the free

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blastocyst. Day 22 marks the peak in estradiol and progesterone levels for the luteal phase. The embryo has initiated invasion into the lining. A portion of the cytotrophoblast population differentiates into a syncytiotrophoblast that synthesizes large 1 amounts of hCG. HCG serves to “rescue” the corpus luteum and maintains luteal function with secretion of progesterone until placental steroidogenesis is established. By midsecretory phase, progesterone is abundant and intraglandular glycogen secretion reaches a peak. Stromal edema and spiral artery development reach a peak on day 22 or 23 in response to progesterone. Decidualization is seen as nuclei enlarge, and cytoplasm becomes very eosinophilic. It begins as a periarteriolar blush of cuffing around the spiral arterioles on day 23. By day 24 the embryo has completely penetrated the endometrial lining and by Day 25 syncytiotrophoblast cells are secreting HCG in amounts that stimulate the corpus luteum to continue to produce progesterone. The wave of decidualization proliferates and will reach a state of confluence by day 26. Decidualization occurs only when the endometrium is sequentially exposed to estrogenic priming followed by progesterone stimulation. Without embryo implantation, decreasing steroid levels lead to increased coiling and constriction of the spiral arteries which supply the upper 2/3 of the functional endometrium. The decreased blood flow to the functional portion of the endometrium furthers the process of ischemia and degradation. Fibrin thrombi begin to occupy endometrial capillaries of premenstrual endometrium. Obstructed vessels lead to increases in hydrostatic pressure. By day 28, the endometrium contains tortuous glands that are fragmented. The stroma consists of dark necrotic fragments. Free hemorrhage is present throughout the tissue. Menstrual bleeding is controlled by vasoconstriction of the ruptured basal arteries in the denuded basal layer. The basalis layer remains intact after menstruation and a new lining is regenerated from this layer. Within 2 days of the onset of menses the surface epithelium begins to regenerate under the influence of estrogen and continues this process while the endometrium is still shedding.

Key Points Events from hypothalamus, pituitary ovary and uterus are integrated via the interaction among GnRH, gonadotropins, HCG and the sex steroids. Embryonic implantation is the culmination of a highly complex sequence of tightly regulated events. Estrogen and progesterone have a central role in directing the changes that facilitate implantation. Embryo quality and endometrial development are the two main determinants of successful nidation. The HPO axis is structured to enable these two determinants to function synchronously. In the absence of pregnancy, the cycle is programmed to slough the endometrium and begin anew.

Suggested Reading 1. Queenan Jr JT, Fazleabas A. Embryo-uterine interactions during implantation. In: Seibel MM, ed. Infertility: A Comprehensive Text. Stamford: Appleton and Lange, 1997:671-685. 2. Mutter GL, Ferenczy A. Anatomy and histology of the uterine corpus. In: Kurman RJ, ed. Blaustein’s Pathology of the Female Genital Tract. 5th ed. New York City: Springer-Verlag, 2002:383-420. 3. Bulun SE, Adashi EY. The physiology and pathology of the female reproductive axis. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. Philadelphia: WB Saunders, 2003:587-663. 4. Clement PB. Anatomy and histology of the ovary. In: Kurman RJ, ed. Blaustein’s Pathology of the Female Genital Tract. 5th ed. New York City: Springer-Verlag, 2002:649-674.

Chapter 2

Puberty and Its Disorders Adelina M. Emmi and Lawrence C. Layman

Normal Puberty Physiology Somatic Changes Normal puberty is a progression of events in both girls and boys that is generally complete in 3-4 years. In females, thelarche (breast buds) is usually the first sign of estrogen production and occurs at an average age of 10.5 years, while pubarche (pubic hair growth) generally occurs about 6 months later. In 10-20% of girls, pubarche is the first event. These are estimates; thelarche varies slightly among different racial groups (white: 10.4 years; black: 9.5 years; Mexican/American: 9.8 years). Tanner Stages are used to classify the stages of puberty in both boys and girls (Table 2.1). Tanner Stage 1 is prepubertal, while Stage 5 is the fully mature adult status. Peak growth rate for girls generally is seen at Tanner Stage 3 breast development. Adrenarche is the result of adrenal androgen production (androstenedione, DHEA, and particularly DHEAS), which begins prior to changes in gonadotropin secretion at 6-8 years of age and continues through the mid-teens. During female puberty, growth in height occurs at a rate of 4-5 cm/year in early puberty. As estrogen production increases, growth hormone increases, resulting in increased IGF-1 and IGFBP-3, which mediates skeletal growth. Maximal growth velocity occurs in girls at age 12 and usually results in about a 9 cm increase in height. Menarche (initiation of menses) occurs on the downward arm of the growth curve at a median age of 12.5 years (white: 12.6 years; black: 12.15 years; Mexican/ American: 12.3 years). A variety of additional factors affect pubertal onset, such as weight, stress, and extreme physical activity. Some authors have noted a younger age of onset of breast development and possibly menarche in African-American girls that may be attributable to a greater BMI. In boys the initial pubertal event is testicular growth, which begins at about 10.5 years of age. When the testes exceed 2.5 cm in any dimension, the onset of puberty is approaching. Pubarche frequently starts simultaneously with testicular development. Axillary hair growth occurs at about the time of peak height velocity (about age 14 years in boys and 12 in girls) (Table 2.2).

Endocrinology of Puberty The GnRH pulse generator is the principal regulator of puberty through its control of pituitary gonadotropins and is active early in life. As a result, gonadotropin levels change throughout fetal development, childhood, puberty and adulthood. Gonadotropins begin to rise at 10 weeks gestation, peak at

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Table 2.1. Tanner staging in females with approximate ages in parentheses Tanner Stages Stage 1 (prepubertal) Stage 2 Stage 3

Stage 4 Stage 5

Breast nipple elevation only

Pubic Hair no pubic hair

breast budding (9.5)

sparse growth, most on labia majora (10.5) coarser, spread to mons (11.5)

increases in gland tissue, no separation of breast from areola (11) areola forms separate mound from breast (12) areola recedes to single breast contour (14)

adult type-limited growth (12) adult type-extends to medial thigh (13.5)

mid-gestation and decline at term because of negative feedback from placental steroids. At birth, there is a withdrawal of gestational steroids, which leads to a rise in FSH and LH with a subsequent decline which is sex specific. Girls tend to have a higher FSH to LH ratio at all times compared to boys, and their gonadotropin levels decline over a 2 to 4 year period. This early neonatal gonadotropin elevation may be significant enough to cause estradiol production and transient breast development in girls or result in testosterone production in boys. Thereafter, gonadotropin levels decline over about a 6-month period in boys. During childhood gonadotropins remain low in both sexes until puberty. Typically, prepubertal gonadotropins tend to exhibit a ratio of LH/FSH that is less than one. Gonadotropins begin to rise by age 9 years, first FSH, then LH. These increases are a reflection of the increasing pulse frequency of GnRH from the pulse generator. The exact central inhibitor of GnRH until this age is unclear. Slower GnRH pulse frequency tends to lead to the preferential secretion of FSH, while faster pulse frequency favors LH secretion. Initially LH pulses are nocturnal, but then become apparent throughout the day and result in gonadal steroid production. Maturation of the hypothalamic-pituitary-gonadal (H-P-G) axis with positive and negative feedback by gonadal steroids and inhibition by inhibin occurs around midpuberty and culminates in menstruation. However, a fully mature H-P-G axis in the female is usually operative within the first two years of menarche with regular ovulatory cycles.

Table 2.2. Usual order of pubertal events in males and females Females Thelarche Pubarche Maximal growth velocity Menarche Adult pubic hair Adult breast

Males Testicular growth Pubarche Maximal growth velocity

2

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In boys, two Sertoli cell proteins, inhibin B and antimullerian hormone (AMH)/ mullerian inhibiting substance (MIS), are produced in the early neonatal period. Inhibin B (human males have minimal inhibin A) increases soon after birth and 2 peaks at 4-12 months of age, declines to low levels by ages 3-9, and then increases again with the onset of puberty (at lower levels than the neonate). AMH/MIS is evident in the first month of life and peaks about 6 months of age, drops during childhood, and becomes very low with puberty, probably secondary to increased testosterone inhibition. These hormones are useful markers of testicular function in early childhood.

Abnormalities of Puberty Precocious Puberty Definitions and Etiology Precocious puberty is defined as the onset of puberty before the age of 8 in girls and age 9 in boys. These ages are 2.5 standard deviations below the mean age of puberty in North American children. This disorder is five times more common in girls than boys. It is classified as either central (GnRH-dependent) or peripheral (GnRH-independent) depending on whether the inciting event has activated the H-P-G axis. In central precocious puberty (CPP), activation of the hypothalamicpituitary axis occurs, leading to premature sexual development that typically follows the normal pattern of puberty except that it is early. In peripheral precocious puberty (PPP), steroid production is independent of activation of the central axis, as is the case in gonadal or adrenal tumors or McCune-Albright syndrome. Precocious puberty is often idiopathic, especially in girls, however, a work-up is indicated in order to rule out significant pathology. If left untreated, final adult height will be compromised because of steroid-induced premature closure of the epiphyses. These children have normal reproductive function and do not appear to be at risk for premature menopause. Psychosocial issues should also be addressed because other aspects of development correspond with chronological age. In addition, more benign variants, premature thelarche and premature pubarche, may also occur.

Diagnosis of Precocious Puberty Precocious puberty may result in a decrease of final adult height; so arresting the growth is an important objective. The history and physical exam are extremely important as are growth charts. A skeletal film of the hand for bone age is very important in assessing the severity of the disorder and need for treatment (Fig. 2.1). Premature thelarche may occur in girls 1-2 years old because of the GnRH pulse generator activity. Normally, this will not result in advanced growth and the bone age is consistent with chronologic age. No treatment is necessary, even though some girls may have follicular activity on ultrasound. Premature adrenarche without other signs of puberty is also a benign process, and if the bone age is normal, these patients can be followed expectantly. Patients with premature adrenarche tend to be taller and heavier than other children their age. These patients may be at risk for polycystic ovary syndrome in the future. If they have hirsutism, serum levels of total testosterone, DHEAS, and 17-hydroxyprogesterone may be indicated. If markedly elevated androgens are present or there is evidence of virilization, adrenal or ovarian neoplasms and congenital adrenal hyperplasia should be excluded as in peripheral precocious puberty (Fig. 2.1).

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2

Figure 2.1. An algorithm that can be used as a guide in the diagnosis of precocious puberty (PP). T, testosterone; DHEAS, dehydroepiandrosterone sulfate; 17OHP, 17-hydroxyprogesterone; US, ultrasound; MAS, McCune-Albright syndrome.

For children who develop breasts and have pubic hair suggesting precocious puberty, the history and physical examination including height, weight, Tanner staging, signs of virilization and estrogenization, thyroid exam, and a thorough neurological exam should be performed. A bone age will demonstrate accelerated growth compared to chronological age (for example, if the bone age for a 5-year old is 8 years). A CT or MRI is usually necessary to exclude a CNS tumor in patients with central or peripheral precocious puberty. In particular, patients with precocious puberty who have a rapid course of progression or who have CNS signs should have an MRI of the brain to exclude a tumor. A “GnRH stimulation test” is useful to determine if CPP or PPP is present. A LH response greater than FSH response indicates a central cause, while a primarily FSH response suggests a peripheral, or GnRH-independent cause. Since native GnRH is not available for these tests, a GnRH-agonist such as leuprolide acetate can be used at a dose of 20 μg/kg S.Q. FSH and LH levels should be drawn at baseline (before agonist administration) and every 15 minutes for 1 hour thereafter. If the LH/FSH ratio exceeds 1 or the maximum level of LH exceeds ~7 mIU/mL (cutoff value should be determined for your own lab), then the etiology is central (mediated through the H-P-G axis). It has also been suggested that if an immunofluorometric LH assay is used, a single unstimulated LH value >0.6 mIU/mL may eliminate the need for a “GnRH stimulation test” (remember there is lab variability and this cutoff level should be determined in your lab). Ovarian volume may also be increased in patients with CPP.

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In patients who do not have evidence of a central cause, ovarian ultrasound or adrenal CT may be helpful to evaluate the presence of a neoplasm. For boys, testicular palpation may indicate a mass needing biopsy. Thyroid studies (TSH and 2 total T4), prolactin, estradiol, DHEAS, testosterone, estradiol, and hCG levels should be considered.

Causes and Treatment of Precocious Puberty Central Precocious Puberty A number of factors can activate the hypothalamic production of GnRH, leading to stimulation of pituitary gonadotrophs and gonadal steroid production. Tumors can impinge on inhibitory neurons causing increased secretion of GnRH. A suspected malignancy should be followed by biopsy for identification. Benign tumors, such as hamartomas (hyperplastic malformations of the tuber cinerum which elaborate GnRH), can be successfully treated with GnRH agonist therapy. Long standing hypothyroidism can cause central precocity (usually associated with retarded bone age). Treatment will curtail symptoms. A careful history may illicit a previous history of an infectious process (i.e., meningitis), trauma, radiation, or developmental abnormalities (hydrocephalus). Ectopic gonadotropin production by tumors accounts for less than 0.5% of the causes of central precocity. The most common of these tumors include chorioepithelioma, dysgerminoma, and hepatoblastomas. Therapy is directed toward arresting further sexual development and skeletal growth. GnRH agonist therapy has become the standard for children with central precocious puberty. The depot form of leuprolide acetate is given at a dose of 300 μg/kg every four weeks. Be aware that 7.5 mg or more may be necessary for treatment in some children rather than the standard 3.75 mg dose. Therapy with leuprolide is continued until an age agreed upon by the patient, family, and the physician, usually 11-12 years of age. Adequate suppression of the H-P-G axis should be assessed by drawing an LH level by a standard GnRH agonist test or by a single LH value 2 hours after a dose of GnRH agonist. The maximal LH should be suppressed to less than 2-5 mIU/mL depending upon the assay used, although most suggest 200 ng/ dL) or DHEAS (>2 times the upper limits of the assay) to assess for ovarian or adrenal virilizing neoplasm; however these conditions are exceedingly rare. Usually the clinical picture suggesting tumors is one of rapid onset of androgen excess and virilization. Cushing’s syndrome is also a rare cause of androgen excess. The clinical picture in this case would likely include hypertension, abdominal striae and easy bruising. Round facial appearance with facial plethora, buffalo hump fat distribution, and centripetal obesity are also features of the syndrome. Ovarian ultrasound to assess for polycystic morphology of the ovaries is neither necessary nor conclusive for diagnosis, but can be confirmatory if the clinical picture is supportive (see Fig. 5.1).

Impact of Obesity It is generally recognized that obesity, although not a defining feature of the syndrome, is highly prevalent in PCOS. Most studies in the United States report higher incidences of obesity (upward of 50%) than those of other countries. There is variable ethnic distribution of obesity in PCOS as well.

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Obesity is overall highly prevalent in most developed countries, and the rate of obesity is growing rapidly. Insulin resistance, a feature seen independently of body weight in PCOS, is almost universally noted with obesity. As noted previously, insulin resistance, in association with obesity, will worsen the clinical presentation of PCOS. Numerous studies demonstrate worse androgen profile and more severe menstrual disturbances in obese subjects with PCOS compared to their lean counterparts. Response to treatment may also be adversely impacted by obesity.

Metabolic Complications Although PCOS often presents in the early reproductive years, it is now recognized that the consequences of PCOS extend beyond the reproductive axis and the reproductive years. Women with PCOS appear to be at substantial risk of developing diabetes and cardiovascular disease. Several studies indicate that the risk of metabolic syndrome in PCOS is approximately 50% in young adulthood. Metabolic syndrome is a constellation of metabolic risk factors that increase the risk of cardiovascular events 2-fold. For women, these include increased abdominal waist circumference (>88 cm), elevated triglycerides (≥ 150 mg/dL), reduced HDL (40. In clinical terms, a BMI >40 correlates to being overweight by 100 lbs in men and 80 lbs in women. Looking to the future, the number of teenagers (age 12-19) classified as overweight increased from 10.5% to 15.5% from 1999-2000, according to the CDC. This trend reinforces the need for obesity to be treated as a public health issue. The increased health risks of obesity include hypertension, elevated serum cholesterol and death related to cardiovascular diseases as well as diabetes, gallbladder disease, osteoarthritis, carpal tunnel, sleep apnea, respiratory problems and endometrial, breast and colon cancers. Specific to the obstetrician/gynecologist, obesity is associated with both increased gynecological and obstetrical morbidity. Major gynecological problems include abnormal uterine bleeding, ovulatory dysfunction and endometrial cancer. Adult weight gain is associated with increased risk for breast cancer in postmenopausal women. An overweight individual undergoing surgery has an increased risk of excess blood loss, increased operating time and longer exposure to anesthesia and infection. Obesity in pregnancy increases the risk of gestational hypertension, preeclampsia gestational diabetes, fetal macrosomia and cesarean delivery. Obesity is an independent risk factor for spontaneous abortion and pregnancy loss among women who undergo infertility treatment, as well as among natural conceptions. Thus, weight should be assessed at every annual gynecologic exam and during reproductive health counseling. It is estimated that 300,000 US adults die of obesity-related causes and the direct cost of obesity and physical inactivity have been estimated at 9.4% of the U.S. healthcare expenditures. Thus as a major cause of preventable death, obesity is a significant public health challenge. The U.S. Preventative Services Task Force issued recommendation of screening for obesity in 2003. The recommendations were to screen all adult patients for obesity and offer intensive counseling and behavioral intervention to promote sustained weight loss for obese adults. Obesity needs to be recognized as a chronic disease, and the patient, as well as practitioner, need to understand that successful treatment requires a lifelong effort.

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Assessment The diagnosis and classification of obesity has come to focus on the evaluation of the body mass index, (BMI). BMI is a practical approach for assessing body fat in a clinical setting. The BMI provides a more accurate measurement of total body fat compared with assessment by weight alone. However, the BMI can be an overestimation of adiposity in persons of short stature or who are very muscular, and an underestimation in persons who have lost muscle mass. BMI disregards gender, age, and ethnicity, but these factors do not markedly influence the validity of BMI for classifying individuals into broad categories of overweight and obesity. Overweight 6 is categorized by a BMI of 25-29.9 kg/m2 and obesity as BMI ≥ 30 kg/m2. The BMI can quickly be determined by using a BMI table or calculated by multiplying weight in lbs. by 703 and dividing by height in inches, squared, which gives a BMI as kg/ m2. There are two physical classifications of body fat distribution; gynecoid and android. Gynecoid is usually seen in women of reproductive age and has a more favorable prognosis. Gynecoid describes a “pear-shaped” distribution where the fat is concentrated on the hips and buttocks. Android type is more common in menopausal women as fat is redistributed to the trunk and abdomen, “apple-shaped”. The waist: hip ratio is >0.8. The android type is associated with increased complications from obesity. Assessment of associated risk for obesity-related diseases and mortality includes determination of degree of obesity and overall health status. Three factors are involved in assessment. 1. BMI 2. Waist circumference. Waist circumference has been found to be an independent risk factor for disease and is a good evaluation of those categorized as normal or overweight. A waist circumference >40 in for men and 35 in for women is associated with an increased risk of diabetes, dyslipidemia and cardiovascular disease secondary to excess abdominal fat. 3. Overall medical risk. High absolute risk of mortality occurs when there is coexisting heart disease or other atherosclerotic disease, type 2 diabetes mellitus, sleep apnea, hypertension, cigarette smoking, high LDL cholesterol, impaired fasting glucose (>110-125), family history of early cardiovascular disease or age ≥55 in women, or postmenopausal status. Obesity is also associated with a greater risk of several non-lethal conditions including: osteoarthritis, gallstones, stress incontinence and menstrual disturbances.

Metabolic Syndrome Metabolic syndrome is a clustering of risk factors for cardiovascular disease. The Expert Panel on the Detection, Evaluation, and Treatment on High Blood Cholesterol in Adults (Adult Treatment Panel III) defines the syndrome as three or more of the following criteria: 1. Abdominal obesity: waist circumference >102 cm in men and >88 cm in women; 2. Hypertriglyceridemia: ≥150 mg/dl; 3. Decreased high-density lipoprotein (HDL) cholesterol: 27 with concomitant obesity-related risk factors or diseases. The amount of extra weight loss attributed to these agents is less than 5 kilograms at 1 year evaluation. Thus, the major role of medications is to help the patient comply with their diet and physical activity plans while losing weight. The use of long term medication to aid in the treatment of obesity may be indicated for carefully selected patients to prevent the weight regain often seen after weight loss, but there are no guidelines for how long a weight loss drug should be continued. Initially, if a patient has not lost 2 kg after 4 6 weeks on a medication, it is not likely that the patient will benefit from the drug.

Categories of Weight Loss Drugs Appetite Suppressants These agents decrease food intake by reducing appetite or increasing satiety. The mechanisms of action are to increase secretion of dopamine, norepinephrine, or serotonin into the synaptic neural cleft, to inhibit the reuptake of these neurotransmitters into the neuron or a combination of the two effects. There are three classes of anorexiant drugs, and all affect neurotransmitters in the brain. 1. Affect catecholamines: dopamine and norepinephrine. These noradrenergic agents are useful for short term treatment and include the drugs phenteremine, diethylpropion, phendimetrazine and benzphetamine. Stimulants act via catecholamine neurotransmitters, such as amphetamines and phenylpropanolamine. Phenylpropanolamine, which was an over-the-counter medication, was removed secondary to an association with hemorrhagic stroke. Side effects of this class of medications include insomnia, dry mouth, constipation, euphoria, palpitations and hypertension. 2. Affect serotonergic: Fenfluramine and dexfenfluramine are included in this class. These medications have been associated with valvular heart disease and pulmonary hypertension. In 1997, the “Phen/fen” combination was withdrawn from the market after reports of valvopathy after as little as one month’s use of this medication. The mechanism apparently involves serotonin stimulation of fibroblast growth and fibrogenesis. 3. Affect more than one neurotransmitter. Sibutramine (Meridia) is an appetite suppressant that works via norepi and serotonergic mechanisms in the brain (Fig. 6.1). Side effects include tachycardia and hypertension. The newly discovered endocannabinoid (EC) system and cannabinoid CB1 receptor play an important role in appetite and energy regulation and offer a novel target for a new class of anti-obesity drugs. Rimonabant, the first specific CB1-receptor blocker to enter clinical development, has been shown to reduce food intake and body weight in treated animals, and there are also beneficial effects in the adipocyte. The results of phase 3 studies involving obese patients have shown that rimonabant induces significant weight loss and improves metabolic risk factors for diabetes and cardiovascular disease. It is anticipated that this drug will be available in the near future for the treatment of obesity in the U.S. Common side effects in preclinical studies included depression, anxiety, and nausea. Certainly, close monitoring for side effects with any weight loss medication is necessary. Several randomized controlled studies of weight loss medications have been performed, but questions remain concerning long-term effects on health, the

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Figure 6.1. Mechanisms of action of sibtramine. Adapted from: Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002; 346(8):591-602.

optimal duration of treatment, and the use of combination regimens including polypharmacy and combination with lifestyle interventions.

Decrease Nutrient Absorption Orlistat (Xenical) binds GI lipases in the lumen of gut, which prevents hydrolysis of dietary fat (triglycerides) into absorbable free fatty acids and monoacylglycerols (Fig. 6.2). Orlistat is an irreversible lipase inhibitor and thus decreases the amount of ingested dietary fat that is absorbed Side effects of this medication include decreased absorption of fat-soluble vitamins and nutrients, flatulence, fecal urgency and incontinence, steatorrhea, oily spotting and increased frequency of defecation.

Other Medications and Herbal Supplements Many agents have as an unintended side effect weight loss. These include metformin, a biguanide used to treat type 2 diabetes, acarbose, an alpha-glucosidase inhibitor also used to treat type 2 diabetes, and topiramate an anti-epileptic drug. It should be noted that these agents do not have an FDA indication for the treatment of obesity and trials, including those specifically in some cases designed as weight loss trials have shown a lack of efficacy or an unfavorable risk benefit ratio. Therefore their use can not be routinely recommended. Dietary supplements and herbal preparations are not prospectively reviewed by the FDA for safety or efficacy. These agents are only reviewed if they are shown to present a “significant or unreasonable risk”, as has been the case with ephedra supplements. Herbals and supplements include chitosan, chromium picolinate, conjugated linoleic acid, ephedra alkaloids (ma huang) and garcinia cambogia. There is insufficient data on these agents except for ephedra alkaloids and caffeine, which do have randomized, controlled trials that indicate efficacy in promoting weight loss. Chromium picolinate, an essential trace mineral and cofactor to insulin, which improves insulin action and is available as an over the counter supplement. A meta-analysis of 10 double-blind randomized clinical trials with this supplement found a relatively small weight reduction of 1.1-1.2 kg (0.08-0.2 kg/wk) compared with placebo during a treatment period of 6-14 wk in patients with an average BMI of 28-33, without any appreciable side effects. Thus the risk benefit ratio for weight loss appears as favorable, if not more so, than with other herbal or pharmacologic medications.

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Figure 6.2. Mechanisms of action of orlistat. Adapted from: Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002; 346(8):591-602.

Surgery Bariatric surgery is currently the most successful approach to rescuing patients with severe obesity and reversing or preventing the development of several diseases associated with obesity. There are an increasing number of surgeries being performed for the treatment of obesity. This rise in procedures can be attributed to the increased population of “extreme obesity” as well as the failure of diet, exercise and medical therapies. Another factor could be the ability to perform the surgery laproscopically. Surgery can be an additional treatment option for patients with a BMI >40 who failed lifestyle changes with or without medication supplementation and have obesity-related comorbid conditions. Surgery alone will not correct any underlying psychological eating disorders. Additionally, reduction of cardiovascular morbidity and mortality does not occur due to weight loss through surgery alone. The Swedish Obese Subjects (SOS) Study, which was an observational study, did show that the average long term weight loss for the surgical patient is 20 kg, versus, no change for those using medical treatment. The SOS study was also able to demonstrate improvements in or prevention of comorbid conditions associated with

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obesity when compared with similar patients undergoing medical therapy. In a 24-month follow-up evaluation, there was a decreased incidence in hypertension, diabetes and lipid abnormalities, but by 8 years, only a decrease in diabetes was noted. Another notable finding was a decreased caloric intake and greater physical activity in surgery vs. control patients throughout the follow-up period. Different surgical procedures are available to treat obesity (Fig. 6.3), and have evolved since the first bariatric surgery performed in the 1950s with the introduction of the jejunoileal bypass and subsequently the gastric bypass in 1967. 1. Roux-en-Y gastric bypass (RYGB) limits gastric capacity and causes mild 6 malabsorption. This procedure involves the construction of a proximal gastric pouch whose outlet is a Y-shaped limb of small bowel of varying lengths. The proximal stomach is separated from the remaining portion of the stomach with staples. 2. Biliopancreatic bypass combines a limited gastrectomy with a long Roux limb intestinal bypass, works primarily through malabsorption. 3. Laparoscopic adjustable gastric band is placed around the upper-most portion of the stomach and restricts capacity, usually less than 30 ml in volume. There is restricted passage to the subsequent part of the stomach, leading to weight loss by decreased dietary intake. The band can be adjusted by the infusion of saline through a subcutaneous port. 4. Vertical banded gastroplasty involves stapling the upper stomach to limit gastric capacity. There is a larger weight loss after gastric bypass compared with other types of surgery, and this may be related to altered gut-to-brain signaling. Surgery is not without risks however. Among surgeons, there is a learning curve in which those with fewer than 20 procedures had a 5% mortality rate, as compared with greater than 50 had a near zero mortality. The length of surgery also stabilized after 150 cases. Complications also decreased from 12.5% for fewer than 100 cases, to 3% after 150 cases. Such complications include anastomotic leak, subphrenic abscess, splenic injury, pulmonary embolism, wound infection and stoma stenosis. Perioperative mortality is influenced by age; in a young patient with a BMI 60 and comorbidities such as diabetes, hypertension, or cardiovascular disease, the mortality jumped to 2-4%. Women of reproductive age who have undergone bariatric surgery require counseling and management of subsequent pregnancies. Patients with adjustable gastric banding should be advised that they are at risk of becoming pregnant unexpectedly after weight loss following surgery. All patients are advised to delay pregnancy for 12-18 months after surgery to avoid pregnancy during the rapid weight loss phase in order to avoid malnutrition and small-for-dates features in the neonate. After restrictive procedures (where iron containing foods such as red meat may be poorly tolerated) increased iron is needed. After gastric bypass procedures (in which the duodenum—where most iron is absorbed—is bypassed) increased iron must be taken during pregnancy to allow adequate absorption in the proximal jejunum. Furthermore, adequate calcium intake or supplementation should be verified. Women with a gastric band should be monitored by their general surgeons during pregnancy because adjustment of the band may be necessary. Women who have undergone bypass surgery do not appear to be at undue risk for adverse pregnancy outcomes, and initial results from larger case series have been promising.

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Figure 6.3. Types of bariatric surgical procedures.

Key Points Obesity is a serious and prevalent disorder whose effective management requires ongoing care and a lifetime commitment. The increased prevalence of obesity in children and adolescents indicates the urgent need to implement effective preventative interventions, beginning early in life, to improve dietary habits and increase physical activity. Medications can be an adjunct only for those at

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substantial medical risk and in whom nonpharmacologic treatment has not resulted in sufficient weight loss to improve health or prevent regain. Surgery is becoming a viable option for the long-term success of maintained weight loss but still requires a commitment to behavioral changes and nutrition education.

Acknowledgements This work was supported by PHS K24 HD01476, a GCRC grant MO1 RR 10732 to Pennsylvania State University and K24 HD01476.

6

Suggested Reading 1. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002; 346(8):591-602, [This is an excellent review article of the treatment of obesity]. 2. Mokdad AH, Ford ES, Bowman BA et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003; 289(1):76-9. 3. North American Association for the Study of Obesity and the National Heart, Lung, and Blood Institute. The practical guide: Identification, evaluation, and treatment of overweight and obesity in adults. Bethesda, MD: National Institutes of Health, 2000, (Report No.: 00-4084), [This is an evidence based and very practical guide for the diagnosis and management of obesity and was central to the preparation of this chapter]. 4. Hu FB. Overweight and obesity in women: Health risks and consequences. J Womens Health 2003; 12(2):163-72. 5. Colditz GA. Economic costs of obesity and inactivity. Med Sci Sports Exerc 1999; 31(11 Suppl):S663-7. 6. McTigue KM, Harris R, Hemphill B et al. Screening and interventions for obesity in adults: Summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2003; 139(11):933-49. 7. Executive summary of the third report of the national cholesterol education program (ncep) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel iii). JAMA 2001; 285(19):2486-97. 8. Ehrmann DA, Liljenquist DR, Kasza K et al. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab 2005. 9. Epstein LH, Valoski A, Wing RR et al. Ten-year outcomes of behavioral family-based treatment for childhood obesity. Health Psychology 1994; 13(5):373-83. 10. Snow V, Barry P, Fitterman N et al. Pharmacologic and surgical management of obesity in primary care: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2005; 142(7):525-31. 11. Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353(20):2121-34. 12. Li Z, Maglione M, Tu W et al. Meta-analysis: Pharmacologic treatment of obesity. Ann Intern Med 2005; 142(7):532-46. 13. Pittler MH, Stevinson C, Ernst E. Chromium picolinate for reducing body weight: Meta-analysis of randomized trials. Int J Obes Relat Metab Disord 2003; 27(4):522-9. 14. Sjostrom L, Lindroos AK, Peltonen M et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351(26):2683-93, [This is the best and longest longitudinal study of a cohort of obese patients, some receiving bariatric surgery and some medical therapy. The long term outcomes for medical therapy are poor compared to bariatric surgery]. 15. Buchwald H, Avidor Y, Braunwald E et al. Bariatric surgery: A systematic review and meta-analysis. Jama 2004; 292(14):1724-37.

Chapter 7

Hormonal Contraception Sarah Prager and Jody Steinauer

Background There are 6.3 million pregnancies annually in the United States, and almost half of them are unplanned. Approximately 50% of the women who become pregnant unintentionally are using some form of contraception at the time of conception. In the United States, unintended pregnancy, especially among women under age 25, is more of a problem than in other Western nations, with teen pregnancy rates in five northern European countries and Canada ranging from 5-53% of the U.S. rate. This is thought to be due, at least in part, to the fact that adolescent women in the U.S. are less likely than their European counterparts to use contraception of any kind; most specifically, hormonal contraceptives. Contraceptive failures occur for a variety of reasons. Most failures are partially due to imperfect use. Some women may not understand how best to use their method or how to handle common mistakes like missed pills or late placement of a contraceptive patch. Providers can help women determine which method will be safest and most effective, given the individual’s particular medical and social situation. By understanding each method’s mechanism, side effects, and contraindications, providers can help women to contracept safely and effectively. Each contraceptive method has characteristics that are more or less beneficial for an individual woman, such as efficacy, cost, frequency of intervention, protection against sexually transmitted infections (STIs), and other health benefits (Tables 7.1 and 7.2). In general, efficacy of a method increases with decreased frequency of intervention (i.e., placing an IUD once every 5-10 years as opposed to taking a contraceptive pill daily). This chapter will deal exclusively with hormonal methods of contraception though other methods (abstinence, lactational amenorrhea, natural family planning, male and female condoms, diaphragms, cervical caps, and copper intrauterine devices) exist and are used effectively by many women (Tables 7.1 and 7.2).

Assessing Evidence about Contraception As we describe each of the contraindications to individual methods, we will be using Medical Eligibility Criteria for Contraceptive Use, a guide produced by the World Health Organization that can be purchased and is available on their Web site. This easy-to-use resource summarizes the evidence for dozens of potential contraindications for contraceptive use and provides guidelines for safety in prescribing every contraceptive method. The guideline ascribes one of four categories to each potential contraindication and method: (1) indicates that the benefits clearly outweigh the risks and the method is safe to be used in any circumstance; (2) indicates that the benefits generally outweigh the risks, and Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

Every 5-7 years Every 10-12 years 0.8%

Copper IUD 0.6%

0.1%

0.05%

3%

3%

8%

8%

8%

8%

15-21%

85%

$250-300

$300-400

$450-750

$45-60

$35

$30-38

$38-45

$30-50

$20-50

$0.25-3

$0

Average Cost

No

No

No

No

No

No

No

No

No

Yes

No

Protection against STDs/AIDS

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

No

Other Health Benefits

Requires clinician visit

Requires clinician visit

Requires clinician visit

Requires clinician visit

Not currently available

Specific prescribing precautions: organ prolapse; chronic vaginitis, constipation.

Condoms and female condoms

Comments

Note that the column STDs/HIV protection means acquisition of the infection. All hormonal methods decrease risk of pelvic inflammatory disease. Modified with permission from: Steinauer J. A new era of contraception. Johns Hopkins Advanced Studies in Medicine 2005; 5(6):285-293.

0.1%

0.05%

0.3%

0.05%

0.3%

0.3%

Levonorgestrel intrauterine system

Monthly

Every 3 years

Weekly

Transdermal patch

Vaginal ring

0.3%

Implants

Daily

Progestin only pills

0.3%

Monthly

Daily

Combined hormonal pills

2-6%

Every 3 months

Each act of intercourse

Barrier methods

85%

1-Month injection

None

No method

Failure Rate Perfect Typical Use Use

3-Month injection

Frequency of Intervention

7

Contraceptive Method

Table 7.1. Comparison of contraceptive methods

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one may almost always use the method; (3) indicates that the risks generally outweigh the benefits and use of the method is usually not recommended unless other more appropriate methods are not available or acceptable; and (4) indicates that the risks always outweigh the benefits, and the method should not be used in any circumstance. For each method described we provide the evidence-based WHO contraindications, and in some cases, these may differ from the product label as approved by the U.S. Food and Drug Administration (FDA).

Combination Hormonal Contraception Combination Oral Contraception Oral contraceptive pills are the most common method of birth control used by women in the United States, with approximately 11.7 million current users (30.6% of the sexually active population). () Over 80% of women born in the United States since 1945 have used oral contraceptive pills at some time in their lives, and this method is currently used by more than 100 million women worldwide. Combination oral contraceptives (COCs) contain an estrogen and a progestin. Ethinyl estradiol (EE) is the most commonly used estrogen, and there are at least seven different progestins commonly used in the U.S. COCs are available in monophasic and multi-phasic (bi- and triphasic) formulations. Monophasic formulations contain the same amount of hormones in each active pill, whereas multiphasic preparations contain varying amounts of estrogen/progestin (usually progestin) in each hormonally active pill. Typically, COCs are packaged with 21 active pills and 7 placebo pills, although in the US there are two exceptions: Mircette with 21 active pills, 5 pills containing EE only and 2 placebo pills, and Seasonale with 84 active and 7 placebo pills. The primary mechanism of action for COCs is ovulation suppression (90-95%). Secondary mechanisms include thickened cervical mucus (which can limit sperm penetration), thinned endometrium (which can limit implantation) and decreased tubal motility. These secondary effects are mostly due to the progestin component of COCs. Combined oral contraceptives have the potential to be a highly effective method of contraception; however actual user failure rates (8%) are higher than perfect user rates (0.3%). Many women have difficulty taking a pill every day, but other obstacles contribute to the failure rate. Insurance limitations on number of packs of pills prescribed, or state limitations on contraception coverage for poor women are also obstacles to using birth control appropriately. As well, many practitioners mistakenly believe that a pelvic examination and pap smear are required before refilling or initiating a prescription for combined hormonal contraception. In actuality, only a blood pressure measurement is required prior to initiating a combined hormonal method. Thus patient and provider education, and policy changes, are necessary to promote maximally effective use of COCs. It is partially because of the high failure rate of COCs that longer term methods of contraception have been developed and are gaining popularity. In addition to its contraceptive effect, women using COCs may benefit from the side effect of decreased menstrual bleeding and more predictable menses. COCs decrease the incidence of anemia and menstrual cramping.

7

7

• • • • • •

• Lactation not affected • Reduced risk of endometrial and ovarian cancers • Fewer ovarian cysts • Less mittelschmerz • Fewer sickle cell crises • May reduce risk of PID, seizures • Can be used with anti-convulsants

Progestin-only injections

• • • • • • • • • •

• Lactation not affected • Decreased menstrual pain and blood loss

Progestin-only pills

Menstrual changes Weight gain Headaches Hair loss Adverse impact on lipids Mood changes

Menstrual changes Mood changes Weight gain or loss Headaches Hair loss

Spotting, bleeding Amenorrhea Mood changes Headaches Hot flashes

Side Effects • Nausea, vomiting • Headaches • Dizziness • Mastalgia • Chloasma • Vaginal spotting and bleeding • Mood changes

Progestin-only implants • Lactation not affected • Less blood loss • Fewer ectopic pregnancies

Noncontraceptive Benefits • Less dysmenorrhea and blood loss • Less PMS • Protects against PID • Decreased ovarian and endometrial cancers • Fewer benign breast masses, ovarian cysts • Fewer ectopic pregnancies • Reduces acne

Method Combined pills, injection, patch, and ring

• • • •

• • • •

continued on next page

Allergic reaction Excessive weight gain Glucose intolerance Depression

Infection at implant site Anesthesic reaction Complicated removal Depression

• None

Complications • VTEs • Myocardial infarction (MI) • Hypertension • Severe depression • Hepatic adenoma • Cervcial adenocarcinoma

Table 7.2. Major methods of contraception and some related safety concerns, side effects and noncontraceptive benefits

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• Prevents most STIs, cervical dysplasia • Enhanced self-image possible

• Reduces risk of STIs and cervical dysplasia • Loss of sensation or spontaneity • Rare anaphylactic reaction • Allergic reaction to latex to latex (use polyurethane • Skin irritation condoms) • May reduce STI and cervical dysplasia risk • Reduces risk of cervical STIs, PID and possibly cervical dysplasia

Abstinence

Male latex condom

Female condom

Diaphragm/cervical cap

• TSS • Anaphylactic reaction to latex

• Potentially,Toxic shock syndrome (TSS)—no cases reported

• None known

• Surgical complications: hemorrhage, infection, organ damage, anesthetic complications, pain • Ectopic pregnancy

Reproduced from: Hatcher R, Zieman M et al. A Pocket Guide to Managing Contraception. Tiger: Bridging the Gap Foundation, 2005.

• Vaginal and bladder infections • Vaginal erosions from poorly fitted device • allergy to spermicide/latex

• Difficult to use • Vaginal and bladder infections

• None excerpt possible peer pressure • Partner may seek sex elsewhere

• Pain at surgical site • Pelvic adhesions • Subsequent regret

• Women: reduced risk of endometrial or ovarian cancer, ectopic pregnancy, PID • Men: none known

• PID following insertion • Uterine perforation • Bleeding with expulsion

Sterilization

Complications

Noncontraceptive Benefits Side Effects • Lactation not affected • Copper-IUD increases menstrual • Copper T and LNG IUDs reduce risk blood loss, cramping for ectopic pregnancy • LNG IUD may cause irregular • LNG IUD reduces cramping and blood loss bleeding or amenorrhea

Method IUD

Table 7.2. Continued

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Combined oral contraceptive use provides protection against many cancers. COC use for 5 years provides a 50% reduction in risk of ovarian cancer, and use for 10 years reduces risk by 80%. This protection extends for 30 years after discontinuation of COCs, and also applies to women carrying BRCA mutations. COCs containing at least 30 μg of estrogen provide protection against endometrial cancer. This is especially important among high-risk groups such as women with polycystic ovarian syndrome, obesity and perimenopausal women. Women who have taken COCs have a reduced risk of death from colorectal cancer. After more than 50 studies about the effect of COCs on risk of breast cancer, the consensus is that COCs have minimal to 7 no effect and may actually protect against metastatic disease. Though COCs appear to be protective for many cancers, their use is associated with a 60% increased risk of adenocarcinoma of the cervix, which is a rare cancer with an annual incidence of 0.5/100,000 women. COCs containing 50 μg or more of estrogen have been associated with an increased risk of hepatocellular adenoma but no increased risk of hepatic carcinoma. Hormonal contraception is not for everyone, and some women have bothersome side effects of COCs. These include physical symptoms such as nausea and vomiting (approximately 12%), especially in the first few cycles, breast tenderness or pain, and headaches. Some women are bothered by intermenstrual spotting, (commonly occurs in the first few cycles) and the uncommon development of amenorrhea. Rarely, women note decreased libido or anorgasmia. Mood changes, depression, anxiety, irritability and fatigue have been reported by women taking COCs, though placebo-controlled studies have demonstrated no increased risk of these side effects. Finally, some women simply don’t like the stress of having to remember to take a pill everyday. Contraindications for all combined hormonal methods, which fall into WHO categories 3 and 4, are listed in Table 7.3. COCs should be used with caution, if at all, in women with these conditions. In particular, pay close attention to the guidelines when considering prescribing COCs to a woman with hypertension, a personal or family history of blood clots or venous thromboembolic events (VTEs), or other types of vascular compromise.

Extended Use Combined Oral Contraception The primary reason for COC failure is forgetting to start the next cycle of contraception at the appropriate time. By the end of the placebo week, up to 25% of women have developed an ovarian follicle large enough to ovulate unless immediately suppressed by hormones. Since the beginning of each pack is a high-risk time to miss pills, a few modifications of the COC regimen might improve efficacy. One method is to shorten the number of placebo days per cycle. Two such pills in Europe continue estrogen and progestin into the fourth week, leaving fewer days for placebo, and in the U.S., Mircette® (desogestrel/ethinyl estradiol [EE]) continues estrogen for 5 days into the fourth week and leaves 2 placebo days. While physiologically it makes sense that shortening the placebo period might increase efficacy, no studies have tested this hypothesis. Another modification to the traditional COC regimen is to reduce the number of “starts” by cycling women for longer than the typical 28-day period. Seasonale® (levonorgestrel/EE), an extended cycle pill approved by the FDA, does this by administering 12 weeks (84 days) of active hormone followed by 7 days of placebo. A woman taking Seasonale® will have only four withdrawal bleeds per year. A large, randomized, multicenter trial found that Seasonale® had a failure rate of 0.60 per

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Table 7.3. When risks outweigh benefits in initiating combined hormonal contraception WHO Medical Condition Category Breastfeeding 6 weeks to ≤6 months 3 Smoking 20 years duration 3 Migraine with aura, at any age 4 Migraine without aura and age ≥35 years 3/4* Headache without aura and age 2 days late: Remove the old patch and place a new one on immediately. Use EC if unprotected intercourse has occurred (especially if she is 4 days or more late applying her patch). • Use back-up method for 7 days. Change the patch each week on the same day of the week. • Remove the patch. • Place a new patch on the usual day. • No back-up method or EC is needed.

Reproduced from: Hatcher R, Zieman M et al. A Pocket Guide to Managing Contraception. Tiger: Bridging the Gap Foundation, 2005.

Research on extended cycle patch use shows results of delayed menses and fewer bleeding days when compared to cyclic patch use. However there is also concern that using the patch in a continuous manner may cause an accumulation of EE in the blood, leading to higher than acceptable levels. Until there are more data, I would caution against using the patch in a continuous manner. The side effect profile for the patch is very similar to that of COCs, with the exception of more common complaints of spotting, breast symptoms and dysmenorrhea as compared to COCs. Spotting and breast symptoms typically resolve after the first two cycles, and dysmenorrhea, though more common with the patch than with COCs, is not usually a cause of discontinuation. Contraindications for the patch are the same as for COC (Table 7.3).

Combined Contraceptive Vaginal Ring NuvaRing® (etonogestrel/EE), introduced in the U.S. in 2001, is another way to administer combined hormonal contraception. The ring has an outer diameter of almost 2 inches, and a cross-sectional diameter of approximately 1/8 inch. It is self-inserted into the vagina, left in place for three weeks, and then removed for one ring-free week. If the ring is initially placed on the first day of menses, no back-up contraception is needed, but if it is placed on day 2-5, a back-up method should be used for seven days. The ring is meant to be left in place during intercourse, though it can be removed for up to three hours without reduced efficacy. The ring releases approximately 120 μg of etonogestrel and 15 μg EE daily through the vagina, and serum levels are adequate for 35 days. This method of administration, similar to transdermal release, avoids first-pass metabolism through

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the liver. The mechanism of action for the ring is the same as for COCs and the patch, but it is unique in that the progestin used in the ring suppresses ovulation in all users. Women generally find it easy to use the ring and use it perfectly in 86% of cycles. The cumulative failure rate is similar to that of COCs (1.18 per 100 woman-years), though among women who use the ring perfectly the cumulative failure rate is lower (0.77 per 100 woman-years). Overall, the ring is well tolerated; 95% of women find it easy to insert and remove, and 83% deny feeling it during intercourse. In addition to the side effects known to be associated with COCs (nausea, head7 aches, breast tenderness, etc), ring users experience unique side effects. Fifteen percent of study participants discontinued the ring due to vaginal symptoms including vaginitis, leukorrhea, “feeling the ring” when it is in place, and, very rarely, expulsion. On the other hand, the ring resulted in a more desirable bleeding pattern when compared with COCs. Studies of extended cycle vaginal ring use have demonstrated high satisfaction rates with continuous use of ring for 49- and 91-days as well as year-long continuous use. Unscheduled bleeding was lowest with the traditional 28-day cycle; however, overall bleeding days were reduced with postponement of withdrawal bleeding. Because each ring, if left in place, releases adequate serum levels for 35 days, it could be used as a once-a-month extended cycle regimen (therefore not requiring additional rings purchased per year). Most of the contraindications and precautions for the ring are similar as those for COCs and the patch, and the World Health Organization (WHO) criteria can be applied (Table 7.3). If a woman removes her ring for more than 3 hours, she should replace it immediately, use EC if applicable, and use a back-up method for 7 days. If she is late in replacing her ring after the ring-free week, she should do the same. Contraindications that are specific to the ring include chronic vaginitis, pelvic organ prolapse and severe constipation.

Injectable Combined Hormonal Contraception Currently, there is not an injectable form of combined hormonal contraception available in the United States. Lunelle® (medroxyprogesterone acetate/estradiol cypionate), a 0.5 ml suspension that is injected intramuscularly into the deltoid or gluteus maximus every 28-30 days, was taken off the market in 2002. It is still used some in other countries and may be available in the U.S. in the future.

Progestin Only Contraceptive Methods Progestin Only Pills The progestin only pill (POP), also commonly called the mini-pill, contains only progestin and is taken daily without any pill-free days. The mechanism of action is identical to the progestin-related mechanisms for COCs. The primary mechanism is thickening of the cervical mucus (this action is short lived, and requires punctual dosing to be effective). Progestin use also causes decreased tubal and endometrial motility and thin, atrophic endometrium. Only about 50% of women will have ovarian suppression with the currently available POP. Because the major mechanism of action requires punctual dosing to maintain effectiveness,

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women must take the POP within one hour of the same time each day. If 27 or more hours have lapsed since the last dose, a woman should take her POP immediately, consider using EC (if indicated), and should also use a back-up method for 2 days. If taken correctly, the efficacy of POPs equals that of COCs, with a failure rate of 0.3%-8%. However, this efficacy may be slightly inflated because most women using POPs are at reduced risk for pregnancy because of their lactating or perimenopausal status. Women using POPs experience many of the same noncontraceptive benefits of women using COCs, such as improvements in menstrual side effects and decreased risk of endometrial cancer. POPs confer no protection against ovarian and 7 colon cancers. The progestin only pill can be safely used in many women for whom estrogen is contraindicated. These include women with a history of clots or VTE, hypertension , coronary artery disease or cerebrovascular disease; women over 35 years who smoke; and recently post-partum or breastfeeding women. The main disadvantage to POP use is the need for a strict dosing regimen. Adherence to daily dosing at the same time every day is often prohibitive, and most women prefer the increased flexibility in timing of administration allowed with COCs. The only absolute contraindication for progestin use is current breast cancer, but there are several conditions in which the risks of POP use generally outweigh the benefits (Table 7.5).

Table 7.5. When risks outweigh benefits in initiating progestin only pills and Levonorgestrel/Etonogestrel implant (Implanon)* WHO Medical Condition Category Breast Feeding (90% of these patients have polycystic ovarian syndrome (PCOS). These patients will have a positive progestin challenge test due to normal endogenous estradiol levels. WHO group III patients have elevated FSH and LH levels. Gonadotropins are elevated (often in the menopausal range) secondary to ovarian follicle depletion. These patients respond poorly to ovulation induction and are candidates for IVF-oocyte donation. Finally, hyperprolactinemic patients (WHO group V/VI), with or without a pituitary adenoma, may have ovulatory dysfunction. Elevated prolactin levels interfere with gonadotropin releasing hormone (GnRH) pulsatility and, as a result, impair ovulation.

Testing Prior to Ovulation Induction Since ovulation induction is pursued in the course of fertility treatment, a comprehensive fertility investigation should be performed prior to instituting therapy. A thorough history and complete physical examination of the female and male partner should be undertaken. Basic investigations for anovulation should include a day 3 FSH level (or random FSH if amenorrhea), thyroid stimulating hormone (TSH) level, and prolactin level. A progestin challenge test may be performed to determine the estrogen status and serves to help distinguish WHO group I from group II. A semen analysis should be performed as 25-40% of infertility has a male-factor component. A hysterosalpingogram may be ordered initially to evaluate uterine and Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

Pulsatile gonadotropin releasing hormone Intrauterine insemination

Adjuvant treatment

Gonadotropins

Primary treatment Secondary treatment

Etiology

Laparoscopic ovarian diathermy Glucocorticoids Intrauterine insemination

Weight Loss Clomiphene citrate Metformin Aromatase inhibitors Gonadotropins

WHO Group II Eugonadotropic hypogonadism

Intrauterine insemination

Oocyte donation

WHO Group III Hypergonadotropic hypogonadism

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WHO Group I Hypogonadotropic hypogonadism

Table 15.1. Ovulation induction treatment and indications

Intrauterine insemination

Gonadotropins

Dopamine agonists

WHO Group V/VI Hyperprolactinemia

Intrauterine insemination

Clomiphene citrate or gonadotropins

Unexplained infertility Endometriosis Male-Factor infertility IVF Clomiphene citrate or gonadotropins

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tubal anatomy, but this may be delayed in an anovulatory patient if there is no evidence of uterine/tubal disease on history and or physical examination. In hyperandrogenic PCOS patients, serum testosterone, dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogesterone levels may be obtained to determine the origin of the elevated androgens. A pelvic ultrasound may be performed as part of the 2003 criteria for PCOS diagnosis. These basic investigations ensure that the cause of anovulation is obtained and determine whether other causes of infertility are present. If other infertility factors are present, these may require additional treatments that are not addressed with ovulation induction, alone.

Ovulation Induction Monitoring The goal of ovulation induction is to maximize the chance of pregnancy while minimizing the complications, namely multiple pregnancy and ovarian hyperstimulation syndrome (OHSS). This is facilitated through ovulation induction monitoring. Ovulation induction monitoring may take the form of a menstrual diary, urine or serum LH measurements, or serial ultrasound with or without serial estradiol measurements. Since ovulation induction is used in conjunction with timed intercourse or intrauterine insemination (IUI), efforts are made to time ovulation with the presence of fresh sperm in the female reproductive tract. Since the oocyte has a lifespan of approximately 24 hours in the female genital tract, and sperm can survive up to 72 hours, the best chance for conception occurs if the sperm are present at the 15 time of, or just prior to ovulation. Ovulation occurs 34-36 hours after the start of the LH surge, 17-26 hours after urine LH detection, and at a follicular diameter of 20-27 mm. Furthermore, when ultrasound is used to monitor follicle development and human chorionic gonadotropin (hCG) is administered for final oocyte maturation (a pharmacological mimic of the LH surge), it appears that 15 mm is the smallest follicular size sufficient for ovulation. These surrogate markers for ovulation serve as a guideline for timing of intercourse or IUI. Estradiol levels are often used in conjunction with ultrasound for monitoring ovulation induction cycles. In unstimulated, monofollicular cycles, estradiol and follicle size show a highly correlated linear increase in the five days preceding ovulation, with a daily increase in follicular diameter of 1.2-2 mm/day (Randall and Templeton, 1991) and a corresponding increase in estradiol to an average preovulatory estradiol of 250 pg/ml. In COH cycles, greater preovulatory follicle numbers and estradiol levels are seen. Compared to natural cycles, there is a weaker correlation between follicle numbers and estradiol levels in multifollicular development. Nonetheless, estradiol levels typically reach 250 pg/ml per preovulatory follicle. Ultrasound monitoring of ovulation induction serves an additional purpose in monitoring endometrial development. A periovulatory endometrial thickness of ≥ 10 mm is a good prognostic factor for conception in COH cycles, and endometrial thickness of 3000 pg/ml, large numbers of follicles and in younger age. For OHSS the best cure is prevention. Ovarian hyperstimulation syndrome does not occur in the absence of ovulation. In ovulation induction cycles deemed to be at risk for OHSS, cycle cancellation and withholding the injection for final follicular maturation (discussed later) will usually prevent OHSS. Another commonly used method of prevention of OHSS involves “coasting.” This involves terminating the ovulation induction medication (gonadotro15 pins) once the largest follicle is ≥14 mm, for 1-4 days, and the estradiol level is 5% has been shown to restore ovulation in some PCOS women. In addition, PCOS women who did not conceive with previous treatment and had a mean weight loss of 10.2 kg went on to have a 77% pregnancy rate with treatment. While this is an often overlooked mode of treatment, it should be considered first line treatment for overweight women with PCOS.

Clomiphene Citrate Clomiphene citrate (CC) is an estrogen analog that was first shown to induce ovulation in 1961 and was approved for clinical use in the United States in 1967. Clomiphene belongs to a family of compounds known as selective estrogen receptor modulators (SERMs). Other well-known SERMs include tamoxifen (breast cancer treatment) and raloxifene (osteoporosis treatment). Clomiphene is used for ovulation induction or controlled ovarian hyperstimulation in patients with normal endogenous estrogen levels. Clomiphene exerts both estrogen agonist and antagonist effects. Clomiphene blocks the negative feedback of endogenous estrogen at the hypothalamic and

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15 Figure 15.1. Ovulation induction treatment algorithm for polycystic ovarian syndrome (PCOS). DHEAS, dehydroepiandrosterone sulfate; IVF, in vitro fertilization.

pituitary levels. This results in a >50% increase in endogenous FSH which subsequently stimulates follicular growth. Ovulation rates approach 80%, with cumulative pregnancy rates of 30-40% over the course of a few cycles. This discrepancy between ovulation and pregnancy rates is thought to be due to the estrogen antagonist effects on the endometrium and cervical mucus. This may be detected by an endometrial thickness of 5 ng/ml. Monitoring of clomiphene citrate cycles may be managed using ovulation prediction kits, basal body temperature monitoring, or ultrasound monitoring. If the woman is attempting conception in conjunction with timed intercourse, the fertile period is a 6-day period which is generally the day of ovulation and the 5 days preceding ovulation (Dunson et al, 1999), and intercourse every second day is recommended. If ovulation induction is used in conjunction with IUI, then the IUI should be performed the day of, or the day following a positive ovulation predictor

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test. Ultrasound monitoring of CC stimulated cycles has demonstrated that on the day of spontaneous LH surge, the preovulatory follicles are usually slightly larger than in natural, unstimulated cycles. If ultrasound monitoring is used in conjunction with IUI, hCG (5,000-10,000 IU) is typically administered when the lead follicle is ≥18 mm, and IUI is performed 36 hours later. While high-technology monitoring has not been shown to increase pregnancy rates over low-technology monitoring, ultrasound monitoring adds additional information on the endometrial effects of CC. Complications of CC include OHSS and multiple pregnancies. Original reports demonstrated twin pregnancy rates of 10% and higher order multiple rate (triplets or greater) of 1%. Clinically significant OHSS is uncommon in CC stimulated cycles. Side effects of CC include breast tenderness, bloating, hot flashes, abdominal discomfort, and mood changes. A rare side effect is changes in vision or sensitivity to light, which requires immediate discontinuation of the medication, as continuation may cause permanent visual changes.

Metformin There has been a plethora of evidence that PCOS is associated with hyperinsulinemia, which leads to the widespread use of insulin sensitizing agents for treatment. The most studied agent is the oral biguanide, metformin. The exact 15 mechanism of action of metformin in PCOS is unclear, but may be related to weight loss or direct suppression of androgen production by the ovary. Metformin is typically used at doses between 1500-2000 mg/day, and the main side effect is GI upset. Metformin may be used alone or in conjunction with CC. When metformin is used alone as an ovulation induction agent, ovulation rates are typically between 30-40%, but evidence for a significant increase in pregnancy rates is lacking. When metformin and CC are used together, ovulation rates approach 90%. In patients who did not previously ovulate with CC therapy, ovulation rates are approximately 75% when treated with CC plus metformin. A recent meta-analysis suggests that CC plus metformin has an approximately 3-fold greater pregnancy rate in PCOS women than CC alone. In clinical practice, metformin is usually used in conjunction with CC in obese PCOS patients or in patients who do not respond to CC. Currently, a large, randomized, double-blind, clinical trial comparing pregnancy rates in patients treated with CC, metformin, or CC plus metformin, is ongoing. This trial should determine the best treatment regimen for achieving pregnancy.

Aromatase Inhibitors Aromatase inhibitors are orally active agents that inhibit estrogen biosynthesis by inhibiting the aromatase enzyme, resulting in decreased circulating levels of estradiol. Under low estrogen conditions, there is decreased negative feedback and greater pituitary FSH release. While this medication is not approved for ovulation induction, it is increasingly being used for this purpose. The most commonly used aromatase inhibitor given for ovulation induction is letrozole. It is typically administered at a dose of 2.5-7.5 mg/day for a 5-day regimen, starting on day 3 of the menstrual cycle or occasionally as a single 20 mg dose given on day 3. While aromatase inhibitors have not been shown to be superior to CC, there are some studies that suggest they may be useful in patients who do not respond to CC.

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Laparoscopic Ovarian Diathermy Laparoscopic ovarian diathermy (LOD) is an endoscopic surgical procedure that has been found to be an effective mode of ovulation induction. This procedure involves creating 3-10 holes per ovary with an electric current or laser (see Chapter 14). Its use has primarily been in the CC resistant population, and a randomized, controlled study in this population has shown similar pregnancy rates in patients undergoing LOD compared to gonadotropin therapy. Furthermore, LOD has been shown to have equivalent pregnancy rates after 6-12 months when compared to 3-6 cycles of gonadotropin therapy with significantly lower multiple pregnancy rates in the LOD group. A recent study comparing metformin treatment versus LOD in a CC resistant population demonstrated similar ovulation rates, but higher pregnancy rates in the metformin group. With an expanding number of ovulation induction agents, the role of LOD in contemporary ovulation induction appears to be limited.

Glucocorticoids While not an ovulation induction agent on its own, glucocorticoids (namely dexamethasone) have occasionally been used in conjunction with CC in women who are unresponsive to CC. A subset of patients with PCOS have increased adrenal androgen production, reflected by elevated DHEAS levels. Administration of dexamethasone suppresses adrenal androgen production and can increase the ovulation rate among women with DHEAS levels >200 μg/dl. The most widely used 15 protocol includes dexamethasone administered at nighttime in a dose of 0.5 mg orally in conjunction with CC treatment.

Pulsatile Gonadotropin Releasing Hormone Gonadotropin releasing hormone (GnRH) was first identified in 1971 and is the hypothalamic releasing hormone responsible for FSH and LH synthesis and release from the pituitary. While it is rarely used in clinical practice, it is the most physiological method of ovulation induction for WHO group I ovulatory disorders, namely women who have hypogonadotropic hypogonadism. These women typically do not have the pulsatile GnRH secretion required for the synthesis and release of gonadotropins from the pituitary that are responsible for ovarian folliculogenesis and regular, cyclic menses. GnRH is typically administered in doses from 2.5-20 μg every 60-120 minutes. GnRH pulsatile therapy may be administered intravenously (IV) or subcutaneously (SC) but appears to be more effective by IV route. The LH surge and subsequent ovulation occur spontaneously, therefore not requiring an injection of hCG to induce follicular maturation, and pulsatile GnRH can be continued in the luteal phase to provide support for the corpus luteum. Ovulation rates are typically 75%/cycle, with pregnancy rates of 23%/ovulatory cycle and multiple pregnancy rate of 3.8%/cycle. The low multiple pregnancy rate is due to monofollicular development using this method of ovulation induction. In spite of high pregnancy rates and low multiple pregnancy rates, due to the need for a pump and indwelling catheter, this method of ovulation induction is not frequently used.

Dopamine Agonists Dopamine agonists are the first-line therapy for patients with anovulation related to hyperprolactinemia. Hyperprolactinemia is often due to prolactin-secreting pituitary adenomas. Hyperprolactinemia interferes with GnRH pulsatile secretion, thereby causing anovulation. Dopamine inhibits prolactin secretion, and administration of

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dopamine agonists results in both a decrease in tumor volume and restoration of ovulatory cycles. The most commonly used dopamine agonist for ovulation induction is bromocriptine, which is administered in a dose of 2.5-10 mg, daily in divided doses. Cabergoline is another dopamine agonist with a better side-effect profile and patient tolerability and is administered in a dose of 0.25-1 mg, given twice weekly. Cumulative pregnancy rates of 80% can be expected with bromocriptine treatment for anovulation due to hyperprolactinemia. Dopamine agonists are typically stopped once conception has occurred.

Gonadotropins for Ovulation Induction Background The anterior pituitary gonadotropins, LH and FSH, and the placental gonadotropin, hCG, are the three identified gonadotropins and all are used in ovulation induction. LH serves two distinct and essential functions. First, it is responsible for stimulating the synthesis of ovarian androgens in ovarian theca cells. These androgens serve as precursors for ovarian estrogen synthesis. Second, the LH surge, which occurs in response to a positive feedback effect of estradiol produced from a preovulatory follicle, causes oocyte maturation with resumption of meiosis, oocyte release, and a shift in production of ovarian steroids from a predominantly 15 estrogen-producing follicle to a progesterone-producing corpus luteum. The placental gonadotropin, hCG, is produced by the early pregnancy and functions through the same receptor as LH. As a result, it has the same activity as LH, and its primary biological purpose is to continue to support progesterone production by the corpus luteum throughout the first trimester and until the placenta develops. Finally, FSH stimulates ovarian follicle growth and stimulates aromatase activity in granulosa cells. The aromatase activity is responsible for conversion of the LH stimulated androgens from the theca cells into estrogens. While the physiological function of these hormones is to ensure regular, monofollicular ovulation and hormonal support in early pregnancy, these hormones can be used pharmacologically to induce ovulation in women with ovulatory defects or to induce superovulation (e.g., multifollicular development) in ovulatory patients to increase the chance of pregnancy. The first live birth from gonadotropin therapy occurred in 1962. The gonadotropins were obtained from the purified urine of postmenopausal women. These preparations were termed human menopausal gonadotropins (hMG) and initially contained 5% gonadotropins and numerous urinary protein contaminants. Due to the impurity and batch-to-batch variability of these preparations, mass was not an appropriate indicator of gonadotropin content. As a result, gonadotropin preparations have traditionally been expressed in international units (IU) of activity, as measured by a standard bioassay. Initial hMG preparations contained equivalent amounts of FSH and LH per unit. These preparations were typically administered by intramuscular injection (IM). Years later, a urinary FSH (uFSH) product was developed that had most of the LH activity removed although it still contained significant impurities. The rationale for this was that endogenous LH levels were adequate and that excessive LH activity could be harmful to folliculogenesis. Subsequently, a highly purified urinary FSH (uFSH-HP) was developed. This was >95% pure and offered the advantage of subcutaneous administration with little local irritation. Finally, the end of the last millennium brought the development

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of recombinant DNA technology and with it the development of recombinant FSH (rFSH). These products contain exclusively recombinant FSH, >99% pure, without significant batch-to-batch variation. Similarly rLH and rhCG have been developed and are available for clinical use. While there has been much progress in the development and use of gonadotropins, there is a paucity of evidence that any one preparation is clinically superior to another. Two different meta-analyses of several randomized, controlled trials gave different results with respect to pregnancy rates when comparing ovulation induction using FSH to hMG. The initial meta-analysis demonstrated a higher pregnancy rate in when FSH was used for ovarian stimulation for in vitro fertilization. In contrast, a reanalysis of this data with a larger number of studies showed little difference between these two preparations. Most recently, a meta-analysis comparing rFSH to hMG demonstrated no difference in clinical pregnancy rates. While the recombinant preparations are more expensive and at this point, they do not appear to offer any clinical advantage over hMG or uFSH, they have less batch variability, virtually no infectious risk that theoretically exists with urinary preparations, an essentially limitless supply that is not constrained by access to urine from postmenopausal women, and the ability to develop novel ovulation induction regimens with varying doses of rFSH, rLH, and rhCG. For most clinical purposes, any of the FSH or hMG preparations may be used interchangeably. 15 Multiple pregnancy and OHSS occur with higher frequency in patients treated with gonadotropins. A recent study of over 4000 gonadotropin plus IUI cycles revealed a 14.4% pregnancy rate/cycle, with an overall 25% multiple pregnancy rate, with a higher order multiple pregnancy rate of 6%. OHSS rates can be up to 11% in PCOS patients undergoing gonadotropin ovulation induction.

Follicular Maturation with hCG—The Terminal Act in Ovulation Induction The purpose of the LH surge is to initiate ovulation, maturation of the oocyte, and development of the corpus luteum. This can occur spontaneously with most types of ovulation induction but is usually brought on pharmacologically in large part for practical reasons. By administering an agent that mimics the LH surge, we are virtually ensure that the events that occur as a result of the LH surge take place, and we can also control the timing of these events. Since the LH surge precedes ovulation by approximately 36 hours, timing of IUI or intercourse may be coordinated with the pharmacologically induced surge. The most common agent used for follicular maturation is hCG. The structure of hCG is similar to LH, and it acts through the LH receptor to mimic the LH surge. There are both uhCG and rhCG products available. It is typically administered in doses of 5000-10000 IU for uhCG administered IM or SC, or 250 μg of rhCG administered SC. Both agents are equally effective in ovulation induction. The lower dose of uhCG may lower the risk of OHSS in patients at greatest risk. While hCG is the most common agent for inducing final follicular maturation, both LH and GnRH agonists may be used. The clinical use of LH for follicular maturation has been limited due to the large dose required for this purpose and its shorter half-life than hCG. GnRH agonists have been also been used, and they hold the advantage of stimulating an endogenous LH surge from the pituitary that is more physiological, potentially lowering the risk of OHSS.

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Gonadotropin Ovulation Induction in PCOS There are numerous protocols for ovulation induction with gonadotropins in PCOS women. The two most common protocols are the low dose step-up protocol and the step-down protocol, both of which are adequate. It has been suggested that the low dose step-up protocol has a lower rate of OHSS and multiple pregnancies, and possibly a higher pregnancy rate. Whatever protocol is used, close ultrasound and estradiol monitoring is essential for avoiding complications. The step-up protocol is typically started on cycle day 2 or 3 of the menstrual cycle, often after a progestin-induced withdrawal bleed (Fig. 15.2). The initial FSH starting dose is typically 75 IU/day, but has been effective at lower doses. The initial dose is given for 7 days, and ultrasound and estradiol levels are obtained. If follicles >10 mm are seen, the same dose is continued and patients return for ultrasound and estradiol testing every 1-2 days until the lead follicle is ≥17 mm in diameter. Follicular maturation is then initiated with hCG, but this may be withheld if there are greater than four follicles with ≥14 mm diameter or estradiol >2000 pg/ml, due to the risk of OHSS and multiple pregnancy. If after 7 days of initial stimulation the follicles are ≤10 mm, the same dose is continued for another 7 days and ultrasound examination is performed again. If the follicles are >10 mm, then the protocol is continued at the same dose (threshold dose) until a follicle ≥17 mm is seen. If the follicles remain ≤10 mm, FSH dose is increased 37.5 IU daily for 7 days, and is 15 increased 37.5 IU every 7 days until a threshold dose is reached.

Figure 15.2. Low dose step-up protocol for gonadotropin ovulation induction. FSH, follicle stimulating hormone; hCG, human chorionic gonadotropin; IUI, intrauterine insemination; IU, international units.

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The step-down protocol is started on cycle day 2 or 3 of the menstrual cycle at an FSH starting dose of 150-225 IU/day for 5 days (Fig. 15.3). Ultrasound and estradiol levels are then performed. If follicles ≥10 mm are seen, the dose is decreased by 37.5 IU every 3 days and the cycle monitored with ultrasound and estradiol every 1-2 days until the lead follicle ≥17 mm. Follicular maturation is then initiated with hCG unless the risk of OHSS or multiple pregnancy is too great. If after 5 days of initial stimulation, all follicles are 10 mm is identified. Criteria for follicular maturation with hCG are identical to other ovulation induction protocols, and the same caution for OHSS and multiple pregnancy risks must be observed.

COH with Gonadotropins in in Vitro Fertilization (IVF) Gonadotropin stimulation is the mainstay of COH in IVF. The purpose of COH in IVF stimulation is to produce multiple follicles for transvaginal oocyte retrieval, in vitro fertilization of oocytes, and subsequent transfer of 1-3 embryos into the uterus after 3-5 days of in vitro embryo culture. The details of these protocols extend beyond the scope of this chapter.

Key Points 1. Ovulation induction remains a mainstay of infertility treatment of women with ovulatory disorders. 2. Weight loss and clomiphene citrate ± metformin are the first-line ovulation induction methods in PCOS women. 3. Gonadotropins are first-line for anovulation due to hypogonadotropic hypogonadism and are second-line therapy for PCOS. 4. The major risks of ovulation induction are OHSS and multiple pregnancy. These risks can be reduced with appropriate monitoring. 5. Future directions in ovulation induction will be directed at greater individualization of protocols to increase pregnancy rates and decrease multiple births through monofollicular ovulation.

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Suggested Reading 1. Dickey RP, Taylor SN, Lu PY et al. Risk factors for high-order multiple pregnancy and multiple birth after controlled ovarian hyperstimulation: results of 4,062 intrauterine insemination cycles. Fertil Steril 2005;83:671-83, [A large review of the risk factors for higher order multiple pregnancy in gonadotropin ovulation induction]. 2. Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 2004;19:2474-83, [A review of the role of pregnancy and ovulatory rates in ovulation induction protocols using metformin]. 3. Guzick DS, Carson SA, Coutifaris C et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999;340:177-83, [A randomized controlled trial examining the pregnancy rates in COH ± IUI in patients with unexplained and mild male-factor infertility]. 4. Dunson DB, Baird DD, Wilcox AJ et al. Day-specific probabilities of clinical pregnancy based on two studies with imperfect measures of ovulation. Hum Reprod 1999; 14:1835-1839. 5. Farquhar C, Vandekerckhove P, Lilford R. Laparoscopic “drilling” by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev 2001; CD001122. 6. Filicori M, Flamigni C, Dellai P et al. Treatment of anovulation with pulsatile gonadotropin-releasing hormone: Prognostic factors and clinical results in 600 cycles. J Clin Endocrinol Metab 1994; 79:1215-1220. 7. Haas DA, Carr BR, Attia GR. Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome. Fertil Steril 2003; 79:469-481. 8. Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: Rationale, results, reflections and refinements. Hum Reprod Update1999; 5:493-499. 9. Mitwally MF, Casper RF. Aromatase inhibitors in ovulation induction. Semin Reprod Med 2004; 22:61-78. 10. Randall JM, Templeton A. Transvaginal sonographic assessment of follicular and endometrial growth in spontaneous and clomiphene citrate cycles. Fertil Steril 1991; 56:208-212. 11. van Santbrink EJ, Hop WC, van Dessel TJ et al. Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle. Fertil Steril 1995; 64:37-43. 12. van Wely M, Westergaard LG, Bossuyt PM et al. Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles. Cochrane Database Syst Rev 2003; CD003973.

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Chapter 16

Assisted Reproductive Technology Tiffany Von Wald and Kim Thornton

Introduction Assisted reproductive technology (ART) is by definition any treatment or procedure that includes the handling of oocytes and sperm or embryos outside the body for the purpose of establishing a pregnancy. In vitro fertilization (IVF) is the most common ART procedure. The first IVF baby was conceived in 1978 (Louise Brown) in Lancashire, England. IVF has been used in the United States since 1981.

Definitions In vitro fertilization (IVF): A process including controlled ovarian hyperstimulation, surgical removal (retrieval) of oocytes, fertilization in the laboratory, and transcervical transfer of embryos into the uterus. Gamete intrafallopian transfer (GIFT): A procedure that involves removing oocytes from a woman’s ovary, combining them with sperm, and using laparoscopy to assist in placing the unfertilized oocytes and sperm into the fallopian tubes. Zygote intrafallopian transfer (ZIFT): A procedure that involves removing oocytes from a woman’s ovary, fertilizing them in the laboratory with sperm, then placing the single-cell embryo (zygote) directly into the fallopian tube utilizing laparoscopy. Tubal embryo transfer (TET): A procedure that involves removing oocytes from a woman’s ovary and fertilizing them in the laboratory with sperm. The resultant embryo(s) are placed directly into the fallopian tube utilizing laparoscopy 2-3 days later. Donor oocytes: Eggs that are removed from one woman’s ovaries to be used by another for IVF. Indications often include premature ovarian failure, gonadal dysgenesis, recurrent IVF failure, natural menopause, and inheritable disorders. Gestational surrogacy: Treatment by which the gametes of the intended parents (genetic parents) are used to produce embryos, which are subsequently transferred to a woman who agrees to act as a host or surrogate carrier of the pregnancy. Microsurgical epididymal sperm aspiration (MESA): A technique whereby a small needle is used to extract fluid and relatively mature sperm directly from an epididymal tubule. Testicular sperm extraction (TESE): A procedure for extracting sperm by removing a small sample of testicular tissue through an incision in the testes under local anesthesia. Intracytoplasmic sperm injection (ICSI): A micromanipulation technique that involves injecting a sperm directly into an egg in order to facilitate fertilization. Assisted hatching (AH): A technique in which the zona pellucida (outer shell of the egg) is chemically or mechanically thinned prior to embryo transfer in order to improve the likelihood of subsequent hatching and implantation of the embryo. Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.

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Preimplantation genetic diagnosis (PGD): A technique used during IVF to test embryos for genetic disorders (aneuploidy or structural chromosomal abnormalities), inheritable single gene disorders, or gender, prior to embryo transfer. The procedure can involve evaluating the chromosomal composition of the oocyte via the extruded polar body, removing one or two blastomeres from the cleavage stage embryo, or by biopsy of the trophoectoderm of the blastocyst stage.

Infertility History and Evaluation An initial infertility evaluation is traditionally begun after one year of unprotected intercourse; however, an earlier evaluation may be indicated for increased maternal age, irregular menstrual cycles, previous pelvic inflammatory disease (PID) or pelvic surgery. One of the most important aspects of evaluating infertility is obtaining a thorough history from both partners. When evaluating the female partner, it is important to include the items listed in Table 16.1. When evaluating the male partner, it is important to include the items listed in Table 16.2. Every infertility evaluation should begin with a complete physical exam. When examining the female partner, it is important to document height and weight, as well as body mass index (BMI = weight in kilograms/height in meters squared). There is a clear association between weight and infertility as well as a correlation between the woman’s weight and the amount of gonadotropins needed to stimulate the ovaries. It is important to check for thyroid enlargement, nodules, or ten- 16 derness, as well as identifying excessive acne or facial hair, which may be associated with increased androgen levels. Evidence of acanthosis nigricans often indicates

Table 16.1. Evaluation of female partner Female: General Category Length of infertility Gravity and parity

Menstrual history

Family history Surgical history Gynecologic history Medication and allergy history Social history Review of systems

Specific Points Coital frequency, previous treatment History of spontaneous pregnancy, specific pregnancy outcomes, complications, history of recurrent pregnancy loss Length of cycles (normal 21-35 days), duration and type of flow (may indicate fibroids or oligovulation), menstrual cramps and breast tenderness (molimina-signs of ovulation), dyspareunia Recurrent pregnancy loss, endometriosis, birth defects, premature ovarian failure Tubal ligation, ovarian cysts, endometriosis, pelvic infections, appendectomy, D&C STDs, PID, abnormal pap smears and subsequent treatment

Tobacco use, alcohol use, illicit drug use Symptoms of thyroid disease, pelvic or abdominal pain, weight changes, hirsutism, galactorrhea

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Reproductive Endocrinology and Infertility

Table 16.2. Evaluation of male partner Male: General Category

Specific Points

Length of infertility

Coital frequency, previous fertility, previous infertility treatment

Childhood illnesses and injuries

Mumps, testicular injuries, undescended testes

Family history

Infertility history, inheritable disorders

Urologic surgery

Vasectomy, herniorrhaphy

Past medical history

Diabetes, multiple sclerosis, STDs, recent febrile illnesses

Environmental toxins

Heat, pesticides, industrial toxins

Medication and allergy history

Sulfasalazine, cimetidine (gonadotoxic but reversible); antihypertensives, antipsychotics, antidepressants (ejaculatory dysfunction); anabolic steroids (decreased spermatogenesis)

Social history

Tobacco use (decreased motility), alcohol use, illicit drug use (marijuana- decreased sperm count)

Review of systems

Impotence, ejaculatory dysfunction

16 insulin resistance, a common finding with polycystic ovarian syndrome (PCOS). Other important features to note are: a “buffalo hump” (Cushing’s syndrome); short stature, webbed neck, and shield chest (Turner’s syndrome). Finally, a complete pelvic examination is crucial during the initial visit and should include evaluation for Mullerian defects, pelvic or abdominal masses, or tenderness, cervical abnormalities, and nodularity in the cul-de-sac. One should consider performing a cervical culture as well due to the association of chlamydia cervicitis and PID. During the examination of the male partner, one should first evaluate height, evidence of disproportionate limb length, secondary sexual characteristics, and gynecomastia (Klinefelter’s syndrome). The genitourinary examination should include location of the urethral meatus (hypospadias), palpating the testes for location and size, palpating bilateral vas deferens, and noting any varicocele. The evaluation of the infertile couple often includes a panel of screening tests. This includes a cervical Pap smear, maternal blood type and Rh, antibody screening, rubella status, RPR (syphilis), varicella status, hepatitis B, and cystic fibrosis. Screening for sexually transmitted diseases is also recommended for patients at high risk, and would include hepatitis C, HIV 1 and 2, HTLV, CMV, chlamydia, and gonorrhea. Once the initial screening tests are obtained, it is important to first document evidence of ovulation. This may be performed using basal body temperature charting (biphasic→ovulatory), urinary LH surge detection kits, or serum progesterone levels (>5 ng/ml→ovulatory). An endometrial biopsy (showing secretory phase) may also be performed, but this has limited use due to the cost and invasive nature of the test. “Luteal phase defect” is a condition in which inadequate progesterone is produced by the corpus luteum as evidenced by endometrial histological dating. This is a controversial topic when used in the evaluation of the infertile couple, and recent

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evidence suggests that an endometrial biopsy for histological dating does not differentiate fertile from infertile women, and thus, should not be used in the routine evaluation of infertility. Routine laboratory tests for infertility include a prolactin level (normal 10 mIU/mL), the test is abnormal. There is some evidence that the sensitivity of the clomiphene challenge test is higher than a basal CD3 FSH level (26% vs. 8%), although both tests are routinely used. 16 Lastly, an antral follicle count (AFC) may be obtained using transvaginal ultrasonography to assess the number of primordial follicles during the early follicular phase. In general, an AFC count of 7.2 20 million/mL >40 million/ejaculate >50% >2 (scale 0-4) >14% normal