Herbal Medicine Applications for Polycystic Ovarian Syndrome 1032383712, 9781032383712

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Herbal Medicine ­Applications for ­Polycystic Ovarian ­Syndrome Polycystic ovarian syndrome (PCOS) is a multifaceted reproductive, metabolic syndrome, and its symptoms involve interactions between hormones, genes, and environmental stressors. The characteristic symptoms of PCOS include menstrual abnormalities such as oligomenorrhea or amenorrhea. The general symptoms of PCOS are anovulation or oligo-ovulation. Herbal Medicine Applications for Polycystic Ovarian Syndrome provides comprehensive information on different aspects of PCOS, including its pathogenesis, symptoms, therapies, and management, particularly through herbal remedies. With 13 chapters related to different aspects of PCOS, this book provides enormous knowledge about the pathogenesis and role of different therapeutic strategies globally. These chapters have been contributed by researchers from across the globe from Europe to Asia, who highlight the importance of herbal medicines in the treatment of a reproductive disorder such as PCOS. This book also serves as a simple compendium for undergraduate and postgraduate students, researchers, and pharmaceutical companies to understand the fundamental concepts of herbal treatment use with regard to basic mechanisms, sources, and positive impact. Readers will find an articulate package of knowledge compiled about pathogenesis and complications of PCOS and the role of herbs in the development of drugs for the treatment of reproductive disorders.

Herbal Medicine ­Applications for ­Polycystic Ovarian ­Syndrome

Edited by

Younis Ahmad Hajam, Rajesh Kumar, D. R. Thakur, and Seema Rai

Designed cover image: © Shutterstock First edition published 2024 by CRC Press 2385 NW Executive Center Drive, Suite 320, Boca Raton FL 33431 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN CRC Press is an imprint of Taylor & Francis Group, LLC © 2024 Younis Ahmad Hajam, Rajesh Kumar, D. R. Thakur, and Seema Rai Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright. com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact mpkbookspermissions@ tandf.co.uk Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. ISBN: 9781032383767 (hbk) ISBN: 9781032383712 (pbk) ISBN: 9781003344728 (ebk) DOI: 10.1201/9781003344728 Typeset in Times by codeMantra

Contents Forewords..................................................................................................................vii Editors........................................................................................................................ix Preface.................................................................................................................... xiii List of Contributors................................................................................................... xv Chapter 1 Polycystic Ovarian Syndrome (PCOS): Signs, Symptoms, Epidemiology, Environmental Stress, Management Strategies and Current Therapies...........................................................................1 Younis Ahmad Hajam, Rajesh Kumar, Neelam, D. R. Thakur, and Seema Rai Chapter 2 Polycystic Ovarian Syndrome (PCOS): Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis: a Perspective Toward Control of PCOS................................................. 19 Namrata, Manisha, Neeru, Indu Sharma, Rajesh Kumar, and Arup Giri Chapter 3 Potential Phytotherapeutic Intervention for the Treatment of Polycystic Ovarian Syndrome............................................................. 71 Seema Rai, Sushmita Pal, Adyasha Purohit, Sunita Patel, Kshipra Xaxa, Gunja Roy, Younis Hajam Ahmad, and Rajesh Kumar Chapter 4 Polycystic Ovarian Syndrome (PCOS): The “Green Healers” an Ayurvedic Eye................................................................................ 91 Shikhar Deep, Ashvani Kumar Srivastav, Sangeeta Rai, and Radha Chaube Chapter 5 Concept of Polycystic Ovarian Syndrome: Anti-PCOS Plants in the Unani System of Medicines.................................................... 111 Neha Salaria, Indu Kumari, Neeraj, Diksha Pathania, and Rajesh Kumar

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Chapter 6 Therapeutic and Pharmacological Perspectives of Some Herbal Resources for the Treatment of Polycystic Ovarian Syndrome: A Fast-Spreading Endocrine Disorder.............................................. 131 Suresh Kumar, N. Mahakud, Adyasha Purohit, Sunita Patel, Kshipra Xaxa, Gunja Roy, Younis Ahmad Hajam, and Seema Rai Chapter 7 Molecular Insight of Active Plant-Based Drug Molecules for the Treatment of PCOS................................................................ 165 Sandhya Sharma, Haleema Sabia, Sonam Singh, and Radha Chaube Chapter 8 Current Understanding on Pathophysiological Insight and Experimental Animal Model to Study Polycystic Ovarian Syndrome (PCOS) and the Role of Phytobiotics as a Potential Therapeutic Intervention................................................................... 191 Shruti Nagrath, Abhinav Bhardwaj, and Vijay K. Bharti Chapter 9 Tanshinone IIA, Curcumin, and Rutin Phytotherapy: A Natural Treatment for Polycystic Ovarian Syndrome................... 213 Rajesh Kumar, Lovepreet Kaur, Neelam, Younis Ahmad Hajam, and Seema Rai Chapter 10 Apigenin, Catechins and Soy Isoflavones as a Natural Treatment for Polycystic Ovarian Syndrome.................................... 227 Aksh Sharma and Surbhi Chapter 11 Resveratrol, 6-Gingerol, and Quercetin as a Natural Treatment for Polycystic Ovarian Syndrome.................................... 253 Zoya Shaikh, Ulas Acaroz, and Ahmad Ali Chapter 12 Role of Environmental Factors in PCOS Development and Progression........................................................................................ 281 Indu Sharma, Chahat Dhawan, Pallavi Arora, Pritika Chandel, and Smita Bhattacharjee Chapter 13 Melatonin as a Possible Chronobiotic/Cytoprotective Therapy in Polycystic Ovarian Syndrome......................................... 301 Daniel P. Cardinali, Seema Rai, and Eduardo Spinedi Index....................................................................................................................... 327

Forewords Dr. V. M. Katoch It is my great pleasure to write the foreword for this book entitled Herbal Medicine Applications for Polycystic Ovarian Syndrome compiled and edited by Dr. Younis Ahmad Hajam, Dr. Rajesh Kumar, Dr. D. R. Thakur, and Dr. Seema Rai. PCOS has emerged as a serious public health problem in India and many other parts of the world. It needs an integrative medicine approach for its prevention and management. Herbal medicine, which has been practiced in both ancient Ayurvedic/Siddha/Unani/other systems and Allopathy/ Phytomedicine, will have relevance for PCOS. This book is rich and diverse in content and presents an extensive range of chapters on the key aspects associated with the different facets of a very common but understudied female reproductive disorder. This book is a compilation of the various aspects of PCOS such as historical perspective, pathogenesis, environmental stress, role of environmental factors in PCOS development and progression, management strategies and current therapies, regulation of hypothalamus–pituitary gonadal axis and steroidogenesis, potential phytotherapeutic interventions for the treatment of PCOS, the “green healers”: an Ayurvedic eye, anti-PCOS plants in the Unani system of medicine, molecular insights into mechanisms of action of active plant-based drug molecules for the treatment of PCOS, the role of different herbal bioactive components, and melatonin as a possible chronobiotic–cytoprotective adjuvant therapy in PCOS, and related aspects. I am optimistic that this compilation will be of immense interest to various categories of readers (students, teachers, researchers, and other academicians) working in different basic as well as applied life sciences; I congratulate the editorial team and all contributors for putting together such an exhaustive compilation of excellent chapters on various aspects of PCOS. In my view, this book has a lot of futuristic value and will further evolve, as science on PCOS grows. I would like to encourage all readers of this book, especially those who may be stimulated by its insights and contents, to join the editors in further strengthening this fascinating, challenging, and rewarding endeavor by sharing their feedback and expectations for the future.

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Forewords

Dr. V. M. Katoch M.D. (Microbiology), MD, FNASc, FASc, FAMS, FNA President, JIPMER, Puducherry; Chairman, LEPRA Society; President, Tuberculosis Association of India; Editor, Indian Journal of Leprosy; Former Secretary, Department of Health Research, Government of India and Director-General, Indian Council of Medical Research & Former President, AIIMS, Madurai; Former NASI-ICMR Chair on Public Health Research at Rajasthan University of Health Sciences (RUHS)

Prof. R. C. Sobti Various treatments are available and used for the treatment of PCOS; however, these drugs are not efficient to eradicate this disorder at the root level. Moreover, this disorder is associated with the development of other metabolic disorders such as diabetes, obesity, and insulin resistance. The prevalence rates of PCOS range from 2.2% to 22.5% in different countries. It is 4% in USA, 8.5% in Brazil, 16.6% in Denmark, and 19.9% in Turkey. In Asian countries, the prevalence of PCOS varies viz. 5.6% in China, 5.3% in Thailand, 15.2% in Iran, and 3.7% to 36% in India. The first volume of this book entitled Herbal Medicine Applications for Polycystic Ovarian Syndrome contains 13 chapters contributed by different researchers across Asia and Europe and provides a balanced approach on the different aspects of PCOS by giving detailed information on pathogenesis and herbal treatments. This book is unique and would be an ideal source of current updated literature towards the development of drugs devoid of side effects for the treatment of PCOS. I greatly appreciate the efforts put by the editors for successfully bringing out this impressive volume.

  Prof. R. C. Sobti (Padma Shree Awardee) M.Sc (Hons Sch), Ph.D., D.Sc., F.T.W.A.S., F.N.A., F.N.A.Sc, F.Z.S., F.A.M.S., F.P.A.S., F.A.M.I., F.S.C.G., Ex VC, PU & BBRAU INSA Sr. Scientist, and Professor Emeritus, Department of Biotechnology Panjab University, Chandigarh, India

Editors Dr. Younis Ahmad Hajam holds a doctorate in Zoology from Guru Ghasidas Vishwavidyalaya (a central university), Bilaspur, Chhattisgarh, India. He is currently working as Assistant Professor in the Department of Life Sciences and Allied Health Sciences, Sant Baba Bhag Singh University, Padhiana, Jalandhar, Punjab, India. Prior to that, Dr.  Younis Ahmad had worked as Assistant Professor and Head, Department of Zoology, Career Point University, Hamirpur, Himachal Pradesh, India. He is teaching undergraduate, postgraduate, and doctorate students. Dr. Younis Ahmad has ­published 35 research papers in leading national and international journals, 35 book chapters, and 4 national proceedings. Dr. Younis Ahmad has published four books as an editor with Taylor & Francis Group. He has guided 5 M.Sc. students under thesis mode and 31 M.Sc. students under project mode. Dr. Younis Ahmad is currently guiding four Ph.D. students and two M.Sc. students on their thesis/dissertation work. Dr. Younis Ahmad has completed one major research project (Co-PI) and three projects under the Himachal Pradesh Chief Minister Startup Scheme. Dr. Younis Ahmad has also served as a Junior Research Fellow in Zoology at the Guru Ghasidas Central University, Bilaspur, Chhattisgarh, India. He has presented his research work in more than 35 national and international conferences and has attended more than 30 national and international conferences and 5 workshops. He has organized various conferences, seminars, workshops, and webinars at national and international level. Dr. Younis Ahmad has also delivered lectures in international conferences. He has received the Young Scientist Award at the national level for his contributions in biological science. He is an editorial member of various international journals and is also member of the Asian Council of Science editors. Dr. Rajesh Kumar did his Masters and Ph.D. in Zoology from Jiwaji University, Gwalior (M.P.), India. He is currently working as Assistant Professor in Department of Biosciences, Himachal Pradesh University, Shimla (Himachal Pradesh), India. He has more than 9 years of experience in teaching and research. His core areas of research are animal physiology, applied zoology, nutraceuticals, and biodiversity conservation. During Ph.D., he was awarded the Junior Research Fellowship by the University Grants Commission under the meritorious students science scheme. Dr. Kumar has successfully completed two major research projects and two CM startup projects in the areas of honeybee physiology/ ix

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nutrition and waste management sponsored by Government of Himachal Pradesh. He has also completed one self-sustaining project entitled “Establishment of vermicompost unit under clean campus green campus”. Dr Kumar has published around 100 research articles, including 25 book chapters in indexed journals/publishers such as Elsevier, Springer, Scopus, WoS, CRC Press, and AAP, 10 research papers in fulllength proceedings, 5 books (CRC Press/Springer, etc.), 04 monographs, and 80 abstracts, and has participated in more than 75 national/international conferences. He has also received 12 awards including best researcher, young scientist and best teacher from various organizations. He has successfully supervised 2 Ph.D., 1 M.Phil., and 43 M.Sc. students on their research work, and currently 3 Ph.D. candidates are working under his supervision. Dr. Kumar has successfully organized more than 20 national-level academic events/conferences by collaborating with various government agencies such as NITI Aayog, DEST, HIMCOSTE, and NABARD and delivered more than 15 invited talks/extension lectures in different institutions. He is life/fellow member of various prestigious scientific agencies such as ISC, HBSRA, STRA, and ISZS and also a reviewer of several journals of national and international repute. Dr. Kumar has more than 300+ google citations, a h-index of 10, i10 index of 12, and a Vidwan score of 9.7/10. Prof. D. R. Thakur (Ph.D, DHE, MJMC) is presently working as Sr. Professor in the Department of Biosciences, Himachal Pradesh University, Summerhill, Shimla, HP. He joined HP University in 2001 after serving as Lecturer in the Department of Education, Government of HP for about 7 years. Dr. D. R. Thakur has served as the Chairman Department of Biosciences and presently serving as Director, UGC-HRDC, ISW and Chairman, University Resource Mobilization Module, Himachal Pradesh University, Shimla. He has guided 2 PDF, 8 Ph.D., and 36 M.Phil. students, and completed 4 research projects from different granting agencies and published about 160 research papers of national and international repute. He is a life member of many national and international academic bodies and has visited many foreign nations for academic activities. He is member expert of State Wetland Authority, HIMCOSTE, Government of HP; Member Task Force, MOEF&CC, Government of India; and member expert, evaluator, examiner, research advisor, and moderator of many state and central universities and State Public Service Commissions. D. R. Thakur has been awarded 6 prizes and awards by different agencies and societies and has published 13 new and first records from India. He is also a pioneer to compile the fauna diversity of a high-altitude wetland called “Chandertal”, which is a Ramsar site in Trans-Himalayas.

Editors

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Dr. Seema Rai, Professor, Department of Zoology, Dean School of Studies of Life Science, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India, grew up in Lucknow, Uttar Pradesh, India, received her Bachelor’s degree in Zoology Honors from the Parana University, Bihar, India, and completed her postgraduation and Ph. D. (Zoology) from Banaras Hindu University, Varanasi, India. She has been awarded the DSST-Young Scientist and CSIR-Pool Scientist. Dr. Rai availed Post Doctoral Fellowship to work in collaboration with the Department of Pharmacology, University of Insubria, Varese, Italy and Institute of Pathology, Locarno Switzerland. She was a recipient of the most prestigious award of INSA Visiting Scientist under INSA Bilateral Exchange Program at the Department of Vertebrate Physiology, University of Warsaw, Poland, in 2012. Recently she was honored with the S L Mishra Medal Award, BIOVED Fellow Award 2020, BRIATS, Allahabad, Dr. Mrs. Jagadiswari Rao Women Scientist Award-2021, and many more for her outstanding contributions in the field of reproductive biology and neuroendocrinology. Professor Rai has successfully guided 3 Ph.D.s, and 4 scholars are presently pursuing their Ph.D. She has more than 60 publications to her credit along with one international book. Professor Rai is a life member of various societies and editorial member of many peer-reviewed national and international journals.

Preface Health is a state of complete physical, mental, and social well-being, and not simply the absence of disease. Reproductive health refers to total wellbeing of all reproduction aspects along with physical, social, emotional and mental state. Because of the active contribution of women in the continuation of race, women’s health decides the health of a society. There are various reproductive issues that women face during their reproductively active phase. Polycystic ovarian syndrome (PCOS) is one of the common reproductive disorders that women are facing in the current era. PCOS is an under-recognized, underdiagnosed, and understudied disease, affecting vast numbers of female population round the globe especially in developing countries. In 1935, Stein and Leventhal first discovered PCOS in women. Therefore, the disease is also known as Stein and Leventhal syndrome. The pathogenesis of PCOS is multifaceted but still it is an understudied disorder. Various mechanisms are proposed that involve interactions between certain hormones, genes, and environmental stressors. The characteristic symptoms of PCOS include menstrual abnormalities, oligomenorrhea, or amenorrhea. The general symptoms of PCOS are anovulation or oligo-ovulation. The excessive production of androgens is only due to cysts which further leads to virilization or the expression of masculine characters in females. As a result, PCOS causes appearance of a range of male-like characters or hyperandrogenism. Physical signs of hyperandrogenism are obesity, abdominal and subcutaneous fat, hirsutism, alopecia, clitoromegaly, deep voice, seborrhea, acne, etc. In addition to these morphological signs, changes in metabolic profile take place. Herbal medicines are complex interventions with the potential for synergistic and antagonistic interactions between compounds. Flavonoids are potential complex molecules having several beneficial properties and exhibit antimicrobial, antiviral, antiulcerogenic, cytotoxic, antineoplastic, antiinflammatory, antioxidant, antihypertensive, hepatoprotective, hypolipidemic and antiplatelet activities. Effects within the body may also show complications by concurrent interactions with different systems of body, both biochemically and by changing functions of organs. Preliminary evidence during preclinical and clinical studies shows that six herbal medicines may have beneficial effects for women with oligo/amenorrhea, hyperandrogenism, and PCOS. Further studies are required to know the mechanism of action of different bioactive components for these common conditions. The current medical treatment is limited by its narrow therapeutic approach and by the side effects of some medications. This book is a compendium of different aspects of PCOS providing enormous knowledge about the pathogenesis and role of different therapeutic strategies across the globe. Therefore, based on the available literature, it becomes clear that bioactive components might be helpful to combat the worst reproductive disorder.

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This book contains 13 chapters from authors of diverse fields such as pathogenesis, symptoms, historical perspective, Ayurvedic, Unani, allopathic drugs, and plant-based products, and these have been broadly discussed in these chapters. These chapters have been contributed by researchers from across the globe from Europe to Asia, thus highlighting the pathogenesis of PCOS and the role of different remedies in the treatment of PCOS. Editors Dr. Younis Ahmad Hajam Dr. Rajesh Kumar Prof. D. R. Thakur Prof. Seema Rai

List of Contributors Ulas Acaroz Department of Food Hygiene and Technology Faculty of Veterinary Medicine Afyon Kocatepe University and ACR Bio Food and Biochemistry Research and Development Afyonkarahisar, Turkey Ahmad Ali Department of Life Sciences University of Mumbai Mumbai, India Pallavi Arora Department of Zoology Punjab University Chandigarh, India Abhinav Bhardwaj Department of Pathology Command Hospital Bangalore, India Vijay K. Bharti DRDO-Defence Institute of High Altitude Research (DIHAR) Ladakh UT, India Smita Bhattacharjee Department of Zoology Punjab University Chandigarh, India Daniel P. Cardinali Faculty of Medical Sciences Pontificia Universidad Católica Argentina Buenos Aires, Argentina

Pritika Chandel Department of Zoology Punjab University Chandigarh, India Radha Chaube Department of Zoology Institute of Science, Banaras Hindu University Varanasi, India Shikhar Deep Department of Zoology Institute of Science, Banaras Hindu University Varanasi, India Chahat Dhawan Department of Zoology Punjab University Chandigarh, India Arup Giri Department of Zoology Baba Mast Nath University Haryana, India Younis Ahmad Hajam Department of Life Sciences and Allied Health Sciences University Institute of Sciences, Sant Baba Bhag Singh University Jalandhar, India Lovepreet Kaur Department of Life Sciences and Allied Health Sciences, University Institute of Sciences Sant Baba Bhag Singh University Jalandhar, India

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Rajesh Kumar Department of Biosciences Himachal Pradesh University Shimla, India Suresh Kumar Department of Biosciences Himachal Pradesh University Shimla, India

List of Contributors

Neeraj Department of Life Sciences, Arni School of Basic Sciences Arni University Kangra, India Neeru Department of Zoology Baba Mastnath University Rohtak, India

Indu Kumari Department of Life Sciences, Arni School of Basic Sciences Arni University Kangra, India

Sushmita Pal Department of Zoology Guru Ghasidas Vishwavidyalaya Bilaspur, India

N. Mahakud Department of Zoology Guru Ghasidas Vishwavidyalaya Bilaspur, India

Sunita Patel Department of Zoology Guru Ghasidas Vishwavidyalaya Bilaspur, India

Manisha Department of Zoology Baba Mastnath University Rohtak, India

Diksha Pathania Department of Life Sciences, Arni School of Basic Sciences Arni University Kangra, India

Shruti Nagrath Department of Microbial Biotechnology Panjab University Chandigarh, India Namrata Department of Zoology Baba Mastnath University Rohtak, India Neelam Department of Life Sciences and Allied Health Sciences University Institute of Sciences, Sant Baba Bhag Singh University Jalandhar, India

Adyasha Purohit Department of Zoology Guru Ghasidas Vishwavidyalaya Bilaspur, India Sangeeta Rai Department of Obstetrics and Gynaecology Institute of Medical Science, Banaras Hindu University Varanasi, India Seema Rai Department of Zoology Guru Ghasidas Vishwavidyalaya Bilaspur, India

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Gunja Roy Department of Zoology Guru Ghasidas Vishwavidyalaya Bilaspur, India Haleema Sabia Department of Zoology Institute of Science, Banaras Hindu University Varanasi, India Neha Salaria Department of Life Sciences, Arni School of Basic Sciences Arni University Kangra, India Zoya Shaikh Department of Life Sciences University of Mumbai Mumbai, India Aksh Sharma Sant Baba Bhag Singh University Jalandhar, India Indu Sharma Department of Zoology Panjab University Chandigarh, India Sandhya Sharma Department of Zoology Institute of Science, Banaras Hindu University Varanasi, India

Sonam Singh Department of Zoology Institute of Science, Banaras Hindu University Varanasi, India Eduardo Spinedi Centre for Experimental and Applied Endocrinology (CENEXA, UNLP-CONICET-FCM) CEAS-CICPBA, La Plata Medical School La Plata, Argentina Ashvani Kumar Srivastav Department of Zoology Institute of Science, Banaras Hindu University Varanasi, India D. R. Thakur Department of Biosciences Himachal Pradesh University Shimla, India Kshipra Xaxa Department of Zoology Guru Ghasidas Vishwavidyalaya Bilaspur, India

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Polycystic Ovarian Syndrome (PCOS) Signs, Symptoms, Epidemiology, Environmental Stress, Management Strategies and Current Therapies Younis Ahmad Hajam Sant Baba Bhag Singh University

Rajesh Kumar Himachal Pradesh University

Neelam Sant Baba Bhag Singh University

D. R. Thakur Himachal Pradesh University

Seema Rai Guru Ghasidas Vishwavidayalaya (A Central University)

CONTENTS 1.1 Introduction.......................................................................................................2 1.1.1 Characteristics.......................................................................................4 1.1.2 Signs and Symptoms..............................................................................4 1.2 History of PCOS................................................................................................4 1.3 Pathogenesis of PCOS.......................................................................................6 1.3.1 Hormones...............................................................................................6 1.3.2 Environmental Stressors........................................................................7 1.3.3 Genetic Factors......................................................................................7

DOI: 10.1201/9781003344728-1

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Herbal Medicine Applications for Polycystic Ovarian Syndrome

1.4 Risk Factors of PCOS........................................................................................7 1.5 Prevalence of PCOS..........................................................................................9 1.6 Effect of the Diagnostic Criteria on Prevalence................................................9 1.7 Conclusion....................................................................................................... 10 Bibliography............................................................................................................. 10

1.1 INTRODUCTION According to the World Health Organization, fitness isn’t always the absence of sickness or infirmity; however, it involves a balance between physical, mental, and social well-being. Although this definition of fitness might also appear unrealistic, nowhere it greater appropriates and is justified than in subject of reproductive fitness. Because of the energetic contribution of females, their fitness makes a society fit and healthy (Fathalla, 1997). Woman who finds it hard to conceive cannot be taken into consideration as healthy and effective because of the stress elevation inside the blood and exposure of fetus to an ordinary biophysical profile. According to this constructive expertise, the reproductive fitness of a country is decided on the basis of physical, mental, and social well-being, as well as the absence of sickness or soreness during the reproductive technique. Reproductive fitness consists of folks who can reproduce, manage fertility, and attain and revel in intimate relationships with the absence of infection or sickness. It additionally indicates that the delivery of a newborn and its survival, healthful boom, and improvement are going well. Sexual fitness of females is utmost important to have a good reproductive system, which makes their lives comfortable, increases the tendency of decisionmaking, and facilitates while planning for pregnancy. Women’s reproductive and sexual fitness issues, together with menstruation, fertility, delivery management, pregnancy, sexually transmitted infections, menopause, endometriosis, and polycystic ovarian syndrome (PCOS), are associated with distinct life stages. Concerns related to the reproductive fitness in women consist of mutilations in reproductive organs or organs that are managed with the aid of using the estrogen in females. Several illnesses related to the reproductive device in women are curable, while a few are chronic or are deadly. Many forms of illnesses or problems disturb fertility while sexual assaults, social sites, pollutants, and exquisite quantity of endocrine toxicants increase instances of hormonal conflicts. All such unusual reproductive and hormonal irregularities, along with endometriosis, may cause absence/untimely periods, PCOS, fibroids, infertility, most cancers in ovary, miscarriage, ectopic pregnancy, untimely delivery, etc. (Akhter et al., 2017; Rai et al., 2015). PCOS is a collection of illnesses, which affects women’s reproductive system, especially those in older age. PCOS is not an unusual endocrine situation that affects women of reproductive age. It is an underrecognized, underdiagnosed, and understudied infection that disproportionately influences women worldwide, particularly in underdeveloped nations. Stein and Leventhal first recognized women with PCOS in 1935 (Azziz and Adashi, 2016). Some researchers also call it Stein and Leventhal syndrome. In preliminary stages, PCOS in women continues to be undiagnosed. Therefore, the long-term hazards associated with PCOS are diabetes

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Signs, Symptoms, Epidemiology, Stress, and Therapies of PCOS

mellitus (T2DM) and cardiovascular disorders. PCOS is an endocrine disorder in addition to reproductive diseases accounting for its incidence among 5%–25% (Gill et al., 2012) in female population. Women of reproductive age had oligoovulation (O), hyperandrogenism (H), and polycystic ovaries (revised 2003 consensus on diagnostic standards, 2004). PCOS is principally H in addition to O at some stages in the reproductive age, leading to infertility (Rosenfield and Ehrmann, 2016) and medical or metabolic disorders (Detti et al., 2015). The characteristics of PCOS are depicted in Figure 1.1. Women who’ve metabolic and reproductive troubles are much more likely to become infertile and develop endometrial cancer; hence, early detection and powerful remedies are essential for its control (Fearnley et al., 2010). Currently, there is powerful proof linking PCOS with obesity, insulin resistance, and a better threat of growing noninsulin-based T2DM (Lee et al., 2009). PCOS is moreover responsible for causing specific continual health troubles, metabolic troubles, and intellectual troubles, such as cardiovascular diseases, horrible self-esteem, venous thromboembolism, and anxiety (Bird et al., 2013). The situation referred to as PCOS alters the quantities of hormones in women. More male hormones are produced than that is normal by means of PCOS-affected women. Due to the imbalance, menstruation may not be in time and may additionally contribute to baldness, frame hair, and facial hair (Basheer et al., 2018; Rani et al., 2022).

Estrogen Progesterone LH:FSH ratio Testosterone

Hormonal alterations

Ros Oxidative enzymes Lipid peroxidation

Oxidative stress

Cysts

Histological changes

Polycystic Ovary

Uterus

d lle ro nt en co rog Un and

Cyst formation sub capsular cyst, hyperplasia of theca interna

Ag te

va

a gr

Androgen excess

Oligoovulation Alopecia

Infertility Hirsutism Acanthosis nigricans

Hyperandrogenism, Anovulation

FIGURE 1.1  The PCOS-induced complications such as hormonal, hirsutism, hyperandrogenism, anovulation, acanthosis nigricans oxidative stress, and histological changes.

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1.1.1  Characteristics

i. One common hormonal situation affecting girls of childbearing age is PCOS. ii. Women with PCOS may also additionally have shorter or longer menstrual cycles because of multiplied testosterone levels. iii. The ovaries may also additionally collect a few fluids (follicles) and no longer launch eggs regularly. iv. Commonly in all cases, females with PCOS may have abnormal menstrual cycles and an additional accumulation of male hormones (androgen). v. The situation is known as, after the invention, an enlarged ovary containing many small cysts (polycystic ovaries). vi. Most women with PCOS have polycystic ovaries.

1.1.2 Signs and Symptoms Some signs and symptoms of PCOS may frequently be seen throughout puberty. Sometimes, PCOS at later stages may develop sizable weight gain. The symptoms and signs of PCOS vary from individual to individual. Irregular intervals: Infrequent, abnormal, or lengthy menstrual cycles are the signs and symptoms of PCOS. For example, one can have fewer than nine intervals a year, more than 35 days among intervals, and really heavy intervals. Excess androgen: Elevated testosterone degrees may exhibit bodily symptoms, which include immoderate facial and frame hair (hirsutism) and occasionally extreme pimples and hair loss. Polycystic ovary: The ovaries might also additionally develop and incorporate follicles surrounding the egg. As a result, the ovaries might also additionally feature irregularly. Type-2 diabetes: It has additionally been pronounced that females with PCOS have a bourgeoned danger of growing T2DM.

1.2  HISTORY OF PCOS PCOS mainly occurs due to misbalancing of sex hormones and leads to the formation of cysts in the antral follicles of female ovaries. A cyst is formed of fluid-filled sacs enclosing the egg. The changing of egg into a cyst is defined as functional cyst, which further prevents ovulation. The process of ovulation gets suppressed, which subsequently disturbs the menstrual cycle and leads to amenorrhea. When multiple cysts are formed in the ovarian follicles because of imbalances in hormones, then it is termed as PCOS. Due to the fluid filled in the cysts, most of the cysts may be as big as 10 mm large, and the ovary size elevates up to 10 cm wide. The process of fertilization and conception is inhibited due to the absence of ovulation and menstrual cycle, thus pregnancy becomes complicated (Sirmans and Pate, 2014). During implantation, there is elevation in abortion and birth risks. Because of this, eclampsia and

Signs, Symptoms, Epidemiology, Stress, and Therapies of PCOS

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the small-for-gestational-age babies can occur. PCOS also causes pregnancy-related problems such as gestational diabetes and hypertension (Homburg, 2009). Usually, support to the growing follicles is provided by theca cells in the formation of mature oocytes (Young and McNeilly, 2010). However, theca cells in patients with PCOS respond agitatedly to the stimulatory effects of insulin; thus, they multiply and cause hypertricosis. The androgen ability elevates in the ovarian theca cells because of insulin resistance, aggravating PCOS (Wang et al., 2009). The increased sensitivity of theca cells toward the stimulation of luteinizing hormone (LH) and follicle stimulating hormone (FSH) helps to androgenism in PCOS. The key feature that is responsible for PCOS is the distressed secretion of the pulsatile gonadotropin-releasing hormone (GnRH) from hypothalamus (Tsutsumi and Webster, 2009). GnRHs give signals to pituitary glands to secrete gonadotropins. Gonadotropins are very important for the two phases (follicular and ovulatory) of the menstrual cycle. In polycystic ovarian condition, as gonadotropins are present in very less amount, the formation of egg does not take place or is unable to liberate from the follicle. Therefore, the menstrual cycle is disturbed and amenorrhea occurs. Amenorrhea may be classified into two categories: primary and secondary. While primary amenorrhea is a condition in which menarche does not take place because of the genetic or anatomical reasons, whereas secondary amenorrhea or hypothalamic amenorrhea is a condition in which menstrual cycle is absent for three- or more repeated months (Klein and Poth, 2013). The activity of GnRH is blocked due to the presence of increased amounts of lactotrophic hormone, which is a peptide hormone (Marques et al., 2018). Polycystic ovarian circumstance likewise takes place because of the extra quantity of androgen secretion by the interior ovary. Various intrinsic elements such as altered steroidogenesis occur in the outer spheres of the ovary. These elements encompass hyperinsulinemia,inflicting intense manufacturing of the male hormone, i.e., androgen. Women with PCOS have higher risk of developing follicles in comparison to the regular control. The family members among the paracrine, endocrine, and apocrine elements aren’t clean and chargeable for the maturation of follicles and most of these can make a contribution to dysregulation of ovary in PCOS. The improvement of primordial follicles takes place in the course of the maturation of follicles and includes oocytes arrested at meiotic segment enclosed through pregranulosa cells. Ovaries are relatively inactive until the start of puberty. The variations inside the morphology of follicles and increased ability are there within the ovarian tissues received from the women of prepubertal and early puberty. Particularly, excessive quantity of nondeveloping follicles is found in prepubertal ovaries compared with pubertal ovaries (Anderson et al., 2014). Follicle density is the only element which has appeared (Gaytan et al., 2015). After the activation from the inactivation pool, the initial increase of follicles until the astral level is gonadotropin-independent. Ovarian granulosa cells secrete a glycoprotein known as antimullerian hormone (AMH) which prevents the recruitment of follicles and suggests follicular reserve. Contrary to mice, AMH prevents the increase of prenatal follicle and the maturation of follicle. In the ovaries of nonhuman primates compared with that in mice or rats, it can be determined that AMH leads in the increase of prenatal follicles to the astral level (Xu et al., 2016). Peak concentrations of AMHs are determined in follicles. The expression of AMH is suppressed through estradiol (Dumont et al., 2018).

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Herbal Medicine Applications for Polycystic Ovarian Syndrome

Notwithstanding preceding statements that androgens negatively affect follicles, the synthesis of androgen takes place in prenatal follicle, and the increase of prenatal and follicles promoted through theca cells set off the expression of granulosa mobileular FSH receptor in early antral follicles (Franks and Hardy, 2018). Androgens aid the expression of aromatase enzyme and, eventually, granulosa cells additionally aid the expression of LH/chorionic gonadotropin receptor (LHCGR). As the maturation of follicles takes place, androgen seems to save the affected women from proliferation and aid mobileular death. This biphasic movement of androgen becomes first to be showed in a nonhistone protein, the marmoset (nonhuman primates); the movement of FSH is extended through androgens in small follicles, however in large follicles an inhibitory effect is confirmed (Laird et al., 2017). Androgen receptors (ARs) mediate the moves of androgens which can be expressed in theca cells of ovary, granulosa cells, oocytes, and stromal cells (Sen and Hammes, 2010). The gene expression of ARs takes place in small follicles (6 mm in diameter) and decreases in antral and preovulatory follicles (Jeppesen et al., 2012). Classically, the single-most effective dominant follicle is taken into consideration (Kristensen et al., 2018). Pituitary FSH decreases due to the bad remarks by growing the secretion of estrogen. The secretion of principal FSH reduces due to the bad remarks. The dominant follicle compensates for this lack of stimulation of FSH through expanded expression of LHCGR and will increase responsiveness to LH stimulation. Secondary follicles undergo atresia, mainly because of relative deficiency of FSH and addition of the male hormone, i.e., androgen. Upon getting excellent attention of estradiol, neuroendocrine mechanisms prompt the LH surge to set off ovulation. The ovarian stroma offers a structural framework underneath regular situations experiencing dynamic changes to hold the follicular increase, although the ovarian stroma from women having PCOS has a tendency to be highly rigid. Abnormal increase in the course of the early levels of follicular increase probably contributes to the ovarian characters of PCOS (Franks and Hardy, 2018).

1.3  PATHOGENESIS OF PCOS The complex pathophysiology of PCOS has remained an understudied condition in the past. There are numerous hypothesized pathways, a number of which contain interactions among genes, hormones, and environmental stresses.

1.3.1 Hormones Gonadotropins, inclusive of the hormones LH and FSH, in addition to estrogen, progesterone, and testosterone, are vital in the pathophysiology of PCOS. In a great populace of females with PCOS, the range of LH and FSH increases and decreases, respectively (Raju et al., 2013; Saadia, 2020). The LH/FSH ratio increases due to it. The incidence of an excessive LH/FSH ratio sometimes does not take place in PCOSinfected females with ordinary weight and mass index, and it has partial correlation with BMI as well. The upward push in LH is defined through a boom inside the pulse frequency of hypothalamic GnRH. LH receptor-sporting theca cells of the ovaries are inspired to supply testosterone due to the upward push in LH.

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Signs, Symptoms, Epidemiology, Stress, and Therapies of PCOS

1.3.2 Environmental Stressors Obesity and prenatal publicity to androgens have been diagnosed as the important causal variables. Multiple genetic variables make a contribution to PCOS susceptibility, and the syndrome in the presence of a specific environment. It is thought that immoderate maternal androgen publicity at some point of being pregnant performs a big position in improvement of PCOS in fetuses. Moreover, oxidative pressure is another thing that supplies upward thrust to numerous issues, consisting of the PCOS situation. Antioxidants are not explained in detail in nutritional dietary supplements nowadays. This has brought about an alternate in favor of the usage of natural and ayurvedic products. The majority of bioactive additives observed in plants/flora have the capability to deal with issues such as PCOS (Figure 1.2).

1.3.3 Genetic Factors There is proof of a genetic thing primarily based on the presence of familial clustering (Diamanti-Kandarakis et al., 2006). Genetically, same twins had better concordance of PCOS than nonsame twins, in accordance to analyze primarily based on dual data (Vink et al., 2006). The mode of inheritance of PCOS remains unknown, and no longer seems to rely upon genes worried within the manufacture and metabolism of testosterone and insulin (Jones, 2008). The role of genetic alterations in the PCOS-induced psychological issues has been mentioned in Figure 1.3.

1.4  RISK FACTORS OF PCOS There are different factors that are accountable in inflicting PCOS along with genetic, way of life changes, and their combos which can reason PCOS. Thyroid dysfunctioning, hyperprolactinemia, androgen-secreting tumors, Cushing’s syndrome, and congenital adrenal hyperplasia can confine pathogenesis of PCOS. The publicity to chemical

Hypothalamus

GnRH

Anterior pituitary gland FSH

LH

Granulosa cells Theca cells

Ovary

Androgens

FIGURE 1.2  The effect of modulated HPO axis on the hormonal circuit.

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Herbal Medicine Applications for Polycystic Ovarian Syndrome Hirsutisum

Genetics

Hormonal change

sed androgens sed ovarian follicals

Psychological issues

Menstrual disturbance

FIGURE 1.3  The role of genetic alteration in the development of psychological issues and menstrual disturbances.

Depression Adrenal cortex Anterior pituitary gland Hypothalamus

Stress/ Obesity

FIGURE 1.4  The effect of stress and obesity on the hypothalamus, pituitary gland, and adrenal cortex and their role in depression.

compounds has additionally been chargeable for the pathogenesis of PCOS. One can uncover chemical compounds by way of means of some of the methods such as accidental (pesticides, vehicles, commercial pollution, etc.) or cosmetics, floor cleansing agents, chemical therapeutics, etc., which are well known in current times. Various nonpublic care merchandise such as deodorants, sunscreens, hair dyes, etc. are the most important reasons at the back of the growing incidents of PCOS. Most of the consumers are unaware that these so-known as harmless hygiene merchandise are endocrine disruptors. These nonpublic care merchandises include numerous chemical compounds together with phthalates, parabens, isopropanol, glutaraldehyde, benzophenones, turpentine oil, and metals such as nickel sulfate, cobalt chloride, etc. (Yang et al., 2017). Various chemical compounds, along with bisphenols A, are also found in packaged and canned food that can be one of the main reasons for numerous reproductive problems together with PCOS (Konieczna et al., 2015). PCOS also causes depression due to stress and obesity by altering the hypothalamic-pituitary adrenal axis (Figure 1.4).

Signs, Symptoms, Epidemiology, Stress, and Therapies of PCOS

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1.5  PREVALENCE OF PCOS The European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM) in 2003, additionally referred to as the Rotterdam standards, and the Androgen Excess Society and PCOS Society (AE-PCOS) in 2006 have been the primary standards for the analysis of PCOS at a worldwide convention held by the NIH in 1990 (Garad et al., 2011). Every diagnostic criterion has precise scientific and biochemical evaluation that decides whether PCOS is present or absent (Okoroh et al., 2012a). According to the NIH’s 1990 standards, PCOS may be identified in sufferers who showcase O and H signs and symptoms. The want for greater complete diagnostic standards brought about the improvement of the Rotterdam standards from 2003 (Okoroh et al., 2012b). The Rotterdam’s standards are carried out if the affected person reveals signs and symptoms of O, H, and polycystic ovaries (Azziz et al., 2009). The AE-PCOS standards, which have been released in 2006, are carried out if people show symptoms and symptoms of H with scientific or laboratory evidence (Azziz et al., 2009). In 2012, a workshop was held to increase new diagnostic standards. The following phenotypes have been advised during the workshop: I. Excessive androgen or ovulatory dysfunction. II. Polycystic ovarian morphology or androgen excess. III. Polycystic ovarian morphology or ovarian ovulatory failure. IV. Polycystic ovarian morphology, excess androgen, or ovarian dysfunction (Johnson et al., 2012). Currently during 2018, International Guidelines for Polycystic Ovarian Syndrome approve the Rotterdam standards with a few cautions. An ultrasound remains encouraged for phenotyping, although it isn’t always vital for analysis if the affected person has abnormal menstrual durations or H. Teenagers should not go through ultrasounds (Wolf et al., 2018). PCOS is a medical disease and studies have proven that there’s no unmarried set of standards for the analysis of polycystic ovaries (Meurer et al., 2006). According to the diagnostic standards employed, the superiority of PCOS stages from 4% to 10% and has an annual value greater than $4.3 billion (Goodarzi and Azziz, 2006 and Azziz et al., 2005).

1.6  EFFECT OF THE DIAGNOSTIC CRITERIA ON PREVALENCE The incidence of PCOS is distinctly laid low with the modifications made within the diagnostic standards. By combining all the three standards, occurrence turned into as little as 1.6% (Okoroh et al., 2012) and as excessive as 18% (March et al., 2010) in comparable Caucasian populations using Rotterdam standards (Lim et al., 2013). It has been mentioned that 50%–75% of girls with polycystic ovaries are unaware that they have been affected by PCOS (Futterweit, 1999). A retrospective study evaluated a set of 204 age-matched girls who were suspected to have polycystic ovary to determine the incidence primarily based on the diagnostic standards (Amato et al., 2008). It has been reported in step with NIH the superiority of PCOS: Within the diagnosed populace the superiority turned into 51%, in step with Rotterdam’s standards the

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Herbal Medicine Applications for Polycystic Ovarian Syndrome

superiority turned into 83%, in step with AE-PCOS it turned into 70.6%, and below all the three standards the superiority turned into simplest 49% (Amato et al., 2008). Findings revealed that there’s a distinction in the superiority, frequency, and severity of signs and symptoms as well. The Rotterdam standards were used to evaluate all the instances, after which it was redefined and a prognosis was made to the use of the standards of NIH to decide the occurrence of polycystic ovaries in step with the two unique definitions (Broekmans et al., 2006). Under the Rotterdam’s standards, there has been an improved price of immoderate weight, insulin sensitivity, and the prognosis of polycystic ovaries itself (Broekmans et al., 2006). The appropriate businesses and the identical topics have been used on this look to evaluate an actual instance of the variations which could take location among the standards. The incidences of the Rotterdam and AE-PCOS whilst as compared to the NIH standards turned almost two times when assessed for identical topics (March et al., 2010). The loss of uniformity and transparency among the diagnostic standards affect the comparison and the consistency of all medical remedies and studies related to polycystic ovaries. Yildiz et al. (2012) reported that the incidence is substantially laid low with diagnostic standards. Over-prognosis is probably there due to the addition of extra phenotypes in diagnostic standards, and the brand-new addition of nonhyperandrogenic phenotype below the Rotterdam’s standards (Copp et al., 2017). Women, who aren’t having hyperandrogenism, have been identified to have much less continual relation with polycystic ovary, and in few instances nonhyperandrogenic girls are misdiagnosed with polycystic ovaries entirely due to the fact that menstrual disturbances and PCO are probably associated with different conditions (Copp et al., 2017). The definition of PCOS follows strict standards for prognosis (Dewailly et al., 2014), as does the definition of hirsutism (Yildiz et al., 2012). Wolf et al. (2018) reported that a great distinction is gifting within the signs and symptoms throughout the diverse geographical places and among diverse races/ethnicities (Wolf et al., 2018). As current facts do stay limited, different research studies mentioned that there are distinctly great variations in the superiority of polycystic ovaries, its signs and symptoms, and cofactors (Chang et al., 2016).

1.7 CONCLUSION PCOS is a multifaceted endocrine-metabolic disorder. It not only causes reproductive complications but also adversely affects the other systems in the body. Moreover, its symptoms are very diverse that have created main issues in finding the treatment for PCOS. Various therapeutic strategies are available in the market but they are not effective to cure this disease at the root level. Therefore, there is a need to dig out the actual molecular mechanism for the pathogenesis of this disorder.

BIBLIOGRAPHY Akhter, S., Rutherford, S., Kumkum, F.A., Bromwich, D., Anwar, I., Rahman, A. and Chu, C., 2017. Work, gender roles, and health: neglected mental health issues among female workers in the ready-made garment industry in Bangladesh. International Journal of Women’s Health, 9, p. 571.

Signs, Symptoms, Epidemiology, Stress, and Therapies of PCOS

11

Amato, M.C., Galluzzo, A., Finocchiaro, S., Criscimanna, A. and Giordano, C., 2008. The evaluation of metabolic parameters and insulin sensitivity for a more robust diagnosis of the polycystic ovary syndrome. Clinical Endocrinology, 69(1), pp. 52–60. Anderson, R.A., McLaughlin, M., Wallace, W.H.B., Albertini, D.F. and Telfer, E.E., 2014. The immature human ovary shows loss of abnormal follicles and increasing follicle developmental competence through childhood and adolescence. Human Reproduction, 29(1), pp. 97–106. Ansong, E., Arhin, S.K., Cai, Y., Xu, X. and Wu, X., 2019. Menstrual characteristics, disorders and associated risk factors among female international students in Zhejiang Province, China: a cross-sectional survey. BMC Women’s Health, 19(1), pp. 1–10. Asunción, M., Calvo, R.M., San Millán, J.L., Sancho, J., Avila, S. and Escobar-Morreale, H.F., 2000. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. The Journal of Clinical Endocrinology & Metabolism, 85(7), pp. 2434–2438. Azziz, R. and Adashi, E.Y., 2016. Stein and Leventhal: 80 years on. American Journal of Obstetrics and Gynecology, 214(2), pp. 247.e1–e11. Azziz, R., Carmina, E., Dewailly, D., Diamanti-Kandarakis, E., Escobar-Morreale, H.F., Futterweit, W., Janssen, O.E., Legro, R.S., Norman, R.J., Taylor, A.E. and Witchel, S.F., 2006. Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. The Journal of Clinical Endocrinology & Metabolism, 91(11), pp. 4237–4245. Azziz, R., Carmina, E., Dewailly, D., Diamanti-Kandarakis, E., Escobar-Morreale, H.F., Futterweit, W., Janssen, O.E., Legro, R.S., Norman, R.J., Taylor, A.E. and Witchel, S.F., 2009. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertility and Sterility, 91(2), pp. 456–488. Azziz, R., Marin, C., Hoq, L., Badamgarav, E. and Song, P., 2005. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. The Journal of Clinical Endocrinology & Metabolism, 90(8), pp. 4650–4658. Azziz, R., Sanchez, L.A., Knochenhauer, E.S., Moran, C., Lazenby, J., Stephens, K.C., Taylor, K. and Boots, L.R., 2004. Androgen excess in women: experience with over 1000 consecutive patients. The Journal of Clinical Endocrinology & Metabolism, 89(2), pp. 453–462. Baillargeon, J.P., Iuorno, M.J. and Nestler, J.E., 2003. Insulin sensitizers for polycystic ovary syndrome. Clinical Obstetrics and Gynecology, 46(2), pp. 325–340. Bajaj, S., Jawad, F., Islam, N., Mahtab, H., Bhattarai, J., Shrestha, D., Wijeyaratne, C., Muthukuda, D.T., Widanage, N.W., Aye, T.T. and Aung, M.W., 2013. South Asian women with diabetes: psychosocial challenges and management: consensus statement. Indian Journal of Endocrinology and Metabolism, 17(4), p. 548. Basheer, M., Rai, S., Ghosh, H. and Hajam, Y.A., 2018. Protective role of seed extract of Tephrosia purpurea in letrozole induced polycystic ovary syndrome in wistar rats. Journal of Biological Sciences, 18(8), pp. 458–467. Bhattacharya, S.M. and Jha, A., 2011. Prevalence and risk of metabolic syndrome in adolescent Indian girls with polycystic ovary syndrome using the 2009 ‘joint interim criteria’. Journal of Obstetrics and Gynaecology Research, 37(10), pp. 1303–1307. Bird, S.T., Hartzema, A.G., Brophy, J.M., Etminan, M. and Delaney, J.A., 2013. Risk of venous thromboembolism in women with polycystic ovary syndrome: a populationbased matched cohort analysis. Canadian Medical Association Journal, 185(2), pp. 115–120. Boyle, J. and Teede, H.J., 2012. Polycystic ovary syndrome: an update. Australian Family Physician, 41(10), pp. 752–756. Broekmans, F.J., Knauff, E.A.H., Valkenburg, O., Laven, J.S., Eijkemans, M.J. and Fauser, B.C.J.M., 2006. PCOS according to the Rotterdam consensus criteria: change in prevalence among WHO‐II anovulation and association with metabolic factors. BJOG: An International Journal of Obstetrics & Gynaecology, 113(10), pp. 1210–1217.

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Carlsson, I.B., Scott, J.E., Visser, J.A., Ritvos, O., Themmen, A.P.N. and Hovatta, O., 2006. Anti-Müllerian hormone inhibits initiation of growth of human primordial ovarian follicles in vitro. Human Reproduction, 21(9), pp. 2223–2227. Chan, J.L., Kar, S., Vanky, E., Morin-Papunen, L., Piltonen, T., Puurunen, J., Tapanainen, J.S., Maciel, G.A.R., Hayashida, S.A.Y., Soares Jr, J.M. and Baracat, E.C., 2017. Racial and ethnic differences in the prevalence of metabolic syndrome and its components of metabolic syndrome in women with polycystic ovary syndrome: a regional cross-sectional study. American Journal of Obstetrics and Gynecology, 217(2), pp. 189.e1–e8. Chang, A.Y., Oshiro, J., Ayers, C. and Auchus, R.J., 2016. Influence of race/ethnicity on cardiovascular risk factors in polycystic ovary syndrome, the Dallas Heart Study. Clinical Endocrinology, 85(1), pp. 92–99. Chung, E.K., Nurmohamed, L., Mathew, L., Elo, I.T., Coyne, J.C. and Culhane, J.F., 2010. Risky health behaviors among mothers-to-be: the impact of adverse childhood experiences. Academic Pediatrics, 10(4), pp. 245–251. Copp, T., Jansen, J., Doust, J., Mol, B.W., Dokras, A. and McCaffery, K., 2017. Are expanding disease definitions unnecessarily labelling women with polycystic ovary syndrome? British Medical Journal, 358. https://doi.org/10.1136/bmj.j3694 Cuhaci, N., Polat, S.B., Evranos, B., Ersoy, R. and Cakir, B., 2014. Gynecomastia: clinical evaluation and management. Indian Journal of Endocrinology and Metabolism, 18(2), p. 150. Dai, J.B., Wang, Z.X. and Qiao, Z.D., 2015. The hazardous effects of tobacco smoking on male fertility. Asian Journal of Andrology, 17(6), p. 954. Davis, S.R., Knight, S., White, V., Claridge, C., Davis, B.J. and Bell, R., 2002. Preliminary indication of a high prevalence of polycystic ovary syndrome in indigenous Australian women. Gynecological Endocrinology, 16(6), pp. 443–446. De Coster, S. and Van Larebeke, N., 2012. Endocrine-disrupting chemicals: associated disorders and mechanisms of action. Journal of Environmental and Public Health. https://doi. org/10.1155/2012/713696 Detti, L., Jeffries-Boyd, H.E., Williams, L.J., Diamond, M.P. and Uhlmann, R.A., 2015. Fertility biomarkers to estimate metabolic risks in women with polycystic ovary syndrome. Journal of Assisted Reproduction and Genetics, 32(12), pp. 1749–1756. Dewailly, D., Lujan, M.E., Carmina, E., Cedars, M.I., Laven, J., Norman, R.J. and EscobarMorreale, H.F., 2014. Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society. Human Reproduction Update, 20(3), pp. 334–352. Diamanti-Kandarakis, E. and Dunaif, A., 2012. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocrine Reviews, 33(6), pp. 981–1030. Diamanti-Kandarakis, E., Piperi, C., Argyrakopoulou, G., Spina, J., Papanastasiou, L., Bergiele, A. and Panidis, D., 2006. Polycystic ovary syndrome: the influence of environmental and genetic factors. Hormones, 5(1), p. 17. Ding, T., Hardiman, P.J., Petersen, I., Wang, F.F., Qu, F. and Baio, G., 2017. The prevalence of polycystic ovary syndrome in reproductive-aged women of different ethnicity: a systematic review and meta-analysis. Oncotarget, 8(56), p. 96351. Dumesic, D.A., Oberfield, S.E., Stener-Victorin, E., Marshall, J.C., Laven, J.S. and Legro, R.S., 2015. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocrine Reviews, 36(5), pp. 487–525. Dumont, A., Robin, G. and Dewailly, D., 2018. Anti-Müllerian hormone in the pathophysiology and diagnosis of polycystic ovarian syndrome. Current Opinion in Endocrinology, Diabetes and Obesity, 25(6), pp. 377–384.

Signs, Symptoms, Epidemiology, Stress, and Therapies of PCOS

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Dunstan, D.W., Zimmet, P.Z., Welborn, T.A., De Courten, M.P., Cameron, A.J., Sicree, R.A., Dwyer, T., Colagiuri, S., Jolley, D., Knuiman, M. and Atkins, R., 2002. The rising prevalence of diabetes and impaired glucose tolerance: the Australian Diabetes, Obesity and Lifestyle Study. Diabetes Care, 25(5), pp. 829–834. Fathalla, M.F., 1997. From Obstetrics and Gynaecology to Women’s Health: The Road Ahead. Nashville, TN: Parthenon Publishing. Fauser, B.C., Tarlatzis, B.C., Rebar, R.W., Legro, R.S., Balen, A.H., Lobo, R., Carmina, E., Chang, J., Yildiz, B.O., Laven, J.S. and Boivin, J., 2012. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRMSponsored 3rd PCOS Consensus Workshop Group. Fertility and Sterility, 97(1), pp. 28–38. Fearnley, E.J., Marquart, L., Spurdle, A.B., Weinstein, P. and Webb, P.M., 2010. Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case–control study. Cancer Causes & Control, 21(12), pp. 2303–2308. Franks, S., 1995. Polycystic ovary syndrome. New England Journal of Medicine, 333(13), pp. 853–861. Franks, S. and Hardy, K., 2018. Androgen action in the ovary. Frontiers in Endocrinology, 9, p. 452. Futterweit, W., 1999. Polycystic ovary syndrome: clinical perspectives and management. Obstetrical & Gynecological Survey, 54(6), pp. 403–413. Ganie, M.A., Vasudevan, V., Wani, I.A., Baba, M.S., Arif, T. and Rashid, A., 2019. Epidemiology, pathogenesis, genetics & management of polycystic ovary syndrome in India. The Indian Journal of Medical Research, 150(4), p. 333. Garad, R., Teede, H.J. and Moran, L., 2011. An evidence-based guideline for Polycystic Ovary Syndrome. The Australian Nursing Journal: ANJ, 19(4), pp. 30–33. Gaytan, F., Morales, C., Leon, S., Garcia-Galiano, D., Roa, J. and Tena-Sempere, M., 2015. Crowding and follicular fate: spatial determinants of follicular reserve and activation of follicular growth in the mammalian ovary. PLoS One, 10(12), p. 0144099. Gill, H., Tiwari, P. and Dabadghao, P., 2012. Prevalence of polycystic ovary syndrome in young women from North India: a community-based study. Indian Journal of Endocrinology and Metabolism, 16(Suppl 2), p. S389. Gleicher, N., Weghofer, A. and Barad, D.H., 2011. The role of androgens in follicle maturation and ovulation induction: friend or foe of infertility treatment? Reproductive Biology and Endocrinology, 9(1), pp. 1–12. Goodarzi, M.O. and Azziz, R., 2006. Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Practice & Research Clinical Endocrinology & Metabolism, 20(2), pp. 193–205. Goodarzi, M.O., Quiñones, M.J., Azziz, R., Rotter, J.I., Hsueh, W.A. and Yang, H., 2005. Polycystic ovary syndrome in Mexican-Americans: prevalence and association with the severity of insulin resistance. Fertility and Sterility, 84(3), pp. 766–769. Hart, R. and Doherty, D.A., 2015. The potential implications of a PCOS diagnosis on a woman’s long-term health using data linkage. The Journal of Clinical Endocrinology & Metabolism, 100(3), pp. 911–919. Hart, R., Doherty, D.A., Mori, T., Huang, R.C., Norman, R.J., Franks, S., Sloboda, D., Beilin, L. and Hickey, M., 2011. Extent of metabolic risk in adolescent girls with features of polycystic ovary syndrome. Fertility and Sterility, 95(7), pp. 2347–2353. Hidaka, T., Yonezawa, R. and Saito, S., 2013. Kami-shoyo-san, Kampo (Japanese traditional medicine), is effective for climacteric syndrome, especially in hormone-replacementtherapy-resistant patients who strongly complain of psychological symptoms. Journal of Obstetrics and Gynaecology Research, 39(1), pp. 223–228.

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Homburg, R., 2009. Androgen circle of polycystic ovary syndrome. Human Reproduction, 24(7), pp. 1548–1555. Huang, Z. and Yong, E.L., 2016. Ethnic differences: is there an Asian phenotype for polycystic ovarian syndrome? Best Practice & Research Clinical Obstetrics & Gynaecology, 37, pp. 46–55. Jeppesen, J.V., Kristensen, S.G., Nielsen, M.E., Humaidan, P., Dal Canto, M., Fadini, R., Schmidt, K.T., Ernst, E. and Yding Andersen, C., 2012. LH-receptor gene expression in human granulosa and cumulus cells from antral and preovulatory follicles. The Journal of Clinical Endocrinology & Metabolism, 97(8), pp. 1524–1531. Johnson, T.R.B., Kaplan, L.K., Ouyang, P., Rizza, R.A. and National Institutes of Health, 2012. Evidence-Based Methodology Workshop on Polycystic Ovary Syndrome. Bethesda, MD: National Institutes of Health. Jones, G.L., Hall, J.M., Balen, A.H. and Ledger, W.L., 2008. Health-related quality of life measurement in women with polycystic ovary syndrome: a systematic review. Human Reproduction Update, 14(1), pp. 15–25. Joshi, B., Mukherjee, S., Patil, A., Purandare, A., Chauhan, S. and Vaidya, R., 2014. A crosssectional study of polycystic ovarian syndrome among adolescent and young girls in Mumbai, India. Indian Journal of Endocrinology and Metabolism, 18(3), p. 317. Kaczmarek, C., Haller, D.M. and Yaron, M., 2016. Health-related quality of life in adolescents and young adults with polycystic ovary syndrome: a systematic review. Journal of Pediatric and Adolescent Gynecology, 29(6), pp. 551–557. Kaewnin, J., Vallibhakara, O., Arj-Ong Vallibhakara, S., Wattanakrai, P., Butsripoom, B., Somsook, E., Hongsanguansri, S. and Sophonsritsuk, A., 2018. Prevalence of polycystic ovary syndrome in Thai University adolescents. Gynecological Endocrinology, 34(6), pp. 476–480. Kauffman, R.P., Baker, V.M., DiMarino, P., Gimpel, T. and Castracane, V.D., 2002. Polycystic ovarian syndrome and insulin resistance in white and Mexican American women: a comparison of two distinct populations. American Journal of Obstetrics and Gynecology, 187(5), pp. 1362–1369. Kaur, J., Patil, M., Kar, S., Jirge, P.R. and Mahajan, N., 2019. Distribution of anthropometric, clinical, and metabolic profiles of women with polycystic ovary syndrome across the four regions of India. The Onco Fertility Journal, 2(1), p. 20. Klein, D.A. and Poth, M.A., 2013. Amenorrhea: an approach to diagnosis and management. American Family Physician, 87(11), pp. 781–788. Knochenhauer, E.S., Key, T.J., Kahsar-Miller, M., Waggoner, W., Boots, L.R. and Azziz, R., 1998. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. The Journal of Clinical Endocrinology & Metabolism, 83(9), pp. 3078–3082. Konieczna, A., Rutkowska, A. and Rachon, D., 2015. Health risk of exposure to Bisphenol A (BPA). RocznikiPaństwowegoZakładuHigieny, 66(1), pp. 5–11. Kristensen, S.G., Liu, Q., Mamsen, L.S., Greve, T., Pors, S.E., Bjørn, A.B., Ernst, E., Macklon, K.T. and Andersen, C.Y., 2018. A simple method to quantify follicle survival in cryopreserved human ovarian tissue. Human Reproduction, 33(12), pp. 2276–2284. Kumarapeli, V., Seneviratne, R.D.A., Wijeyaratne, C.N., Yapa, R.M.S.C. and Dodampahala, S.H., 2008. A simple screening approach for assessing community prevalence and phenotype of polycystic ovary syndrome in a semiurban population in Sri Lanka. American Journal of Epidemiology, 168(3), pp. 321–328. Laird, M., Thomson, K., Fenwick, M., Mora, J., Franks, S. and Hardy, K., 2017. Androgen stimulates growth of mouse preantral follicles in vitro: interaction with follicle-stimulating hormone and with growth factors of the TGF β superfamily. Endocrinology, 158(4), pp. 920–935.

Signs, Symptoms, Epidemiology, Stress, and Therapies of PCOS

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Lauritsen, M.P., Bentzen, J.G., Pinborg, A., Loft, A., Forman, J.L., Thuesen, L.L., Cohen, A., Hougaard, D.M. and Nyboe Andersen, A., 2014. The prevalence of polycystic ovary syndrome in a normal population according to the Rotterdam criteria versus revised criteria including anti-Müllerian hormone. Human Reproduction, 29(4), pp. 791–801. Lee, H., Oh, J.Y., Sung, Y.A., Chung, H. and Cho, W.Y., 2009. The prevalence and risk factors for glucose intolerance in young Korean women with polycystic ovary syndrome. Endocrine, 36(2), pp. 326–332. Li, R., Zhang, Q., Yang, D., Li, S., Lu, S., Wu, X., Wei, Z., Song, X., Wang, X., Fu, S. and Lin, J., 2013. Prevalence of polycystic ovary syndrome in women in China: a large community-based study. Human Reproduction, 28(9), pp. 2562–2569. Lim, S.S., Norman, R.J., Davies, M.J. and Moran, L.J., 2013. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obesity Reviews, 14(2), pp. 95–109. Mani, H., Davies, M.J., Bodicoat, D.H., Levy, M.J., Gray, L.J., Howlett, T.A. and Khunti, K., 2015. Clinical characteristics of polycystic ovary syndrome: investigating differences in White and South Asian women. Clinical Endocrinology, 83(4), pp. 542–554. March, W.A., Moore, V.M., Willson, K.J., Phillips, D.I., Norman, R.J. and Davies, M.J., 2010. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Human Reproduction, 25(2), pp. 544–551. Marques, P., Skorupskaite, K., George, J.T. and Anderson, R.A., 2018. Physiology of GNRH and gonadotropin secretion. In Endotext, edited by Feingold, K.R., Anawalt, B., and Blackman, M.R. South Dartmouth, MA: MDText Publisher. Mehrabian, F. and Eessaei, F., 2012. The laparoscopic ovarian electrocautery versus gonadotropin therapy in infertile women with clomiphene citrate-resistant polycystic ovary syndrome; a randomized controlled trial. Journal of Pakistan Medical Association, 62(2), pp. S42–S44. Meurer, L.N., Kroll, A.P. and Jamieson, B., 2006. What is the best way to diagnose polycystic ovarian syndrome? Journal of Family Practice, 55(4), pp. 351–354. Moran, C., Tena, G., Moran, S., Ruiz, P., Reyna, R. and Duque, X., 2010. Prevalence of polycystic ovary syndrome and related disorders in Mexican women. Gynecologic and Obstetric Investigation, 69(4), pp. 274–280. Nidhi, R., Padmalatha, V., Nagarathna, R. and Amritanshu, R., 2011. Prevalence of polycystic ovarian syndrome in Indian adolescents. Journal of Pediatric and Adolescent Gynecology, 24(4), pp. 223–227. Noonan, G.O., Ackerman, L.K. and Begley, T.H., 2011. Concentration of bisphenol A in highly consumed canned foods on the US market. Journal of Agricultural and Food Chemistry, 59(13), pp. 7178–7185. Ogden, C.L., Carroll, M.D., Kit, B.K. and Flegal, K.M., 2012. Prevalence of obesity among adults: United States. NCHS Data Brief, 2013(131), pp. 1–8. Okoroh, E.M., Hooper, W.C., Atrash, H.K., Yusuf, H.R. and Boulet, S.L., 2012a. Prevalence of polycystic ovary syndrome among the privately insured, United States, 2003– 2008. American Journal of Obstetrics and Gynecology, 207(4), pp. 1–7. https://doi. org/10.1016/j.ajog.2012.07.023 Okoroh, E.M., Hooper, W.C., Atrash, H.K., Yusuf, H.R. and Boulet, S.L., 2012b. Is polycystic ovary syndrome another risk factor for venous thromboembolism? United States, 2003– 2008. American Journal of Obstetrics and Gynecology, 207, pp. 377.e1–e8. Özen, S. and Darcan, Ş., 2011. Effects of environmental endocrine disruptors on pubertal development. Journal of Clinical Research in Pediatric Endocrinology, 3(1), p. 1. Pfieffer, M.L., 2019. Polycystic ovary syndrome: diagnosis and management. Journal for Nurse Practitioners, 44, pp. 30–35.

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Pulman, A., 2010. A patient centred framework for improving LTC quality of life through Web 2.0 technology. Health Informatics Journal, 16(1), pp. 15–23. Rai, S., Basheer, M., Ghosh, H., Acharya, D. and Hajam, Y.A., 2015. Melatonin attenuates free radical load and reverses histologic architect and hormone profile alteration in female rat: an in vivo study of pathogenesis of letrozole induced poly cystic ovary. Clinical & Cellular Immunology, 6, pp. 1–8. Raju, G.A.R., Chavan, R., Deenadayal, M., Gunasheela, D., Gutgutia, R., Haripriya, G., Govindarajan, M., Patel, N.H. and Patki, A.S., 2013. Luteinizing hormone and follicle stimulating hormone synergy: a review of role in controlled ovarian hyper-stimulation. Journal of Human Reproductive Sciences, 6(4), p. 227. Rani, R., Hajam, Y.A., Kumar, R., Bhat, R.A., Rai, S. and Rather, M.A., 2022. A landscape analysis of the potential role of polyphenols for the treatment of Polycystic Ovarian Syndrome (PCOS). Phytomedicine Plus, 2(1), p. 100161. Razak, F., Anand, S., Vuksan, V., Davis, B., Jacobs, R., Teo, K.K. and Yusuf, S., 2005. Ethnic differences in the relationships between obesity and glucose-metabolic abnormalities: a cross-sectional population-based study. International Journal of Obesity, 29(6), pp. 656–667. Rosenfield, R.L. and Ehrmann, D.A., 2016. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocrine Reviews, 37(5), pp. 467–520. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and Sterility, 81(1), pp. 19–25. Saadia, Z., 2020. Follicle stimulating hormone (LH: FSH) ratio in polycystic ovary syndrome (PCOS)-obese vs. non-obese women. Medical Archives, 74(4), p. 289. Sakamoto, M., Nishimura, R., Irako, T., Tsujino, D., Ando, K. and Utsunomiya, K., 2012. Comparison of vildagliptin twice daily vs. sitagliptin once daily using continuous glucose monitoring (CGM): crossover pilot study (J-VICTORIA study). Cardiovascular Diabetology, 11(1), pp. 1–7. Seifert, S.M., Schaechter, J.L., Hershorin, E.R. and Lipshultz, S.E., 2011. Health effects of energy drinks on children, adolescents, and young adults. Pediatrics, 127(3), pp. 511–528. Sen, A. and Hammes, S.R., 2010. Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Molecular Endocrinology, 24(7), pp. 1393–1403. Shannon, M. and Wang, Y., 2012. Polycystic ovary syndrome: a common but often unrecognized condition. Journal of Midwifery & Women’s Health, 57(3), pp. 221–230. Sirmans, S.M. and Pate, K.A., 2014. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clinical Epidemiology, 6, p. 1. Stepto, N.K., Cassar, S., Joham, A.E., Hutchison, S.K., Harrison, C.L., Goldstein, R.F. and Teede, H.J., 2013. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemichyperinsulaemic clamp. Human Reproduction, 28 (3), pp. 777–784. Stracquadanio, M. and Ciotta, L., 2015. Metabolic Aspects of PCOS. Heidelberg, NY: Springer. Tan, B.K., Adya, R., Farhatullah, S., Lewandowski, K.C., O’Hare, P., Lehnert, H. and Randeva, H.S., 2008. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes, 57(4), pp. 801–808. Teede, H., Deeks, A. and Moran, L., 2010. Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BioMed Central Medicine, 8(1), pp. 1–10. Teede, H.J., Misso, M.L., Deeks, A.A., Moran, L.J., Stuckey, B.G., Wong, J.L., Norman, R.J. and Costello, M.F., 2011. Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline. The Medical Journal of Australia, 195(6), p. S65.

Signs, Symptoms, Epidemiology, Stress, and Therapies of PCOS

17

Tsutsumi, R. and Webster, N.J., 2009. GnRH pulsatility, the pituitary response and reproductive dysfunction. Endocrine Journal, 56(6), pp. 729–737. Victor, V.M., Apostolova, N., Herance, R., Hernandez-Mijares, A. and Rocha, M., 2009. Oxidative stress and mitochondrial dysfunction in atherosclerosis: mitochondria-targeted antioxidants as potential therapy. Current Medicinal Chemistry, 16(35), pp. 4654–4667. Vink, J.M., Sadrzadeh, S., Lambalk C.B., and Boomsma, D.I. Heritability of polycystic ovary syndrome in a Dutch twin-family study. Journal of Clinical Endocrinology Metabolism, 91(6), pp. 2100–2104. Wang, Q., Li, W., Zhang, Y., Yuan, X., Xu, K., Yu, J., Chen, Z., Beroukhim, R., Wang, H., Lupien, M. and Wu, T., 2009. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell, 138(2), pp. 245–256. Wedin, W.K., Diaz-Gimenez, L. and Convit, A.J., 2012. Prediction of insulin resistance with anthropometric measures: lessons from a large adolescent population. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 5, p. 219. Wijeyaratne, C.N., Balen, A.H., Barth, J.H. and Belchetz, P.E., 2002. Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference? Clinical endocrinology, 57(3), pp. 343–350. Wilfley, D., Berkowitz, R., Goebel-Fabbri, A., Hirst, K., Ievers-Landis, C., Lipman, T.H., Marcus, M., Ng, D., Pham, T., Saletsky, R. and Schanuel, J., 2011. Binge eating, mood, and quality of life in youth with type 2 diabetes: baseline data from the today study. Diabetes Care, 34(4), pp. 858–860. Williams, S., Sheffield, D. and Knibb, R.C., 2015. ‘Everything’s from the inside out with PCOS’: exploring women’s experiences of living with polycystic ovary syndrome and co-morbidities through Skype™ interviews. Health Psychology Open, 2(2), p. 2055102915603051. Winter, E., Wang, J., Davies, M.J. and Norman, R., 2002. Early pregnancy loss following assisted reproductive technology treatment. Human Reproduction, 17(12), pp. 3220–3223. Wolf, W.M., Wattick, R.A., Kinkade, O.N. and Olfert, M.D., 2018. Geographical prevalence of polycystic ovary syndrome as determined by region and race/ethnicity. International Journal of Environmental Research and Public Health, 15(11), p. 2589. Xu, J., Bishop, C.V., Lawson, M.S., Park, B.S. and Xu, F., 2016. Anti-Müllerian hormone promotes pre-antral follicle growth, but inhibits antral follicle maturation and dominant follicle selection in primates. Human Reproduction, 31(7), pp. 1522–1530. Yang, Y., Ok, Y.S., Kim, K.H., Kwon, E.E. and Tsang, Y.F., 2017. Occurrences and removal of pharmaceuticals and personal care products (PPCPs) in drinking water and water/ sewage treatment plants: a review. Science of the Total Environment, 596, pp. 303–320. Yildiz, B.O., Bozdag, G., Yapici, Z., Esinler, I. and Yarali, H., 2012. Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. Human Reproduction, 27(10), pp. 3067–3073. Young, J.M. and McNeilly, A.S., 2010. Theca: the forgotten cell of the ovarian follicle. Reproduction, 140(4), p. 489. Zawadeski, J.K. and Dunaif, A., 1992. Diagnostic criteria for polycystic ovary syndrome: Towards a more rational approach. In Polycystic Ovary Syndrome, edited by Dunaif, A., Givens, J.R. and Haseltine, F. Boston, MA: Blackwell Scientific, pp. 377–384. Zhao, Y. and Qiao, J., 2013. Ethnic differences in the phenotypic expression of polycystic ovary syndrome. Steroids, 78(8), pp. 755–760. Zuo, T., Zhu, M. and Xu, W., 2016. Roles of oxidative stress in polycystic ovary syndrome and cancers. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2016/8589318

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Polycystic Ovarian Syndrome (PCOS) Regulation of HypothalamusPituitary-Gonadal Axis and Steroidogenesis: a Perspective Toward Control of PCOS Namrata, Manisha, and Neeru Baba Mastnath University

Indu Sharma Panjab University

Rajesh Kumar Himachal Pradesh University

Arup Giri Baba Mastnath University

CONTENTS 2.1 Introduction.....................................................................................................20 2.2 Brief Account on PCOS................................................................................... 21 2.3 Risk Factors of PCOS and Their Implications................................................ 22 2.3.1 Obesity................................................................................................. 22 2.3.1.1 Role of Obesity as a Risk Factor in PCOS Patients.............. 22 2.3.2 Dyslipidemia........................................................................................24 2.3.2.1 Role of Dyslipidemia in the Development of Various Anomalities...........................................................................24 2.3.3 Insulin Resistance and PCOS..............................................................26 2.3.4 Premature Ovarian Failure.................................................................. 27 2.3.5 Genetic Causes.................................................................................... 27

DOI: 10.1201/9781003344728-2

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2.3.6 Genetics of PCOS and Its Inheritance................................................. 30 2.3.7 Adrenal Dysfunction and PCOS.......................................................... 31 2.3.7.1 Metabolism of Cortisol and Adrenocortical Biosynthesis in Women with PCOS...................................... 31 2.3.8 Elevation of APA in PCOS.................................................................. 32 2.3.8.1 Elevated APA May Act as a Risk Factor in PCOS............... 32 2.3.9 Oxidative Stress................................................................................... 33 2.3.9.1 Sources Producing Free Radicals in PCOS.......................... 33 2.3.10 Markers of Inflammation.....................................................................34 2.3.10.1 C-Reactive Protein................................................................34 2.3.10.2 Cytokines and Chemokines Involved in Chronic Inflammation.........................................................................34 2.3.11 Lifestyle and Hormonal Misbalance to Develop PCOS...................... 35 2.3.11.1 Lifestyle Changes.................................................................. 35 2.3.11.2 Smoking................................................................................ 35 2.3.11.3 Sleep...................................................................................... 36 2.3.11.4 Impact of Stress in Lifestyle................................................. 36 2.3.11.5 Diet........................................................................................ 36 2.3.11.6 Obesity.................................................................................. 37 2.3.11.7 Hormonal Imbalance in PCOS............................................. 38 2.4 Management of PCOS..................................................................................... 43 2.4.1 Management of Hypothalamic-Pituitary Failure................................ 43 2.4.1.1 Neurokinin 3 Receptor Reducing GnRH Pulsatility............ 43 2.4.1.2 Use of Oral Contraceptives and Letrozole............................ 43 2.4.1.3 Mechanistic Pathways Information.......................................44 2.4.2 Evaluation and Management of Ovarian Insufficiency....................... 45 2.4.2.1 Hyperandrogenism................................................................ 45 2.4.2.2 Chronic Anovulation............................................................46 2.4.3 Therapeutic Interventions for PCOS...................................................46 2.4.3.1 Treatment of Androgen-Related Symptoms.........................46 2.4.3.2 Treatment of Infertility......................................................... 47 2.4.3.3 Treatment of Mensuration Dysfunction................................ 50 2.4.3.4 Other Therapeutic Possibility against PCOS........................ 50 2.4.3.5 Statins................................................................................... 50 2.4.3.6 Traditional/Folk Medicine in PCOS..................................... 50 2.4.3.7 Vitamin D and Calcium........................................................ 51 2.5 Conclusion....................................................................................................... 51 Bibliography............................................................................................................. 52

2.1 INTRODUCTION According to recent studies, polycystic ovarian syndrome (PCOS) is a result of a complex interaction between environmental and genetic factors. Ovarian dysfunction associated with infertility is the major feature of PCOS. Most of the androgenic hormones are elevated in this disease. Nowadays, PCOS cases are frequent and most

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of the studies indicate altered lifestyles. Obesity is increasing in the population, and this factor is the most effective culprit behind PCOS. This central obesity may also cause increased anovulation (Carmina et al., 2009; Rai et al., 2015), insulin resistance (Kalra et al., 2009), hyper androgenemia (Godoy-Matos et al., 2009), and dyslipidemia (Lord et al., 2006). Apart from this, premature ovarian failure (POF) exhibits hyper gonadotrophic amenorrhea. PCOS results in infertility, hyperandrogenism, and ovulatory disorders in 5% to 10% of women in their reproductive phase (Franks, 1995; Norman et al., 2007). PCOS is caused by changes in many genes, such as aromatase (AR), cytochrome family p450, fat mass obesity (FTO), insulin gene, follicular-­ stimulating hormone receptor (FSHR), and CAPN10 (Ajmal et al., 2019; Urbanek, 2007). Therefore, there is a need for evaluation and proper management of ovarian insufficiency. Some signs and symptoms such as amenorrhea, breast tenderness, uterine cramps, goiter, temperature intolerance, galactorrhea, hypertension, buffalo hump, rapid virilization, frequent urination, back pain, abdominal swelling, weight loss, and fatigue have been found during ovarian insufficiency (Boyle et al., 2018; Misso et al., 2018; Xie et al., 2018). Many treatments have been tried, but most of them don’t work very well because PCOS has a complicated cause. In this context, this chapter emphasizes the normal homeostatic role of hypothalamic-pituitary-gonadal axial hormones and steroidogenesis. This chapter also discusses the different things that can mess up the hypothalamic-pituitary-gonadal axis and how that affects the growth of ovarian cysts.

2.2  BRIEF ACCOUNT ON PCOS In the polycystic ovary, it has been found that size of 12 or more follicles may increase up to 2–9 mm in diameter (Rotterdam, 2003). Normal ovarian size remains equal to or less than 10 mL. Ovarian ultrasonography can be used to diagnose polycystic ovaries. New ultrasound machines allow diagnosis of up to 25 small follicles in PCOM (Figure 2.1). Meanwhile, anti-Mullerian hormone (AMH) acts as the main key indicator that regulates and maintains the ovary structure during PCOs. Overproduction of AMH hinders follicular growth, resulting in ovarian dysfunction. Nowadays, among all other endocrinopathy, the incidence of PCOS is higher throughout the world. One in every ten women in India has PCOS, according to PCOS society studies. It is assumed that the complex nature between environmental and genetic factors enhance PCOs. Menstrual irregularities, varying sizes of cysts in the ovary, androgen excess, weight gain, acne, and sometimes hirsutism are clinical symptoms of PCOS, although there are significant differences between people (Mohammad and Seghinsara, 2017; Rani et al., 2022). An elevated level of androgenic hormones, including luteinizing hormone (LH), follicular-stimulating hormone (FSH), and gonadotropin-releasing hormone (GnRH), is present in the bloodstream of PCOS patients. As a result, thecal cells produce an abundance of testosterone, androstenedione, and the androgen dehydroepiandrosterone sulfate (DHEAS).

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FIGURE 2.1  Diagrammatic representation of normal ovary and polycystic ovary.

2.3  RISK FACTORS OF PCOS AND THEIR IMPLICATIONS 2.3.1 Obesity Obesity is a pathological condition in which excess fat is accumulated in the body and makes an individual more susceptible to anomalies such as hypertension, depression, cardiovascular risks, respiratory problems, airway disease, type 2 diabetes, fatty liver, and various types of cancer. It acts as a major factor in the determination of PCOS, as most of the patients affected with PCOS are found to be overweight and suffer from obesity. Since all obese women do not have hyperandrogenism, these characteristics are not taken as the standard for the diagnosis of PCOS. It has been reported that on an average 60%– 80% of patients with PCOS are obese. According to a few other studies, it has also been observed that obese patients with PCOS are at a higher risk of being affected by menstrual problems and hirsutism as compared to nonobese patients with PCOS (Gibson-Smith et al., 2016; Moran et al., 2012). 2.3.1.1  Role of Obesity as a Risk Factor in PCOS Patients Obesity is closely linked to PCOS and plays a key role in its pathophysiology. Hyperandrogenism and menstrual disorders are even worsened in obese PCOS patients. Many studies support the higher prevalence of PCOS among obese women. A total of 28% obese women are PCOS patients in Spain (Lim et al., 2012).

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It may even worsen clinical manifestations such as reproductive disorders in PCOS patients, and thus there are higher chances for it to be diagnosed, which supports the fact that PCOS and obesity are associated. Women diagnosed with PCOS generally have more adiposity in their central body parts as compared to standard body mass index (BMI) (Karabulut et al., 2012). This central obesity may also lead to increased insulin resistance (Kalra et al., 2009), anovulation (Carmina et al., 2009), dyslipidemia (Lord et al., 2006), and hyperandrogenemia (Godoy-Matos et al., 2009). According to some studies, obesity in PCOS patients is also responsible for gonadotropic abnormalities. However, nonobese PCOS patients show higher dissociation of LH to FSH in comparison with obese women having PCOS. But such a case has not been reported in other studies (Moran et al., 2003) (Figure 2.2). Although insulin resistance can be found in PCOS patients in any weight category, obese women are more susceptible to it. It increases by two folds and is much more frequent in cases of obesity. Being overweight is directly proportional to insulin resistance in people suffering from PCOS (Li and Shao, 2014; Moran et al., 2012). Due to the frequent co-occurrence of PCOS with obesity, their inherent complexity and being linked with anomalies such as insulin resistance and cardiometabolic disorders can make their pathogenic pathways more complex and challenging. PCOS and obesity are correlated since an increase in weight directly contributes to the development of PCOS. Also, a few mechanisms state that PCOS can lead to weight gain in women and pose hindrances to weight loss. Although obesity and PCOS are closely associated, the chances of obesity occurring in women with PCOS vary depending upon their age, culture, and the geographical region they belong to (Barber et al., 2019; Lim et al., 2012; Reynolds et al., 2007).

FIGURE 2.2  PCOS in obese and nonobese women.

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2.3.2 Dyslipidemia Recent studies have discovered various abnormalities such as insulin resistance, obesity, oxidative stress, dyslipidemia, and some metabolic disorders, but the anomaly that is found most commonly in PCOS patients is dyslipidemia (Macut et al., 2013; Ramezani et al., 2014). Lipid-associated abnormalities and mild hypercholesterolemia are quite common in women with PCOS (Pergialiotis et al., 2018). PCOS exhibits diverse lipid patterns such as total cholesterol, lower levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDLC), a higher amount of triglycerides (TG), and elevated lipoprotein concentrations (Ghaffarzad et al., 2016; Tsouma et al., 2014). In an animal study conducted on prepubertal rats fed with a diet rich in fats, it was observed that there were changes in ovarian and metabolic activity that indicate a significant effect of hyperlipidemia on hormonal levels in rats (Patel and Shah, 2018). Further, lipotoxicity causes mitochondrial dysfunction, and stress in the endoplasmic reticulum and apoptosis, which further results in early embryo growth and affects the quality of the oocyte (Broughton and Moley, 2017). Meanwhile, androgens act as a major factor in hyperlipidemia (Pan et al., 2018; Liu et al., 2019). All these studies conclude that lipid abnormalities occur when there are alterations in the genes linked with lipids, and this eventually develops into hyperandrogenism (Pergialiotis et al., 2018). Disturbance in lipid metabolism can also advance the pathophysiology of insulin resistance, infertility, and oxidative stress in PCOS. Women with PCOS have a higher chance of being affected with cardiovascular diseases (Kumar et al., 2017). Consequently, lipid abnormalities promote the pathogenesis of PCOS (Diamanti-Kandarakis et al., 2007) (Figure 2.3). 2.3.2.1  Role of Dyslipidemia in the Development of Various Anomalities 2.3.2.1.1  Insulin Resistance Due to Dyslipidemia Insulin resistance is a pathological condition where elevated insulin response results in hyperinsulinemia and is a distinctive characteristic of PCOS, as it contributes to the pathogenesis of PCOS (Mu et al., 2019) (Figure 2.4). On average, 50%–70% of PCOS women were found to have IR, and the risk of developing type II diabetes is 5–10 times higher in PCOS women than in healthy women (Ovalle and Azziz, 2002). Almost 70% of women with PCOS also show dyslipidemia (Kim and Choi, 2013). In PCOS patients with obesity, dyslipidemia is linked with central fat because the presence of adipocytes in central fat was found to be detrimental to plasma. Accumulation of visceral fat in the abdomen might lead to disorders related to lipid metabolism (Diamanti-Kandarakis et al., 2007; Yildirim et al., 2003). Likewise, the distribution pattern of fat in the central region has also been associated with IR (Neeland et al., 2012). A few other studies claim that in young patients with PCOS, their glucose and insulin homeostasis are predisposed by BMI (Abruzzese et al., 2017), claiming that IR is linked with obesity. 2.3.2.1.3  Hyperandrogenism Due to Dyslipidemia Levels of HDL are noted to be lower in PCOS patients with no hyperandrogenism (Yang et al., 2016). Studies suggest that androgenic conditions are harmful to lipid

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

FIGURE 2.3  Factors affecting adrenal cortex in case of PCOS.

FIGURE 2.4  Insulin resistance in PCOS.

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metabolism, whereas dyslipidemia has no such direct effect on metabolism in women with PCOS. However, Göbl et al. (2016) reported that liver fat is strictly linked to hyperandrogenism and leads to metabolic risks. Meanwhile, PCOS patients showed higher level of SHBG and testosterone (Li et al., 2017). Subcutaneous adipose storage in nonobese PCOS patients is related to deposition of fat in the abdominal region and an increase in the number of small subcutaneous adipocytes which are potential enough to constrict subcutaneous adipose storage and advance metabolic dysfunction (Dumesic et al., 2016; Sharma et al., 2022). Dysfunctioning of adipose tissue in the subcutaneous region is also observed in PCOS patients. This indicates that there is a change in the size of adipocytes and expression, and secretion of leptin and adiponectin and is generally linked with hyperandrogenemia (Basheer et al., 2018; Echiburú et al., 2018). 2.3.2.1.3  Anovulation Due to Dyslipidemia Anovulation is also known to be linked with dyslipidemia in women with PCOS (Norman, 2001). According to a study, women having anovulatory PCOS have elevated levels of TGs, LDL-C, and TC and decreased levels of HDL-C as compared to ovulatory PCOS (Rizzo et al., 2009). It has also been found that oxidized lipid has the tendency to damage the mitochondrial structure and ultimately follicular atresia takes place. Activation of a few oxLDL receptors such as lectin-like oxLDL receptor-1 (LOX-1), cluster of differentiation 36 (CD36), and toll-like receptor 4 (TLR4) led to disturbance in the ovulatory process and apoptosis of granulosa cells in humans (Schube et al., 2014). Abdominal obesity further increases production of adrenal and ovarian androgens, while the concentration of SHBG is lowered in PCOS. Increased testosterone concentration might promote obesity and inflammation in the abdomen region, making the condition even worse. Lipid metabolism also alters the environment of the oocyte. Follicular fluids in PCOS conditions have a higher concentration of lipid (LDL) and glycerol as compared to fluids in normal follicles. Additionally, concentrations of FFAs such as palmitoleic acid and linoleic acid are elevated in PCOS conditions (Zhang et al., 2017). These studies showed that PCOS patients having dyslipidemia may develop follicles, which make them unable to give birth to children.

2.3.3 Insulin Resistance and PCOS It is a condition in which an increased concentration of insulin leads to an abnormal biological response. Typically, this is an impaired sensitivity of the body toward glucose (Barber et al., 2016). Most PCOS patients (50%–90%) have insulin resistance (Venkatesan et al., 2001). A compensatory response is generated toward insulin resistance in which hyperinsulinemia cointeracts with LH in the ovarian theca cells (Franks et al., 1997). As a result, CYP17 is activated, which further increases the production of androgens (Morin-Papunen et al., 2000). Insulin in the ovaries seizes the development of preantral follicles (Willis et al., 1998). Hyperinsulinemia also results in extra ovarian pleiotropic effects and increased LH pulse amplitude, suppressed hepatic sex hormone, and initiation of P450c17α activity. Various studies support the

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

27

role of insulin resistance toward the development and progression of PCOS. It is also reported that improving the condition of insulin sensitivity leads to improvement in hyperandrogenic, metabolic, and reproductive features (Barber et al., 2016).

2.3.4 Premature Ovarian Failure POF exhibits hypergonadotrophic amenorrhea. The dysfunction in ovarian function during the reproductive phase and up to 40 years of age causes infertility risks and interferes in family planning (Wallach and Coulam, 1982). The probability of the occurrence of POF is 1% per year (Coulam et al., 1986). PCOS results in infertility, hyperandrogenism, and ovulatory disorders in 5% to 10% of women in their reproductive phase (Franks, 1995; Norman et al., 2007). The pathophysiology of anovulation is not yet clear. Some recent genetic studies on POF and PCOS reveal that many genes, either through interaction with one another or the environment, increase the incidence of these diseases. FSH can be one of these susceptible genes responsible for causing POF and PCOS. It acts as a major factor and is required for the development of gonads, sexual maturation, and the formation of gametes during the reproductive phase (Simoni and Nieschlag, 1995). FSHR, which is present on ovarian granulosa cells, mediates the effect of FSH (Themmen and Huhtaniemi, 2000). The location of the FSHR gene is on chromosome 2p21 and it has ten exons (Minegish et al., 1991). Two polymorphic sites have been found in the coding segment of the FSHR gene (Aittomäki et al., 1995). These are Thr307Ala (rs6165), located in the extracellular domain of the receptor, and Asn680Ser (rs6166), which are located in the intracellular domain. It is said that both these polymorphisms have an impact on the efficiency of FSH (de Castro et al., 2003). Infertile women with the Ser680 variant have elevated levels of basal FSH (Mayorga et al., 2000). However, it is unclear whether exon 10 polymorphism is pathogenic or permissive in chronic anovulation (Du et al., 2010).

2.3.5 Genetic Causes Predisposition to PCOS is linked with genetics. Various genes, such as AR, Cytochrome family p450, FTO, Insulin gene, FSHR and CAPN10, play a major role in the development of PCOS (Ajmal et al., 2019) (Table 2.1). The androgen receptor gene is located on chromosome Xq12 and codes for an over 90 kb protein which has three functional domains. It has 11 exons and is also associated with PCOS. Inactivation of X disturbs the signaling pathway of androgen and its concentration is increased (Ajmal et al., 2019; Urbanek, 2007). FSHR gene is present on chromosome 2p16.3 and encodes a protein known as the G-coupled receptor, which plays a major role in the development of gonads. This gene has 14 exons (Ajmal et al., 2019). Disturbance in hormonal levels directly affects the endocrine and reproductive systems. Along with other hormones, an imbalance of FSH leads to severe PCOS. The FSH receptor encodes for FSH. Any kind of abnormality in FSHR ultimately affects the follicular and ovarian functions. A study using statistical analysis and RFLP was carried out in Northern Iraq in order to compare and study the variations in healthy and affected individuals (Baban et al., 2018).

Sl. No. 11

14

14

12

Xq12

2p16.3

16q12.2

2q37.3

Androgen receptor gene

Follicular-stimulating hormone receptor (FSHR)

Fat mass obesity (FTO) gene (α-ketoglutarate) CAPN10 (Caplain10)

15q24.1

8q24.3

CYP11A1

CYP11b2

Aromatase

9

10

No. of Exons

Gene

Location (Chr No)

Cysteine protease Calpain 10

90 kb protein with three functional domain G-coupled receptors responsible for gonadal development

Encodes

TABLE 2.1 Candidate Genes Responsible for the Development of PCOS Identification of Mutation

References

Regulates steroidogenesis pathway Formation of aldosterone synthetases

Type 2 diabetes and insulin resistance

Obesity and type II Genetic and diabetes statistical analysis

(Continued)

CYP11A1 cytochrome P450 family, Homo sapiens, database on the internet (2018) Ajmal et al. (2019)

Ajmal et al. (2019); Urbanek (2007)

Ajmal et al. (2019); Rizwan et al. (2018)

Disrupts androgen Genome-wide Ajmal et al. (2019); Urbanek signaling pathway association (2007) mapping Disrupts endocrine RFLP and statistical Ajmal et al. (2019); Baban et al. reproductive analysis (2018) system (specifically FSH)

Function

28 Herbal Medicine Applications for Polycystic Ovarian Syndrome

Sl. No.

10q24.32

15q24.1

7q22.1 DHEAS

15q21.2

CYP1A1

CYP3A7

CYP19A1

Location (Chr No)

CYP17A1

Gene

17 introns and 18 exons

13

7

8

No. of Exons

Encodes

TABLE 2.1 (Continued) Candidate Genes Responsible for the Development of PCOS

Affects the metabolic pathway of androgen Dysfunctioning of aromatase activity

Affects the metabolic pathways

Function RFLP PCR

Identification of Mutation

References

CYP19A1 cytochrome P450 family, Homo sapiens, database on the internet (2018)

CYP17A1 cytochrome P450 family, Homo sapiens, database on the internet (2018) CYP1A1 Gene, Homo sapiens, database on the internet (2018) Goodarzi et al. (2008)

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis 29

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Herbal Medicine Applications for Polycystic Ovarian Syndrome

FTO is also known as α-ketoglutarate-dependent dioxygenase. It is located on chromosome 16q12.2 and has a total of four exons. A study that was carried out in Pakistan has also reported polymorphic forms of the FTO gene in PCOS patients. Intronic variants of PCOS patients were found to have rs9939609 SNP. Statistical and genetic studies on PCOS patients further revealed that there is a significant difference in the BMI of affected individuals in comparison to normal unaffected individuals (Ajmal et al., 2019; Rizwan et al., 2018). Calpain 10 is another name for the CAPN10 gene. CAPN10 is a cysteine protease that is dependent on calcium. Its cytogenetic location is on chromosome 2q37.3 with 12 exons in total. CAPN10 is heterodimeric and it is also known to be linked with type 2 diabetes. It encodes for calpain 10, which is a cysteine protease. This calpain 10 regulates the action of insulin and its secretion. Any form of abnormality or mutation in CAPN10 can result in PCOS, as both type 2 diabetes and insulin resistance are linked to PCOS. Because of this, CAPN10 is also thought to be a possible gene that causes PCOS (Ajmal et al., 2019; Urbanek, 2007). AR, an enzyme involved in steroidogenesis and a member of the cytochrome P450 family, is crucial in the conversion of steroids. It facilitates androgen conversion to estrogen. The mechanism is disrupted by an AR gene deficit, and steroid conversion stops (Harada et al., 1992). Additionally, this impairment will prevent C19 from being converted to C18, which will impair ovarian function and cause an increase in androgen levels. In PCOS databases, the AR genes CYP11A1, CYP17A1, CYP1A1, CYP11B1, CYP19A1, CYP21A2, and CYP3A7 were all discovered (Joseph et al., 2016). The likelihood of developing severe PCOS is increased by any cytochrome P450 abnormality.

2.3.6 Genetics of PCOS and Its Inheritance PCOS is a heritable syndrome and is inherited in the manner of familial patterns (Azziz, 2007). There is evidence to support the fact that women suffering from PCOS can pass this on to their first-degree female relatives (Kahsar-Miller et al., 2001). However, candidate genes and polymorphisms are still being searched for and no clear statement has been obtained in this case until now. Several genes have been selected as candidates and are grouped into four categories: (a) genes linked to insulin resistance; (b) genes responsible for androgen biosynthesis; (c) genes linked to responses to inflammatory cytokines; and (d) others (Deligeoroglou et al., 2009). Some studies have mentioned that the inheritance pattern of PCOS is autosomal dominant, whereas twin studies and family studies showed a baffled pattern of inheritance and do not follow the Mendelian pattern of inheritance. A study conducted on monozygotic and dizygotic twins (their comparison) did not show much difference. On the other hand, according to a Dutch study, a higher association was observed between PCOS diagnoses in monozygotic twin pairs in comparison with dizygotic singleton sisters (Raperport and Homburg, 2019). Recently, 16 more genetic loci have been reported by genome-wide association studies (GWAS) in groups that fit the diagnostic criteria of NIH (Day et al., 2015). There is evidence that genetic variants are linked to PCOS and depression, which makes sense since depression is common among people with PCOS. PCOS genetic loci are linked to reproductive, metabolic, and neuroendocrine pathways, and are

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31

also linked to depression, menopause, male pattern baldness, and metabolic disorders (Raperport and Homburg, 2019).

2.3.7 Adrenal Dysfunction and PCOS Even though ovaries are considered to be the primary source of increasing androgen levels in PCOS patients, elevated concentrations of adrenal androgens such as androstenedione and DHEA have been reported in PCOS patients along with adrenocortical abnormalities (Yildiz and Azziz, 2007). So far, the role of elevated androgen levels in the determination of or resulting in PCOS is still not clear (Goodarzi et al., 2015). According to studies, the hypothalamic-pituitary-adrenal axis has an important role in developing PCOS and it is observed in patients having congenital adrenal hyperplasia (classic or nonclassic) exhibiting characteristic features of PCOS such as hyperandrogenism linked with ovary, PCOM, and higher levels of LH. In addition, premature adrenarche in individuals might pose a greater risk of developing PCOS. Elevated levels of DHEAS indicate an excess of adrenal androgen in women with PCOS (Baskind and Balen, 2016). 2.3.7.1 Metabolism of Cortisol and Adrenocortical Biosynthesis in Women with PCOS Women with PCOS have increased levels of adrenocortical hormones such as cortisol, 11-deoxycortisol, DHEA, pregnenolone, hydroxy pregnenolone, and androstenedione. This is generally because the adrenal cortex shows hyperresponsiveness to ACTH stimulation and also elevated enzymatic activity of 17α-hydroxylase. It is also said that this might cause an increase in the activity of P450c17α, which is directly linked to hyperinsulinemia. Therefore, there is evidence which supports that putative dysfunction of CYP17α1 is a characteristic of PCOS, which is determined genetically (Baskind and Balen, 2016). Several extra-adrenal factors, including ovarian secretions, insulin and glucose concentrations, and obesity, may also contribute to elevated 17 hydroxylase activity (Goodarzi et al., 2015). Hence, biosynthesis of adrenocortical androgen is elevated in PCOS and this might partially be a result of intraadrenal to peripheral influences. In a study conducted on PCOS patients, they were found to exhibit increased peripheral metabolism of cortisol. This further increases the biosynthesis of ACTH to maintain normal levels of cortisol but with the consequence of elevated biosynthesis of adrenal androgen (Stewart et al., 1990). The increased inactivation of cortisol by the enzyme 5α-reductase and the disturbed reactivation of cortisone by the enzyme 11-βhydroxysteroidogenase-1 can cause lowered feedback inhibition of ACTH secretion. However, this theory is still questionable because a significant rise in ACTH levels in PCOS patients hasn’t been seen before and the rate of total cortisol production is normal (Roelfsema et al., 2010). 2.3.7.1.1 Impact of Extra-Adrenal Factors on Adrenal Steroidogenesis in Women with PCOS A number of factors which are obtained nonadrenally are known to be responsible for the production of adrenal androgen. For instance, testosterone produced by the

32

Herbal Medicine Applications for Polycystic Ovarian Syndrome

ovaries can cause adrenal hyperandrogenism by enhancing the sulfation process in DHEA and forming DHEAS (Goodarzi et al., 2015). Administration of GnRHa, which causes ovarian repression, is linked with lower levels of DHEAS (Azziz et al., 1998), but these findings have not been confirmed by other scientists (Cedar et al., 1992). The impact of obesity on the biosynthesis of adrenal androgen has been investigated in PCOS patients and the results are quite conflicting. Even though obesity isn’t linked to higher levels of DHEAS (Kumar et al., 2005), a few authors have said that obese women have a stronger response to ACTH, which leads to more cortisol, DHEA, and androstenedione being made (Azziz et al., 1991) (Figure 2.3). However, these studies aren’t considered to be representative of all cases (Goodarzi et al., 2015). Explanation for such a response comprises mediators such as adipocytokines, which are generated by adipocytes and insulin resistance.

2.3.8 Elevation of APA in PCOS Increased levels of adrenal precursor androgen are estimated by the enhanced serum levels of 11b-hydroxyandrostenedione, and DHEAS has been observed to occur in nearly 50% of PCOS patients (Carmina et al., 1986; Carmina et al., 1992; Hoffman et al., 1984; Moran et al., 1999; Steinberger et al., 1984). 2.3.8.1  Elevated APA May Act as a Risk Factor in PCOS Increased APA levels are present in PCOS either due to an untimely excess of APA or due to enhanced steroidogenesis of androgens in PCOS. Patients with the onset of early axillary hair and the development of apocrine sweat glands are at an elevated risk of having PCOS as compared to normal individuals. For instance, according to a study, almost 50% of individuals with PA consequently develop PCOS (Goodarzi FEMALE REPRODUCTIVE SYSTEM

Normal ovary

Polycystic ovary

Difference between Normal Ovary and Polycystic Ovary

FIGURE 2.5  Diagrammatic representation of normal and polycystic ovary.

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33

et al., 2015). In addition, daughters of women affected by PCOS were reported to have increased levels of DHEAS and AP more often as compared to daughters of normal women (Maliqueo et al., 2009). Scientists have also suggested that during peripubertal time, stress can elevate the APA secretion, which ultimately poses the risk of increased incidence of PCOS.

2.3.9 Oxidative Stress Oxidative stress is a pathological condition in which reactive oxygen species (ROS) accumulate in the body (Sies, 1991) and are further converted into harmful substances which oxidize the cellular components. Lipid radicals are formed in the body because components of lipids such as polyunsaturated fatty acids are more prone to oxidation. Peroxidation of lipids can cause serious damage to the membrane integrity and eventually result in the impairment of cellular compartmentalization. Similarly, proteins are oxidized by attacking their sulfhydryl groups, which leads to alteration in the activity of proteins and their selective degradation (Halliwell, 1991). 2.3.9.1  Sources Producing Free Radicals in PCOS 2.3.9.1.1  Adipose Tissue Excess adipose tissue in obese women results in increased oxidative stress because proinflammatory cytokines produced by adipocytes and preadipocytes can stimulate the formation of ROS and reactive nitrogen species. Adipose tissue can also produce angiotensin II, which further braces the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Fernández-Sánchez et al., 2011). 2.3.9.1.2  Oxidation of Fatty Acids Studies have shown that regardless of whether there is obesity or not, the expression of chemotactic factors is controlled in adipose cells by the mechanism of ROS formation and stimulates the cells responsible for oxidative stress. The increased ROS production is hypothesized to be caused by oxidation of fatty acids in the liver’s peroxisomes and mitochondria as well as additional activation of NADPH oxidase because of saturated fatty acids in muscle cells (Fernández-Sánchez et al., 2011; Macut et al., 2013). 2.3.9.1.3  Hyperglycemia and ROS It has been reported that hyperglycemia can induce or enhance the production of ROS, specifically radicals of superoxide and peroxynitrite. The activities of NADPH oxidase and nitric oxide synthase (inducible) are increased due to hyperglycemia. Hyperglycemia causes ROS to be made, which messes up the signaling pathways that are sensitive to redox (Simic et al., 2006). 2.3.9.1.4  Mitochondrial Dysfunction and PCOS Most amounts of ROS are produced in the mitochondria and eventually disturb the mitochondria’s metabolism. Recently, abnormal and impaired mitochondrial

34

Herbal Medicine Applications for Polycystic Ovarian Syndrome

functions have been reported in cases of PCOS. It is stated that ROS synthesized in PCOS targets the complex I in the electron transport chain, which results in the decreased consumption of O2 by mitochondria following increased ROS generation and tumor necrosis factor α (TNFα) levels. The link between oxidative stress and PCOS is based on an increase in plasma lipids (primarily malondialdehyde and isoprostanes) and oxidative damage to protein SH groups (González et al., 2006; Macut et al., 2011). 2.3.9.1.5  Chronic Low-Grade Inflammation Despite the fact that the pathophysiology of PCOS is still unclear, there is evidence to suggest that the number of women with PCOS who experience persistent lowgrade inflammation is increasing. Other significant PCOS characteristics, such as insulin resistance and cardiovascular risk, are also associated with inflammation. Additionally, endothelial dysfunction and atherosclerosis are both known to be primarily characterized by inflammation (Ross, 1999).

2.3.10 Markers of Inflammation 2.3.10.1  C-Reactive Protein It is considered a key marker of chronic inflammation. C-reactive protein (CRP) is synthesized by hepatocytes in response to the stimulation generated by proinflammatory cytokines such as TNF and interleukin-6 (IL-6) (Castell et al., 1989). According to some studies, CRP is not only a marker but also acts as a mediator in the process of inflammation (Han et al., 2004; Venugopal et al., 2005). For instance, CRP causes endothelial dysfunction and advances the process of chemotaxis mediated by monocyte chemoattractant protein-1 (MCP-1) (Han et al., 2004). Increased levels of high-sensitivity CRP (hsCRP) serve as an important marker and indicate the hazard of cardiovascular disorders (Ridker et al., 2003). 2.3.10.2  Cytokines and Chemokines Involved in Chronic Inflammation The pathways of chronic inflammation are linked with an increase in certain cytokines and chemokines which are proinflammatory, for instance, macrophage inflammatory protein-1 (MIP-1), IL-18, and MCP-1. IL-18 is known to be closely associated with metabolic syndrome and insulin resistance. It also plays a key role in indicating abiding cardiovascular mortality (Furtado et al., 2009; Zirlik et al., 2007). One of the most important and widely studied chemokines, MCP-1, is said to be responsible for causing atherosclerosis. MIP-1 having a C-C motif, also known as chemokine ligand 3 (CCL3), acts as a key factor in recruiting and activating leukocytes, which further helps in the prediction of potential cardiovascular events (de Jager et al., 2008). PCOS is directly linked to the increased levels of these proinflammatory factors. Several studies have reported enhanced levels of IL-18 in PCOS patients (EscobarMorreale et al., 2004; Kaya et al., 2010; Yang et al., 2011; Zhang et al., 2006). The association of IL-18 was unknown, but its linkage with PCOS was reported during the estimation of age and BMI of the individuals. Moreover, the serum level of IL-18 is interrelated with the total testosterone level and is inversely proportional to the insulin sensitivity index (Escobar-Morreale et al., 2004; Yang et al., 2011).

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35

A few other studies have stated the presence of increased levels of MCP-1 (Glintborg et al., 2009; González et al., 2009; Hu et al., 2011). Patients with isolated hirsutism were also found to exhibit elevated levels of MCP-1 and MIP-1 (Glintborg et al., 2009). Besides, the serum of women having PCOS was compared with the controls and it was observed that the expression of MCP-1 was elevated significantly in human monocyte cell lines, namely THP-1 (Hu et al., 2011; Rostamtabar et al., 2021).

2.3.11 Lifestyle and Hormonal Misbalance to Develop PCOS Adopting a certain lifestyle decides whether our body is free from diseases or not. For example, according to many recent studies, lifestyle choices including overeating and depression lead to PCOS. PCOS is characterized by ovulatory dysfunction, increased levels of androgens, and morphological abnormalities (Figure 2.5). According to the National Institutes of Health, PCOS can be defined as “hyperandrogenism with ovulatory dysfunction.” PCOS affects 6%–10% of women during their reproductive years, with the prevalence rate potentially doubled (Conway et al., 2014; Livadas and Diamanti-Kandarakis, 2013; Lujan et al., 2008; Pasquali and Gambineri, 2014). It is a serious concern for women’s health and has major life-threatening conditions. Of the women suffering from PCOS, 50%–80% are obese, 8%–10% have diabetes or a family history of diabetes, and 30%–35% have glucose intolerance (Barber et al., 2007; Cassar-Vu et al., 2016; Ehrmann et al., 1999; Legro et al., 1999). Other than this, the observed clinical features of PCOS are excess facial growth because of excess testosterone, irregular menstrual cycles, decreased ovulation, polycystic ovaries, reduced fertility, and acne. Apart from this, PCOS is also related to diabetes, cardiovascular disease risk factors with an elevated level of insulin resistance, abnormal metabolic features, and cholesterol levels. Psychological features such as depression and anxiety may aggravate the symptoms of PCOS (Moran et al., 2011). 2.3.11.1  Lifestyle Changes Maintaining a proper healthy life and mental health is an alternative to pharmacological treatment. It’s not an immediate fix and it is an individual’s personal choice, but it should be still included in the daily routine. PCOS shows up in body lifestyle with irregular physical activity, being overweight, not having a healthy dietary pattern, tobacco use, and depression. Focusing on physical activities and mental health is an important step toward a healthy and fulfilling life (Del Pup and Cagnacci, 2021) (Figure 2.6). 2.3.11.2 Smoking According to a study, ovulatory dysfunction was found to be linked to smoking in a dose-dependent way (Zhang et al., 2020). Studies have shown that smoke toxicants can interfere with folliculogenesis and cause preovulatory follicles to luteinize too early. Increased reduction of primordial follicles and oocyte maturation is also caused by these toxicants (Dechanet et al., 2011; Sadeu and Foster 2011).

36

Herbal Medicine Applications for Polycystic Ovarian Syndrome

OVER EATING

LACK OF EXERCISE

DEPRESSION

IRREGULAR SLEEP

IRREGULAR PERIODS

SMOKING

FIGURE 2.6  Lifestyle to develop PCOS.

2.3.11.3 Sleep Treating sleep-related conditions is an important step toward treating PCOS. Sleep disorders have a significant impact on the etiology, depression, and anxiety seen in PCOS (Yang et al., 2021). IR and obesity are associated with sleep deprivation (Reutrakul and Van Cauter, 2018). Sleep symptoms are the first signs of body’s weakening immune response and increasing insulin resistance pathways, which are associated with PCOS (Szczuko et al., 2021). 2.3.11.4  Impact of Stress in Lifestyle The way of dealing with stress has a great impact on women’s health and ability to implement a lifestyle change. Stress is an inhibitor to change. A woman should have proper knowledge about stress-surviving strategies, for example, physical activity, and she should understand the link between stress and PCOS. This would help them change their lifestyle and improve their mental health to get better results from PCOS (Pirotta et al., 2021). 2.3.11.5 Diet According to recent studies, physical health is affected by nutritional habits which are considered to be one of the dimensions of lifestyle. To maintain and initiate normal functioning of fertility and puberty, proper diet is a principle factor (Altieri et al., 2013) (Table 2.2). Androgen levels and ovulation can be normalized by adjusting

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

37

TABLE 2.2 Dietary Causes Related to PCOS Sl. No.

Symptoms of PCOS

Dietary Cause

Ovulation failure and high infertility risk Ovulation failure and high infertility risk Ovulation failure and high infertility risk Ovulation failure and high infertility risk Disrupted normal ovary functioning and hyperandrogenemia Reduced insulin resistance

Due to dairy products

Hyperandrogenemia

Low-fat diary

References

Low-fat dairy and soda

Altieri et al. (2013)

Diet with high glycemic index Complete carbohydrate diet High amount of animal protein consumption Insulin resistance

Altieri et al. (2013) Altieri et al. (2013) Altieri et al. (2013) Pourghassem Gargari et al. (2011) Pourghassem Gargari et al. (2011) Pourghassem Gargari et al. (2011)

exercise and diet, and can be regarded as the first line of treatment for PCOS patients these days. According to some reports, low-fat dairy and soda, diets with a high glycemic index, complete carbohydrates, and a high amount of animal protein consumption are responsible for ovulation failure and high infertility risk, and these show a strong relationship (Altieri et al., 2013). Disrupted normal ovary functioning and hyperandrogenemia are caused by insulin resistance. Other than this, dairy products reduce insulin resistance and hyperandrogenemia is related to low-fat dairy (Pourghassem Gargari et al., 2011). In short, maintaining a healthy diet in our daily lifestyle can help us deal with any disease. 2.3.11.6 Obesity It has been found in recent decades that excess weight and obesity are crucial chronic diseases all around the world. Due to obesity, infertility, hyperandrogenism, pregnancy complications, and hirsutism-like features are increased. Insulin resistance and obesity are responsible for increased cardiovascular disease and type 2 diabetes mellitus. Other than this, obesity worsens the metabolism and reproductive characteristics, as well as damages insulin resistance. Obesity is also linked to late pregnancy complications, pregnancy loss, and anovulation (gestational diabetes, preeclampsia). Failure of many treatments, such as laparoscopic ovarian diathermy, clomiphene citrate, and gonadotropins, is associated with obesity in women with PCOS. According to reports, improvement in ovulation and spontaneous pregnancy was seen after reducing 5% of the initial weight in obese PCOS women. Weight loss is considered the first line of treatment (exercise and diet) for obese women with PCOS because it increases the number of live births (Beatriz Motta, 2012). Obesity increases infertility; increased hyperandrogenism; more pregnancy complications; hirsutism-like features are increased; cardiovascular disease and type 2

38

Herbal Medicine Applications for Polycystic Ovarian Syndrome

diabetes mellitus; worsens the metabolism and reproductive characteristics; damages the insulin resistance; late pregnancy complications; pregnancy loss and anovulation (gestational diabetes, preeclampsia); failure of many treatments such as laparoscopic ovarian diathermy; and clomiphene citrate and gonadotropins (Beatriz Motta, 2012). 2.3.11.7  Hormonal Imbalance in PCOS PCOS is the most common endocrine disorder in which androgen levels are often seen being high, and the disorder also involves insulin resistance and hyperinsulinemia (Rojas et al., 2014). According to various reports, it has been concluded that malformation-associated follicular development and steroidogenesis are critically involved in PCOS development (Lujan et al., 2008; Rotterdam, 2004) (Figure 2.7). Regular menstrual cycles are interrupted by distress in reproductive hormones such as testosterone, estrogen, FSH, and LH hormones, which may also lead to amenorrhea- and oligomenorrhoea-like conditions (Bulsara et al., 2021). Hormones which are imbalanced in PCOS are listed in Figure 2.7. 2.3.11.7.1 Insulin The effects of insulin on differentiation, cell proliferation, metabolism, and cellbound surface receptors are all strongly influenced by these factors. Additionally, a variety of signaling pathways are involved in insulin. As one of insulin’s many metabolic and growth-promoting actions, insulin resistance is defined as a diminished influence of insulin on glucose metabolism, particularly the restricted export of blood glucose into adipose tissue and skeletal muscle. Not all insulin-responsive organs and insulin signaling pathways, meanwhile, are similarly impacted. The

Testosterone Insulin

Anti-Mullerian hormone

Follicle stimulating hormone

HORMONES IMBALANCED IN PCOS

Androgen

Estrogens

Luteinizing hormone Gonadotropin releasing hormone

FIGURE 2.7  Hormonal imbalance during PCOS.

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39

metabolic effects of insulin can occasionally be overexpressed. Ovaries and adrenal glands are two examples of tissues that respond to insulin. Insulin is responsible for high androgen secretion. High androgen secretion is due to insulin. An example of an androgen excess disorder is PCOS, in which the pathogenicity of androgen excess disorder is due to insulin resistance (Unluhizarci et al., 2021). 2.3.11.7.1.1  Insulin Signaling Pathway under Normal Physiological Conditions  As a result, numerous pathways are activated or inhibited once insulin binds to the insulin receptor. Insulin displays an anabolic state as a result. Then the insulin receptor underwent autophosphorylation, and the insulin receptor substrate underwent tyrosine phosphorylation (IRS). Glucose uptake, glycogen synthesis, and lipid synthesis are all regulated by the phosphatidylinositol-3-kinase/serine/ threonine-specific protein kinase B (AKT) signaling pathway, which is activated by IRS. Gluconeogenesis and lipolysis are also inhibited. Mechanistic targeting of rapamycin complex 1 (mTORC1), which is also activated by AKT kinases, encourages the de novo production of lipids and proteins. Transforming proteins with the Src homology 2 domain and the mitogen-activated protein kinase (MPK)/extracellular signal-related kinase (ERK) pathway are two components of the insulin signaling pathway that aid in protein synthesis and cell division (Figure 2.8). 2.3.11.7.1.2  Insulin Signaling Pathway in Presence of Insulin Resistance  Not all instances of insulin resistance are equal; occasionally, it is partial or selective. IRS activates phosphatidylinositol-3-kinase/serine/threonine-specific protein kinase B pathway (PI3K/AKT) in the partial insulin resistance pathway, which in turn limits glucose uptake, lipolysis, gluconeogenesis, and also triggers reduced endothelial nitric oxide synthase. Lipid synthesis is also activated by the (PI3K/AKT) pathway (mTORC1). Through the mechanistic target of rapamycin complex 1 and MEK/ERK pathway, insulin resistance-associated hyperinsulinemia encourages anabolic cell activity (Figure 2.8). Additionally, the MEK/ERK pathway promotes protein synthesis, cell proliferation, and increased expression of endothelin (ET 1) and plasminogen 1 (PA 1). This pathway also inhibits nuclear factor 2, distressing the cell defense mechanisms against radical stress (Unluhizarci et al., 2021). 2.3.11.7.2  Antimullerian Hormone “Anti-Müllerian Hormone (AMH, also called Müllerian inhibiting substanceMIS) is a homodimeric glycoprotein belonging to the transforming growth factor-β (TGF-β) superfamily” (Lv et al., 2020; Silva and Giacobini 2021). AMH is expressed by both women and men; in men it is released by the testes, and in women it is released through the ovaries. Prenatally, it has an important role in gonadal sexual differentiation by repressing Müllerian ducts in males (Silva and Giacobini 2021). Ovarian follicles are also developed by AMH and it also affects the hypothalamicpituitary-gonadal axis throughout numerous stages of development (Moolhuijsen and Visser 2020). Growing follicles express AMH up to 8 mm in women (Lv et al., 2020).

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Herbal Medicine Applications for Polycystic Ovarian Syndrome In the presence of Insulin

Insulin receptor

IRS

SHC

PIK3/AKT pathway

mTORC1 MEK/ERK pathway

Inhibition Protein of nuclear synthesis factor 2 Increased action of ET-1 and PT-1

Cell proliferation

Inhibition of glucose uptake Inhibition of gluconeogenesis

Decreased eNOS

Lipid synthesis Inhibition of lipolysis

FIGURE 2.8  Insulin signaling pathway in the presence of insulin resistance (Unluhizarci et al., 2021).

AMH expression is higher in tiny antral and preantral follicles and lower in primordial follicles during the FSH independent phase. AMH expression, however, is inhibited during the FSH-dependent phase and is seen to be lower in the preovulatory follicle. As a result, in the absence of AMH, a high level of estradiol is found in antral and preovulatory follicles. In PCOS, AMH expression is enhanced twofold, which leads to more recruited follicles. Thus, by suppressing the selection phase and preventing the creation of preovulatory follicles, an increase in AMH reduces estradiol synthesis and FSH expression (Rudnicka et al., 2021). 2.3.11.7.3 Androgen Androgens belong to the steroid hormone family, and their over secretion is thought to be the primary clinical symptom of PCOS. Because androgens are so vital to the reproductive health of women, it is crucial to understand how they are produced and regulated. It is crucial to comprehend their production and secretion as a result. Androgens include testosterone (T), DHEAS, androstenedione (A4), dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA). Of these, only T and DHT have androgenic receptors. The strong production of androgens is carried out by the ovaries and adrenal glands, and the steriodogenic enzymes control the synthesis of these hormones (Chow et al., 2017; Li et al., 2010; Ma et al., 2016; Martinat et al., 2005; Yang et al., 2016).

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2.3.11.7.4  Hyperandrogenism and Pathophysiology of PCOS “Hyperandrogenism represents a chief attribute of PCOS as elevated androgen levels are the most constant feature, with the majority of patients exhibiting hyperandrogenism” (Rotterdam definition) (Livadas et al., 2014). In addition, pro-androgens such as androstenedione (A4) and testosterone (T) are seen higher in women having hyperandrogenic PCOS (Keefe et al., 2014) (Table 2.3). Enhanced levels of androgens can be stimulated by hyperinsulinemia and insulin resistance because they are responsible for causing reduced sex hormone-binding globulin levels, resulting in increased unfavorable metabolic profiles and free androgens (Pappalardo et al., 2010, Pappalardo et al., 2017). As a result of androgen hypersecretion in the case of congenital adrenal hyperplasia, the women show elevated levels of androgens along with enlarged, multicystic ovaries, theca interstitial hyperplasia, and ovarian PCOS morphological traits (Hague et al., 1990). Apart from this, an elevated level of androgen secretion is observed in cultured theca cells of humans after removing PCOS ovaries and it continues up to long-term culture (Nelson et al., 1999). All these observations state the part of androgens in the addition of PCOS ovarian characteristics (Rodriguez Paris and Bertoldo 2019). 2.3.11.7.5  Hypothalamic Pituitary Failure The successive LH secretion, increased amplitude, and frequency level of GnRH are very important pathophysiological characteristics of PCOS (Roland and Moenter, 2014). The primary cause of gonadotropin inhibitory hormone (GnIH) dysfunction is impaired GnRH secretion (Shaaban et al., 2018). According to some studies, women having PCOS were found to have a faster GnRH pulse frequency throughout the entire ovulatory cycle. Serum kisspeptin levels are seen higher in women with PCOS, as proven by various studies (Figure 2.9). It is hypothesized through various observations of studies that overexpression of the serum kissepeptin system in polycystic ovary syndrome is the main

TABLE 2.3 Effects of Androgen in PCOS-Affected Women Sl. No.

Effects of Androgen in Women with PCOS Dehydroepiandrosterone sulfate (DHEAS), pro-androgens androstenedione, testosterone (T) is seen higher in women having hyperandrogenic PCOS. Enzymes required for the conversion of pro-androgens to bioactive androgens and 3β-hydroxysteroid dehydrogenase in serum is also seen higher. Elevated level of androgens might be stimulated by hyperinsulinemia and insulin resistance showing ovarian PCOS morphological traits showing ovarian PCOS morphological traits in case of congenital adrenal hyperplasia. When PCOS ovaries were removed and theca cells were cultured androgen secretions were observed higher.

References Keefe et al. (2014)

Keefe et al. (2014)

Hague et al. (1990)

Nelson et al. (1999)

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cause of hypothalamic-pituitary-gonadal axis hyperactivity. All these cause ­hyperandrogenism, menstrual disorders, and hyperandrogenemia (Szeliga et al., 2022). Gonadotropin hormone is released from the pituitary and activated after the secretion of GnRH from the hypothalamus. In ovarian theca cells, androgen production is promoted because of LH, which activates the gonadotropin hormone. Simultaneously, FSH activates the FSH receptor, which in turn converts the androgens to estrogens in ovarian granulosa cells, which are responsible for promoting follicle growth (Ashraf et al., 2019). It has been presumed that an imbalance in the hypothalamic-pituitary-ovarian axis resulting in excess gonadotropin is because of neuroendocrine system dysregulation. As a result, there is a significant increase in the LH to FSH ratio in PCOS (Tsutsumi and Webster 2009; Walters et al., 2018). Mentioning the hypothalamic level, there are coexpressing KNDy neurons (kisspeptin, Neurokinin B and Dynorphin) which secrete kisspeptin for the regulation of GnRH release. In the pituitary gland, low frequency GnRH signals favor FSH secretion from the pituitary gonadotrophs and high frequency GnRH pulses favor the luteinizing hormone release (Figure 2.10). Sexual steroids are feedbacking the hypothalamicpituitary-gonadal axis through androgen, progesterone, and estrogen receptors on KNDy neurons. Hypothalamic GnRH secretion is regulated by γ‐aminobutyric acid (GABA) and AMH (Garg et al., 2022).

Dynorphin

NK3R

Neurokrinin B Other potential regulators: GABA,AMH

Kisspeptin

Low frequency GnRH pulses

FSH secretion

KNDy neurons

ER PR AR

Oestrogen Progesterone Androgens

GnRH neurons

High frequency GnRH pulses

LH secretion

FIGURE 2.9  Neuroendocrine regulation of GnRH (adapted from Garg et al., 2022).

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis Hypothalamus

43

Hypothalamus

GnRH

Increased GnRH pulsality

NEUROENDOCRINE REGULATION OF GnRH Anterior Pituitary

Anterior Pituitary

LH,FSH

LH Normal Ovaries

Ostrogen, Progesterone, Androgens NORMAL GnRH PULSALITY

Polycystic ovaries Androgens,Ovulatory Dysfunction INCREASED GnRH PULSALITY

FIGURE 2.10  GnRH pulsatility with neuroendocrine regulation (adapted from Garg et al., 2022).

2.4  MANAGEMENT OF PCOS 2.4.1 Management of Hypothalamic-Pituitary Failure Till date, the treatments have mostly focused on concerns such as subfertility or hyperandrogenism instead of pathophysiological disturbances. Treatments such as accurate phenotyping of PCOS patients and increased pharmaceutical apparatus which specifically targets increased GnRH pulses are considered as appropriate clinical responses (Garg et al., 2022). 2.4.1.1  Neurokinin 3 Receptor Reducing GnRH Pulsatility Reduced AMH levels were seen due to neurokinin 3 receptor (NK3R) antagonism in females with PCOS at 12 weeks (Fraser et al., 2021). If GnRH pulsatility is reduced, AMH levels can be reduced by manipulating KNDy (Kisspepetin, Neurokinin B, and Dynorphin) signaling. We can assume AMH receptor antagonism could also be helpful in PCOS treatment, but there is no data found regarding this till now. Research is still in progress on AMHR2 signaling pathways in which AMH antagonism may be its basis in the future (Hart et al., 2021). 2.4.1.2  Use of Oral Contraceptives and Letrozole PCOS patients who desire to conceive need ovarian suppression along with combined oral contraceptive pills (OCPs). The gain of various non-contraceptives comes

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along with the utilization of OCPs by reversing hyperandrogenism shrinking magnified ovarian stroma, regulating menses, and diminishing the risk of endometrial and ovarian cancer (de Melo et al., 2017). Ovulating inducing agents are required for those who desire pregnancy. According to many spontaneous clinical trials, letrozole is found to be the best ovulation inducing agent with clomiphene citrate (CC), which is a second-line agent, as per recommendations (Legro et al., 2013, Legro et al., 2014). According to some reports, letrozole showed benefits such as decreased rates of multiple gestations and attaining a triple proliferative pattern of endometrium needed for implantation to be successful as compared to CC. Despite all these advantages, letrozole is a better and newer ovulation inducing agent with restricted long-term data as compared to CC (Mikhael et al., 2019). 2.4.1.3  Mechanistic Pathways Information Hypothalamus-pituitary failure with respect to hormonal contraceptives, lactation, insulin-sensitizing agents, reproductive development, and pregnancy is poorly understood. Therefore, to understand how these pathways are disrupted, human mechanistic studies should be done. Human mechanistic studies inspect many ways these pathways are disrupted, and it would be helpful in guiding recent treatments for PCOS. Likewise, more studies should be done to inspect the proposed disrupted pathways. Studies such as acupuncture, which treats sympathetic overactivity in PCOS women, might increase the utilization of such treatment alternatives (Kuang et al., 2013) (Table 2.4).

TABLE 2.4 Possible Treatment of Patient Hypothalamus Pituitary Failure S. No.

Management Phenotyping of PCOS patients Increased pharmaceuticals apparatus NK3R antagonist Utilization of OCPs

Letrozole

Acupuncture

Target

References

Increased GnRH pulses

Garg et al. (2022)

Increased GnRH pulses

Garg et al. (2022)

Reducing gonadotropin-releasing hormone pulsatility Reversing hyperandrogenism shrinking magnified ovarian stroma, regulating menses, and diminishing risk of endometrial and ovarian cancer Decreased rates of multiple gestations, attaining triple proliferative pattern of endometrium Sympathetic overactivity in PCOS

Fraser et al. (2021) de Melo et al. (2017)

Mikhael et al. (2019)

Kuang et al. (2013)

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2.4.2 Evaluation and Management of Ovarian Insufficiency The evaluation of PCOS entails the presence or absence of hyperandrogenism (clinical and biochemical), chronic anovulation (oligomenorrhea or amenorrhea) and polycystic ovaries (Dumesic et al., 2015) (Table 2.5). There are multiple sets of criteria to diagnose women with PCOS (Lizneva et al., 2016; Rotterdam, 2004). According to the National Health Service (NHS), menstrual irregularity, elevation of androgenic hormones, and scans showing polycystic ovaries are the particular criteria for PCOS (Lujan et al., 2008). PCOS was defined by the Androgen Excess Society as “hyperandrogenism with ovarian dysfunction or polycystic ovaries”. So, according to Androgen Excess Society, androgen excess is a key event in the development and pathophysiology of PCOS (Azziz et al., 2006). If PCOS is suspected in patients, then history and physical examinations are very critical in diagnosing PCOS. Diabetes, endometrial cancer, a family history of PCOS, lifestyle factors such as smoking, and a physical exam that includes the menstrual cycle, blood pressure, acne, and ovarian enlargement are all required investigations. It is important to rule out conditions that resemble PCOS in clinical characteristics. These conditions include hyperprolactinemia, thyroid illness, Cushing syndrome, drug-induced androgen excess, etc. (Boyle et al., 2018; Misso et al., 2018; Xie et al., 2018). So, to exclude all other conditions, differential diagnoses are needed. The entire given test should be performed on every patient. After PCOS is diagnosed, most patients are at high risk of developing cardiovascular disease, psychotic illnesses, type II diabetes, endometrial dysplasia, obesity, and infertility (Goodarzi et al., 2015). 2.4.2.1 Hyperandrogenism The presence of acne, hirsutism, and measuring androgen levels can all be used to make a clinical diagnosis of hyperandrogenism. Both the ovary and the adrenal affected in steroidogenesis condition, which leads to increased androgen levels and

TABLE 2.5 Differential Diagnoses and Screening Test Sl. No.

Diagnosis Pregnancy Hypothyroidism Hyperprolactinemia Cushing syndrome Adrenal tumor Ovarian tumor

Signs and Symptoms Amenorrhea, breast tenderness, and uterine cramps Goiter, weight changes fatigue, and temperature intolerance Galactorrhea Hypertension and buffalo hump Rapid virilization Frequent urination, back pain, abdominal swelling, weight loss, and fatigue

Laboratory Evolution HCG level TSH Prolactin Cortisol DHEA Transvaginal ultrasound

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DHEA levels in PCOS women. Family studies also show prevalence of hyperandrogenism in relatives of women with PCOS (Kahsar-Miller et al., 2001; Legro et al., 1998; Sam et al., 2006). Hirsutism is directly affected by hyperandrogenism. Hirsutism is defined as excessive terminal hair growth in regions which are usually hairless or have limited hair growth, such as the pubic region, face, under thigh region, chest, and abdomen (Redmond et al., 1990). The Ferriman-Gallwey score can be used to categorize the degree of hirsutism. Acne severity can be graded as mild, moderate, or severe depending on the lesions. In PCOS, testosterone concentration is typically 150 ng/dL. In PCOS women, an elevated level of testosterone to androstenedione ratio can be seen (Misichronis et al., 2012). 2.4.2.2  Chronic Anovulation The disruption of reproductive hormones such as LH, FSH, estrogen, and testosterone causes oligomenorrhea and amenorrhea-like disturbances in the menstrual cycle. The detection of ovarian dysfunction is mainly through a history of irregular menstrual cycles associated with oligomenorrhea (cycle length of more than 35 days) or amenorrhea (absence of menstruation for 6 to 12 months) (Conway et al., 1989; Kiconco et al., 2021). Ovulatory dysfunction causes infertility, endometrial cancer, and endometrial hyperplasia (Elting et al., 2003).

2.4.3 Therapeutic Interventions for PCOS For the management and treatment of PCOS, a number of complementary therapies and forms of therapy have been proposed. Due to PCOS’ complex pathophysiology, treatment varies greatly based on the indications and symptoms already present and is very infrequently mono therapeutic. 2.4.3.1  Treatment of Androgen-Related Symptoms The most likely androgen-related symptoms include excess body and facial hair (hirsutism), male pattern baldness, acne, and alopecia. The signs and symptoms vary from one individual to another (Sirmans and Pate, 2014). Lifestyle changes are seen as a cost-effective first-line treatment option and as an essential supplement to ongoing medication (Legro et al., 2013; Misso et al., 2014). According to studies (Moran et al., 2011), small modifications in lifestyle such as nutrition, exercise, and attitude have been shown to have a positive effect on body weight, insulin resistance, metabolic dysfunction, fertility, mood, and testosterone levels. Oral hormonal contraceptives are the first-line treatment for high androgen levels. OCPs lower testosterone levels, reducing hirsutism and acne. Improvement in the menstrual cycle, testosterone level, and hyperandrogenemia can be seen in two to three months of treatment. OCPs are the first-line management protocol for women with PCOS who do not desire to ovulate. Estrogen and progestin combos are the main OCs used in treatment (Legro et al., 2013; Misso et al., 2014). By suppressing the hypothalamic-pituitary-ovarian axis, oral contraceptives raise sex hormone-binding globulin levels in the liver while lowering free androgen levels in the blood, and this improves acne and hirsutism symptoms of hyperandrogenism

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and corrects menstrual abnormalities (Rotterdam, 2004). In women with dyslipidemia, OCPs should be used with caution because they can raise TG levels. To achieve satisfactory results against acne and hirsutism, an OCP regimen of at least six months is usually recommended (Yildiz, 2007). Low-dose oral contraceptives with anti-androgenic or neutral progestins are regarded as the best choice for symptomatic treatment (Yildiz, 2007). One of the most recent OCPs comprises a mix of nonandrogenic progestin (drospirenone) and ethinylestradiol, which may be suitable for the treatment of PCOS in women. According to a 2015 Cochrane review (van Zuuren et al., 2015), oral estrogen replacement therapy is effective for the majority of women (70%–80%). Contraceptives are the most efficient first-line treatment for mild hirsutism. Spirolactone (100 mg daily) and flutamide (250 mg twice daily) are safe for patients to consume (van Zuuren et al., 2015). New OCPs such as norethindrone, desogestrel, and norgestimate contain less androgenic progesterone. Drospirenone and dienogest are some newer progestins that have antimineralocorticoid and antiandrogenic properties (Badawy and Elnashar, 2011). Other treatments include electrolysis, laser, and pulsed light (Somani et al., 2014). Women frequently use laser treatment methods and other mechanical methods because pharmacological treatment fails to provide desirable outcomes (ACOG Committee, 2009). Treatment methods also include eflornithine hydrochloride. Eflornithine combined with laser remedy resulted in a more rapid decrease in facial hair, but data is limited (Hamzavi et al., 2007; Smith et al., 2006). Antiandrogens such as spironolactone, flutamide, and finasteride are used to treat hyperandrogenism through inhibiting androgen receptors. Spironolactone binds to androgen receptors as an antagonist, causing menstrual irregularity. Because of this, it is often used with OCPs to make them work better together and solve the problem (Rittmaster, 1999). Finasteride suppresses the formation of dihydrotestosterone by inhibiting type 2 (5-a-reductase) and reduces the severity of hirsutism (Lumachi and Rondinone, 2003). Metformin and thiazolidinediones can decrease androgen levels by improving insulin resistance. These drugs are useful because women with PCOS are more likely to develop insulin resistance, which can lead to metabolic disorders and cardiovascular diseases. Metformin works indirectly by lowering insulin levels and decreasing CYP17 cytochrome activity, which is linked to the production of androgens. It also raises SHBG and lowers free testosterone. 2.4.3.2  Treatment of Infertility Treatment for infertility should begin with information regarding success rates, the cessation of dangerous habits (particularly smoking), the screening for medical comorbidities, and the treatment of excess weight. A PCOS patient has a 5%–10% lower chance of conceiving in comparison to women without PCOS. Weight loss is recommended as the first-line remedy for the management of infertility in overweight/obese women with PCOS. Observational studies (Homburg, 2003) showed that a weight loss of 5%–10% can lead to more ovulation and pregnancies. Anovulatory infertility is treated with clomiphene citrate as a first-line treatment (Legro et al., 2013; Misso et al., 2014). It is frequently used in the treatment of ovulation. The live birth rate related to Clomiphene citrate is 23.3% (Deveci et al., 2015;

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Dong et al., 2013). Its antiestrogenic effect on the hypothalamus causes a shift in GnRH pulse frequency, resulting in a rise in the release of FSH from the pars distalis. Through the drug clomiphene, 73% of women ovulated, 36% of successful pregnancies were achieved, but approximately 29% gave birth (Homburg, 2005). When clomiphene citrate with or without metformin fails to establish conception, exogenous gonadotropins, in-vitro fertilization, and laparoscopic ovarian drilling are used as a second line of treatment (Spritzer, 2014). Another class of drugs, AR inhibitors, were introduced as an option for ovulation induction in 2001 (Franik et al., 2018). Anastrozole, letrozole, and other AR inhibitors reduce estrogen levels by inhibiting the conversion of testosterone and androstenedione into estrogen and estrone (Figure 2.11). This led to the release of negative feedback from the hypothalamus and an increase in FSH levels (Casper and Mitwally, 2011). Letrozole is administered on the third day of the menstrual cycle at a dose range of 2.5–7.5 mm/day (Pritts, 2010). In a comparative analysis of letrozole with clomiphene, studies suggest that letrozole was more likely to increase the pregnancy rates as well as the live birth in subfertile women presented with anovulatory polycystic ovarian disease (Figure 2.11). In a risk difference analysis between letrozole and clomiphene citrate, both were found to be equally safe for ovarian hyperstimulation and miscarriage (Badawy et al., 2009; Polyzos et al., 2008). There was no difference in rates of pregnancy, miscarriage, or multiple pregnancies between letrozole and laparoscopic ovarian drilling. According to the Australian Therapeutic Goods Administration, letrozole is classified as a category D drug for pregnancy. The drug should not be given to pregnant women. A health counselor should inform and counsel prior to using letrozole (Figure 2.11). Metformin is generally used to treat insulin resistance and to restore menstrual abnormalities in PCOS women. Metformin is known to reduce inflammation and pregnancy problems and does not have any teratogenic effects in pregnant women (Glueck et al., 2019). Metformin combined with clomiphene citrate improves ovulation and conception rate in sterile PCOS patients. Metformin also improves menstrual cycles, odd waist-to-hip ratio, and vascular markers in nonobese women with PCOS (Teede et al., 2018) (Figure 2.11). Clomiphene may be combined with other drugs to increase the likelihood of ovulation. Antidiabetes drugs can make people more fertile, lower insulin resistance, and lower testosterone levels in the blood. Gonadotropin therapy and laparoscopic ovarian diathermy are both used as second-line therapies for ovulation induction according to ESHRM (Thessaloniki, 2008). The job of gonadotropin is to cause ovulation and control the growth of follicles by controlling FSH. The negative aspect of gonadotropin is the increased risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies due to multifollicular development. A low-dose gonadotropin protocol is generally recommended by ASRM (Christin-Maitre and Hugues, 2003). In general, treatment begins with a low dose of approximately 37.5–50 IU/day and is gradually increased up to 50% depending on the condition.

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FIGURE 2.11  Different pharmacotherapy against PCOS.

A generally low-dose regimen resulted in 70% ovulation induction and a 5.7% live birth rate with a very low rate of OHSS and multiple pregnancies (Maggs et al., 1998). A maximum of six cycles of gonadotropin is advised. In clomiphene and gonadotropin-resistant PCOS women, laparoscopic ovarian surgery and laser are another acceptable alternative. In a comparable analysis between LOD and gonadotropin therapy, no evidence of any difference between live birth and miscarriage rate was observed, according to the Cochrane review. LOD inhibits LH and androgen production and restores menstrual regularity (63%–85%) of PCOS women (Al-Fadhli et al., 2004). LODS entails drilling four to ten holes in the ovary’s stroma and surface using a laser or electrocautery. A single therapy leads to the establishment of the menstrual cycle in 92% of women and a 58% pregnancy rate (Gjönnaess, 1984). In vitro fertilization (IVF) technique is considered third-line therapy after repeated failure attempts with clomiphene, gonadotropins, and letrozole (Thessaloniki, 2008). IVF is the first choice when a woman has severe endometriosis, her tubes are blocked, or something similar, and when a man has no sperm. In IVF treatment, the cycle cessation is more frequent and the stimulation cycles usually take significantly longer duration in women with PCOS (Heijnen et al., 2006).

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2.4.3.3  Treatment of Mensuration Dysfunction PCOS is characterized by hormonal misbalance that leads to amenorrhea (menstrual cycle absent) and oligomenorrhea-(prolonged or irregular menstrual cycle) like conditions. Along with menstrual irregularity, endometrial hyperplasia and carcinoma are caused by chronic anovulation (Balen, 2001). There are certain drugs which help in managing hormonal levels. For example, cyclic progestin and oral contraceptives containing estrogen and progesterone can inhibit proliferation. These drugs are used in women who don’t wish to ovulate. Birth control pills result in the inhibition of ovulation. 2.4.3.4  Other Therapeutic Possibility against PCOS Medroxyprogesterone acetate is used to treat amenorrhea in women who don’t desire to conceive. The recommended dosage range for MPA is 5–10 mg/day for 10–14 days each month. Progesterone medication prevents aberrant endometrial growth (Azziz et al., 2006). MPA may improve lipid profiles and insulin sensitivity in PCOS patients (Bagis et al., 2002; Haydardedeoglu et al., 2009; Özdemir et al., 2008). 2.4.3.5 Statins In general, for prolonged use, statins seem to be a safe drug. They are commonly required to reduce hyperlipidemia, regulate the LH-FSH ratio, safeguard against long-term cardiovascular morbidity, and may provide extra advantages for women with PCOS (Claessen et al., 2020). Studies have shown that statins to reduce androgen levels and DHEA in PCOS patients (Chen et al., 2021). Studies found that statins with simvastatin and mostly with atorvastatin treatment lower testosterone levels by inhibiting the mevalonate pathway, hence lowering the cholesterol required for androgen synthesis (Banaszewska et al., 2007). For example, statins are assessed as a high-risk drug in pregnancy, so more investigation is needed for women to avoid any potential risk to the fetus with statin use (Cassidy-Vu et al., 2016). 2.4.3.6  Traditional/Folk Medicine in PCOS In today’s times, PCOS patients prefer traditional or herbal remedies. China has been using herbal medicine for PCOS since many years ago. Several studies looked into the therapeutic effects of herbs on menstrual irregularity and metabolic syndrome in PCOS (Moini Jazani et al., 2019). Various herbs, including cinnamon, Vitex agnuscastus, flaxseed, and liquorice, may have beneficial effects on improving different aspects of PCOS. Cinnamon supplementation regulates insulin resistance, weight/BMI, insulin, and AMH in PCOS patients, according to studies (Borzoei et al., 2018; Hajimonfarednejad et al., 2018; Kort et al., 2014; Wang et al., 2007). Various flavonoids and phenolic compounds present in cinnamon help against oxidative stress in PCOS by decreasing ROS (Khodaeifar et al., 2019). Studies suggest that Vitex agnus-castus herbs stimulate fertility and regulate menstrual cycles by increasing progesterone levels, slightly restricting FSH release, promoting LH release, suppressing type II dopamine receptors, rising CAMP levels, and

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reducing prolactin levels (Roemheld-Hamm, 2005; Wuttke et al., 2003). This herb can regulate oxidative stress. Flavonoid compounds present in herbs can reduce the level of testosterone by converting it into estradiol through the increasing activity of AR (Ahangarpour et al., 2016; Webster et al., 2006). Flaxseed, a lignin-rich food, aids in weight loss and lowers the basal metabolic rate in PCOS patients (Shim et al., 2014). Liquorice (Glycyrrhiza glabra) root reduces serum testosterone levels and adjuvant therapy for hirsutism (Armanini et al., 2004; Armanini et al., 2007). Berberine active compound Rhizoma coptidis shows an ­optimistic effect on insulin resistance in PCOS (Li et al., 2013; Zhang et al., 2020). When compared to metformin, berberine seems to be more effective than metformin to decrease androgen levels, the LH/FSH ratio, and improve dyslipidemia (Xie et al., 2019). Nicker Bean, a medicinal shrub, is currently in the news for its positive PCOS treatment outcomes. Seed extracts demonstrate anti-androgenic, hypoglycemic, and anti-inflammatory effects (Meera Murugesan et al., 2020; Ramadurai et al., 2020). 2.4.3.7  Vitamin D and Calcium Women of reproductive age suffer from vitamin D deficiency or inadequacy (Bodnar et al., 2007; Nesby-O’Dell et al., 2002). A study indicated that vitamin D deficiency was linked significantly to a lower rate of ovulation, pregnancy, and ultimately lower chances of delivering a live birth in women with PCOS who underwent ovarian stimulation for the treatment of infertility (Butts et al., 2019). Vitamin D plays an important role in the reduction of insulin resistance, Hyperandrogenism, as well as improvement in lipid metabolism in PCOS patients. Vitamin D also helps in follicular development and calcium absorption (Miao et al., 2020). Vitamin D and calcium supplementation improve menstrual regularity, hyperandrogenism, and follicular development in women with PCOS (Firouzabadi et al., 2012). Regular supplementation of vitamin D and calcium improves 25-­hydroxyvitamin D levels in obese PCOS patients. A study reveals that a significant drop (12%) in testosterone and androgen levels (17%) was seen after supplementation of vitamin D and calcium (Pal et al., 2012). Vitamins C, E, and omega-3 fatty acids have also been shown to help with PCOS (Chen et al., 2020; Iervolino et al., 2021; Izadi et al., 2019; Yang et al., 2018).

2.5 CONCLUSION Complex pathogenesis in PCOS is the main barrier to cure this disease. To some extent, vitamins D, C, E, and calcium supplementation, omega 3 fatty acid rich feed, flaxseed, licorice (Glycyrrhiza glabra) root, Rhizoma coptidis, Nicker Bean, etc., have the potency to reduce the occurrence of PCOS. It has been found that the application of different pharmacological medicines and hormonal therapy may initially reduce PCOS, but they have the possibility to induce other health anomalies. Ultimately, our lifestyle should be normalized to maintain the normal state of hypothalamic-pituitary-gonadal axial hormones and steroidogenesis.

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BIBLIOGRAPHY Abruzzese, Giselle A., Gloria E. Cerrrone, Juan M. Gamez, Mabel N. Graffigna, Susana Belli, Gustavo Lioy, Eduardo Mormandi, Patricia Otero, Oscar A. Levalle, and Alicia B. Motta. “Lipid accumulation product (LAP) and visceral adiposity index (VAI) as markers of insulin resistance and metabolic associated disturbances in young argentine women with polycystic ovary syndrome.” Hormone and Metabolic Research 49, no. 01 (2017): 23–29. https://doi.org/10.1055/s-0042-113463. Ahangarpour, Akram, Seyedeh Asma Najimi, and Yaghoob Farbood. “Effects of Vitex agnuscastus fruit on sex hormones and antioxidant indices in a d-galactose-induced aging female mouse model.” Journal of the Chinese Medical Association 79, no. 11 (2016): 589–596. https://doi.org/10.1016/j.jcma.2016.05.006. Aittomäki, Kristiina, JoséLuis Dieguez Lucena, Pirjo Pakarinen, Pertti Sistonen, Juha Tapanainen, Jörg Gromoll, Riitta Kaskikari et al. “Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure.” Cell 82, no. 6 (1995): 959–968. https://doi.org/10.1016/0092-8674(95)90275-9. Ajmal, Nida, Sanam Zeib Khan, and Rozeena Shaikh. “Polycystic ovary syndrome (PCOS) and genetic predisposition: a review article.” European Journal of Obstetrics & Gynecology and Reproductive Biology: X 3 (2019): 100060. https://doi.org/10.1016/j. eurox.2019.100060. Al-Fadhli, Raedah, and Togas Tulandi. “Laparoscopic treatment of polycystic ovaries: is its place diminishing?” Current Opinion in Obstetrics and Gynecology 16, no. 4 (2004): 295–298. https://doi.org/10.1097/01.gco.0000136495.56958.1a. Altieri, Paola, Carla Cavazza, Francesca Pasqui, Antonio M. Morselli, Alessandra Gambineri, and Renato Pasquali. “Dietary habits and their relationship with hormones and metabolism in overweight and obese women with polycystic ovary syndrome.” Clinical Endocrinology 78, no. 1 (2013): 52–59. https://doi.org/10.1111/j.1365-2265.2012.04355.x. Armanini, Decio, Mee Jung Mattarello, Cristina Fiore, Guglielmo Bonanni, Carla Scaroni, Paola Sartorato, and Mario Palermo. “Licorice reduces serum testosterone in healthy women.” Steroids 69, no. 11–12 (2004): 763–766. https://doi.org/10.1016/j.steroids.2004. 09.005. Armanini, Decio, Roberto Castello, Carla Scaroni, Guglielmo Bonanni, Gianbattista Faccini, Donatella Pellati, Alessandro Bertoldo, Cristina Fiore, and Paolo Moghetti. “Treatment of polycystic ovary syndrome with spironolactone plus licorice.” European Journal of Obstetrics & Gynecology and Reproductive Biology 131, no. 1 (2007): 61–67. https:// doi.org/10.1016/j.ejogrb.2006.10.013. Ashraf, Sairish, Mudasar Nabi, Fouzia Rashid, and Shajrul Amin. “Hyperandrogenism in polycystic ovarian syndrome and role of CYP gene variants: a review.” Egyptian Journal of Medical Human Genetics 20, no. 1 (2019): 1–10. https://doi.org/10.1186/ s43042-019-0031-4. Azziz, Ricardo, ed. The Polycystic Ovary Syndrome: Current Concepts on Pathogenesis and Clinical Care. Endocrine Updates. Springer, 2007. https://doi.org/10.1007/978-0387-69248-7. Azziz, Ricardo, Enrico Carmina, Didier Dewailly, Evanthia Diamanti-Kandarakis, Hector F. Escobar-Morreale, Walter Futterweit, Onno E. Janssen et al. “Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline.” The Journal of Clinical Endocrinology & Metabolism 91, no. 11 (2006): 4237–4245. https://doi.org/10.1210/jc.2006-0178. Azziz, Ricardo, Howard A. Zacur, C. Richard Parker Jr, Edwin L. Bradley Jr, and Larry R. Boots. “Effect of obesity on the response to acute adrenocorticotropin stimulation in eumenorrheic women.” Fertility and Sterility 56, no. 3 (1991): 427–433. https://doi. org/10.1016/s0015-0282(16)54535-x.

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

53

Azziz, Ricardo, V. Black, G. A. Hines, L. M. Fox, and L. R. Boots. “Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamicpituitary-adrenal axis.” The Journal of Clinical Endocrinology & Metabolism 83, no. 7 (1998): 2317–2323. https://doi.org/10.1210/jc.83.7.2317. Baban, Aesha Sh Sh, Sabah H. Korsheed, and Anas Y. Al Hayawi. “The FSHR polymorphisms association with polycystic ovary syndrome in women of Erbil, Kurdistan in North of Iraq.” Ibn AL-Haitham Journal For Pure and Applied Sciences (2018): 257–272. https:// doi.org/10.30526/2017.ihsciconf.1799. Badawy, Ahmed, and Abubaker Elnashar. “Treatment options for polycystic ovary syndrome.” International Journal of Women’s Health 3 (2011): 25. https://doi.org/10.2147/ijwh.s11304. Badawy, Ahmed, Ibrahim Abdel Aal, and Mohamed Abulatta. “Clomiphene citrate or anastrozole for ovulation induction in women with polycystic ovary syndrome? A prospective controlled trial.” Fertility and Sterility 92, no. 3 (2009): 860–863. https://doi. org/10.1016/j.fertnstert.2007.08.034. Bagis, Tayfun, Adnan Gokcel, Hulusi Bulent Zeyneloglu, Ebru Tarim, Esra Bulgan Kilicdag, and Bulent Haydardedeoglu. “The effects of short-term medroxyprogesterone acetate and micronized progesterone on glucose metabolism and lipid profiles in patients with polycystic ovary syndrome: a prospective randomized study.” The Journal of Clinical Endocrinology & Metabolism 87, no. 10 (2002): 4536–4540. https://doi.org/10.1210/ jc.2002-020294. Balen, Adam. “Polycystic ovary syndrome and cancer.” Human Reproduction Update 7, no. 6 (2001): 522–525. https://doi.org/10.1093/humupd/7.6.522. Banaszewska, Beata, Leszek Pawelczyk, Robert Z. Spaczynski, James Dziura, and Antoni J. Duleba. “Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective, randomized, crossover trial.” The Journal of Clinical Endocrinology & Metabolism 92, no. 2 (2007): 456–461. https://doi.org/10.1097/01. ogx.0000265908.59079.34. Barber, Thomas M., George K. Dimitriadis, Avgi Andreou, and Stephen Franks. “Polycystic ovary syndrome: insight into pathogenesis and a common association with insulin resistance.” Clinical Medicine 16, no. 3 (2016): 262. https://doi.org/10.7861/ clinmedicine.16-3-262. Barber, Thomas M., John A. H. Wass, Mark I. McCarthy, and Stephen Franks. “Metabolic characteristics of women with polycystic ovaries and oligo‐amenorrhoea but normal androgen levels: implications for the management of polycystic ovary syndrome.” Clinical Endocrinology 66, no. 4 (2007): 513–517. https://doi.org/10.1111/j.1365-2265.2007.02764.x. Barber, Thomas M., Petra Hanson, Martin O. Weickert, and Stephen Franks. “Obesity and polycystic ovary syndrome: implications for pathogenesis and novel management strategies.” Clinical Medicine Insights: Reproductive Health 13 (2019): 1179558119874042. https://doi.org/10.1177/1179558119874042. Baskind, N. Ellissa, and Adam H. Balen. “Hypothalamic–pituitary, ovarian and adrenal contributions to polycystic ovary syndrome.” Best Practice & Research Clinical Obstetrics & Gynaecology 37 (2016): 80–97. https://doi.org/10.1016/j.bpobgyn.2016.03.005. Basheer, M., Rai, S., Ghosh, H., and Hajam, Y. A. “Protective role of seed extract of Tephrosia purpurea in letrozole induced polycystic ovary syndrome in wistar rats.” Journal of Biological Sciences 18, no. 8 (2018): 458–467. Beatriz Motta, Alicia. “The role of obesity in the development of polycystic ovary syndrome.” Current Pharmaceutical Design 18, no. 17 (2012): 2482–2491. https://doi. org/10.2174/13816128112092482. Bodnar, Lisa M., Hyagriv N. Simhan, Robert W. Powers, Michael P. Frank, Emily Cooperstein, and James M. Roberts. “High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern United States and their neonates.” The Journal of Nutrition 137, no. 2 (2007): 447–452. https://doi.org/10.1093/jn/137.2.447.

54

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Borzoei, Azam, Maryam Rafraf, Shirin Niromanesh, Laya Farzadi, Fateme Narimani, and Farideh Doostan. “Effects of cinnamon supplementation on antioxidant status  and serum lipids in women with polycystic ovary syndrome.” Journal of Traditional and Complementary Medicine 8, no. 1 (2018): 128–133. https://doi.org/10.1016/j. jtcme.2017.04.008. Boyle, Jacqueline A., Rebecca Xu, Emily Gilbert, Millicent Kuczynska-Burggraf, Bryan Tan, Helena Teede, Amanda Vincent, and Melanie Gibson-Helm. “Ask PCOS: identifying need to inform evidence-based app development for polycystic ovary syndrome.” Seminars in Reproductive Medicine 36, no. 01 (2018): 059–065. https://doi. org/10.1055/s-0038-1667187. Broughton, Darcy E., and Kelle H. Moley. “Obesity and female infertility: potential mediators of obesity’s impact.” Fertility and Sterility 107, no. 4 (2017): 840–847. https://doi. org/10.1016/j.fertnstert.2017.01.017. Bulsara, Jeshica, Priyanshi Patel, Arun Soni, and Sanjeev Acharya. “A review: brief insight into polycystic ovarian syndrome.” Endocrine and Metabolic Science 3 (2021): 100085. https://doi.org/10.1016/j.endmts.2021.100085. Butts, Samantha F., David B. Seifer, Nathanael Koelper, Suneeta Senapati, Mary D. Sammel, Andrew N. Hoofnagle, Andrea Kelly et al. “Vitamin D deficiency is associated with poor ovarian stimulation outcome in PCOS but not unexplained infertility.” The Journal of Clinical Endocrinology & Metabolism 104, no. 2 (2019): 369–378. https://doi. org/10.1016/j.fertnstert.2017.07.220. Carmina, E., E. Guastella, R. A. Longo, G. B. Rini, and R. A. Lobo. “Correlates of increased lean muscle mass in women with polycystic ovary syndrome.” European Journal of Endocrinology 161, no. 4 (2009): 583. https://doi.org/10.1530/eje-09-0398. Carmina, Enrico, F. Rosato, and A. Janni. “Increased DHEAs levels in PCO syndrome: evidence for the existence of two subgroups of patients.” Journal of Endocrinological Investigation 9, no. 1 (1986): 5–9. https://doi.org/10.1007/bf03348052. Carmina, Enrico, Frank Z. Stanczyk, Lilly Chang, Rachel A. Miles, and Rogerio A. Lobo. “The ratio of androstenedione: 11β-hydroxyandrostenedione is an important marker of adrenal androgen excess in women.” Fertility and Sterility 58, no. 1 (1992): 148–152. https://doi.org/10.1016/s0015-0282(16)55152-8. Casper, Robert F., and Mohamed F. M. Mitwally. “Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome.” Clinical Obstetrics and Gynecology 54, no. 4 (2011): 685–695. https://doi.org/10.1097/ grf.0b013e3182353d0f. Cassar, Samantha, Marie L. Misso, William G. Hopkins, Christopher S. Shaw, Helena J. Teede, and Nigel K. Stepto. “Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic–hyperinsulinaemic clamp studies.” Human Reproduction 31, no. 11 (2016): 2619–2631. https://doi.org/10.1093/humrep/ dew243. Cassidy-Vu, Lisa, Edwina Joe, and Julienne K. Kirk. “Role of statin drugs for polycystic ovary syndrome.” Journal of Family & Reproductive Health 10, no. 4 (2016): 165–175. Retrieved from https://bit.ly/3ywk0AE. Castell, José V., Maria J. Gómez-Lechón, Martina David, Tilo Andus, Thomas Geiger, Ramón Trullenque, Ricardo Fabra, and Peter C. Heinrich. “Interleukin‐6 is the major regulator of acute phase protein synthesis in adult human hepatocytes.” FEBS Letters 242, no. 2 (1989): 237–239. https://doi.org/10.1016/0014-5793(89)80476-4. Cedars, Marcelle I., Kenneth A. Steingold, Dominique de Ziegler, Philip S. Lapolt, R. Jeffrey Chang, and Howard L. Judd. “Long-term administration of gonadotropin-releasing hormone agonist and dexamethasone: assessment of the adrenal role in ovarian dysfunction.” Fertility and Sterility 57, no. 3 (1992): 495–500. https://doi.org/10.1016/s00150282(16)54890-0.

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

55

Chen, Jianguo, Chaoran Huang, Tongtong Zhang, Wuqing Gong, Xiaofeng Deng, Hua Liu, Jinbo Liu, and Yuanbiao Guo. “The effects of statins on hyperandrogenism in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials.” Reproductive Biology and Endocrinology 19, no. 1 (2021): 1–11. https://doi.org/10.1186/s12958-021-00863-5. Chen, Jie, Qian Guo, Ying-hao Pei, Qing-ling Ren, Lei Chi, Rong-kui Hu, and Yong Tan. “Effect of a short-term vitamin E supplementation on oxidative stress in infertile PCOS women under ovulation induction: a retrospective cohort study.” BMC Women’s Health 20, no. 1 (2020): 1–9. https://doi.org/10.1186/s12905-020-00930-w. Chow, Lisa S., Douglas G. Mashek, Qi Wang, Sam O. Shepherd, Bret H. Goodpaster, and John J. Dubé. “Effect of acute physiological free fatty acid elevation in the context of hyperinsulinemia on fiber type-specific IMCL accumulation.” Journal of Applied Physiology 123, no. 1 (2017): 71–78. https://doi.org/10.1152/japplphysiol.00209.2017. Christin‐Maitre, S., and J. N. Hugues. “A comparative randomized multicentric study comparing the step‐up versus step‐down protocol in polycystic ovary syndrome.” Human Reproduction 18, no. 8 (2003): 1626–1631. https://doi.org/10.1093/humrep/deg336. Claessen, Bimmer E., Paul Guedeney, C. Michael Gibson, Dominick J. Angiolillo, Davide Cao, Norman Lepor, and Roxana Mehran. “Lipid management in patients presenting with acute coronary syndromes: a review.” Journal of the American Heart Association 9, no. 24 (2020): e018897. https://doi.org/10.1161/jaha.120.018897. Conway, G. S., J. W. Honour, and H. S. Jacobs. “Heterogeneity of the polycystic ovary syndrome: clinical, endocrine and ultrasound features in 556 patients.” Clinical Endocrinology 30, no. 4 (1989): 459–470. https://doi.org/10.1111/j.1365-2265.1989.tb00446.x. Conway, Gerard, Didier Dewailly, Evanthia Diamanti-Kandarakis, Hector F. Escobar-Morreale, Steven Franks, Alessandra Gambineri, Fahrettin Kelestimur et al. “European survey of diagnosis and management of the polycystic ovary syndrome: results of the ESE PCOS Special Interest Group’s Questionnaire.” European Journal of Endocrinology 171, no. 4 (2014): 489–498. https://doi.org/10.1530/eje-14-0252. Coulam, Carolyn B., Steven C. Adamson, and John F. Annegers. “Incidence of premature ovarian failure.” Obstetrics and Gynaecology 67, no. 4 (1986): 604–606. https://doi. org/10.1097/00006254-198703000-00020. CYP11A1 cytochrome P450 family 11 subfamily A member 1 [Homo sapiens (human)] [database on the Internet]. 2018. https://www.ncbi.nlm.nih.gov/gene/1583. CYP17A1 cytochrome P450 family 17 subfamily A member 1 [Homo sapiens (human)] [database on the Internet]. 2018. https://www.ncbi.nlm.nih.gov/gene/1586. CYP19A1 cytochrome P450 family 19 subfamily A member 1 [Homo sapiens (human)] [database on the Internet]. 2018. Available from https://www.ncbi.nlm.nih.gov/gene/1588. CYP1A1 Gene [database on the Internet]. Human gene databases. 2018. Available from: https://www.genecards.org/cgi-bin/carddisp.pl?gene=CYP1A1. Day, Felix R., David A. Hinds, Joyce Y. Tung, Lisette Stolk, Unnur Styrkarsdottir, Richa Saxena, Andrew Bjonnes et al. “Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome.” Nature Communications 6, no. 1 (2015): 1–7. https://doi.org/10.1038/ncomms9464. de Castro, Francisco, Rocío Ruiz, Luis Montoro, Dámaso Pérez-Hernández, Elisa Sánchez-Casas Padilla, Luis M. Real, and Agustín Ruiz. “Role of follicle-stimulating hormone receptor Ser680Asn polymorphism in the efficacy of follicle-stimulating hormone.” Fertility and Sterility 80, no. 3 (2003): 571–576. https://doi.org/10.1016/s0015-0282(03)00795-7. de Jager, Saskia C. A., Adriaan O. Kraaijeveld, Robert W. Grauss, Wilco de Jager, Su-San Liem, Bas L. van der Hoeven, Berent J. Prakken et al. “CCL3 (MIP-1α) levels are elevated during acute coronary syndromes and show strong prognostic power for future ischemic events.” Journal of Molecular and Cellular Cardiology 45, no. 3 (2008): 446– 452. https://doi.org/10.1016/j.yjmcc.2008.06.003.

56

Herbal Medicine Applications for Polycystic Ovarian Syndrome

de Melo, Anderson Sanches, Rosana Maria Dos Reis, Rui Alberto Ferriani, and Carolina Sales Vieira. “Hormonal contraception in women with polycystic ovary syndrome: choices, challenges, and noncontraceptive benefits.” Open Access Journal of Contraception 8 (2017): 13. https://doi.org/10.2147/oajc.s85543. Dechanet, Clotilde, T. Anahory, J. C. Mathieu Daude, X. Quantin, Lionel Reyftmann, Samir Hamamah, Bernard Hédon, and Hervé Déchaud. “Effects of cigarette smoking on reproduction.” Human Reproduction Update 17, no. 1 (2011): 76–95. https://doi.org/10.1093/ humupd/dmq033. dehghani Firouzabadi, Raziah, Abbas Aflatoonian, Seyedehzalfa Modarresi, Leila Sekhavat, and Somayeh MohammadTaheri. “Therapeutic effects of calcium & vitamin D supplementation in women with PCOS.” Complementary Therapies in Clinical Practice 18, no. 2 (2012): 85–88. https://doi.org/10.1016/j.ctcp.2012.01.005. Del Pup, Lino, and Angelo Cagnacci. “Improve lifestyle in polycystic ovary syndrome: a systematic strategy.” Gynecological Endocrinology 37, no. 10 (2021): 875–878. https://doi. org/10.1080/09513590.2021.1871892. Deligeoroglou, Eythimios, Christina Kouskouti, and Panagiotis Christopoulos. “The role of genes in the polycystic ovary syndrome: predisposition and mechanisms.” Gynecological Endocrinology 25, no. 9 (2009): 603–609. https://doi. org/10.1080/09513590903015619. Deveci, Canan Dura, Berfu Demir, Ozlem Sengul, Berna Dilbaz, and Umit Goktolga. “Clomiphene citrate ‘stair-step’ protocol vs. traditional protocol in patients with polycystic ovary syndrome: a randomized controlled trial.” Archives of Gynecology and Obstetrics 291, no. 1 (2015): 179–184. https://doi.org/10.1007/s00404-0143398-y. Diamanti-Kandarakis, Evanthia, Athanasios G. Papavassiliou, Stylianos A. Kandarakis, and George P. Chrousos. “Pathophysiology and types of dyslipidemia in PCOS.” Trends in Endocrinology & Metabolism 18, no. 7 (2007): 280–285. https://doi.org/10.1016/j. tem.2007.07.004. Dong, Xiyuan, Yu Zheng, Xiuhua Liao, Ting Xiong, and Hanwang Zhang. “Does progesterone-induced endometrial withdrawal bleed before ovulation induction have negative effects on IUI outcomes in patients with polycystic ovary syndrome?” International Journal of Clinical and Experimental Pathology 6, no. 6 (2013): 1157–1163. Retrieved from https://bit.ly/3O7U1oV. Du, Jing, Wenjing Zhang, Lingli Guo, Zhaofeng Zhang, Huijuan Shi, Jian Wang, Huiqin Zhang, Linghan Gao, Guoyin Feng, and Lin He. “Two FSHR variants, haplotypes and meta-analysis in Chinese women with premature ovarian failure and polycystic ovary syndrome.” Molecular Genetics and Metabolism 100, no. 3 (2010): 292–295. https://doi. org/10.1016/j.ymgme.2010.03.018. Dumesic, Daniel A., Alin L. Akopians, Vanessa K. Madrigal, Emmanuel Ramirez, Daniel J. Margolis, Manoj K. Sarma, Albert M. Thomas et al. “Hyperandrogenism accompanies increased intra-abdominal fat storage in normal weight polycystic ovary syndrome women.” The Journal of Clinical Endocrinology & Metabolism 101, no. 11 (2016): 4178–4188. https://doi.org/10.1210/jc.2016-2586. Dumesic, Daniel A., Sharon E. Oberfield, Elisabet Stener-Victorin, John C. Marshall, Joop S. Laven, and Richard S. Legro. “Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome.” Endocrine Reviews 36, no. 5 (2015): 487–525. https://doi.org/10.1210/er.2015-1018. Echiburú, Bárbara, Francisco Pérez-Bravo, José E. Galgani, Daniel Sandoval, Carolina Saldías, Nicolás Crisosto, Manuel Maliqueo, and Teresa Sir-Petermann. “Enlarged adipocytes in subcutaneous adipose tissue associated to hyperandrogenism and visceral adipose tissue volume in women with polycystic ovary syndrome.” Steroids 130 (2018): 15–21. https:// doi.org/10.1016/j.steroids.2017.12.009.

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

57

Ehrmann, David A., Randall B. Barnes, Robert L. Rosenfield, Melissa K. Cavaghan, and Jacqueline Imperial. “Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.” Diabetes Care 22, no. 1 (1999): 141–146. https://doi. org/10.2337/diacare.22.1.141. Elting, Mariet W., Janet Kwee, Ted J. M. Korsen, Lyset T. M. Rekers-Mombarg, and Joop Schoemaker. “Aging women with polycystic ovary syndrome who achieve regular menstrual cycles have a smaller follicle cohort than those who continue to have irregular cycles.” Fertility and Sterility 79, no. 5 (2003): 1154–1160. https://doi.org/10.1016/ s0015-0282(03)00152-3. Escobar-Morreale, Héctor F., José I. Botella-Carretero, Gemma Villuendas, José Sancho, and José L. San Millán. “Serum interleukin-18 concentrations are increased in the polycystic ovary syndrome: relationship to insulin resistance and to obesity.” The Journal of Clinical Endocrinology & Metabolism 89, no. 2 (2004): 806–811. https://doi. org/10.1210/jc.2003-031365. ESHRE, The Thessaloniki, and ASRM-Sponsored PCOS Consensus Workshop Group. “Consensus on infertility treatment related to polycystic ovary syndrome.” Fertility and Sterility 89, no. 3 (2008): 505–522. https://doi.org/10.1016/j.fertnstert.2007.09.041. Fernández-Sánchez, Alba, Eduardo Madrigal-Santillán, Mirandeli Bautista, Jaime EsquivelSoto, Ángel Morales-González, Cesar Esquivel-Chirino, Irene Durante-Montiel, Graciela Sánchez-Rivera, Carmen Valadez-Vega, and José A. Morales-González. “Inflammation, oxidative stress, and obesity.” International Journal of Molecular Sciences 12, no. 5 (2011): 3117–3132. https://doi.org/10.3390/ijms12053117. Franik, Sebastian, Stephanie M. Eltrop, Jan A. M. Kremer, Ludwig Kiesel, and Cindy Farquhar. “Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome.” Cochrane Database of Systematic Reviews 5 (2018). https://doi.org/10.1002/14651858. cd010287.pub3. Franks, Stephen. “Polycystic ovary syndrome.” New England Journal of Medicine 333, no. 13 (1995): 853–861. https://doi.org/10.1056/nejm199509283331307. Franks, Stephen, Helen Mason, Davinia White, and Debbie Willis. “Mechanisms of anovulation in polycystic ovary syndrome.” Steroids 11, no. 62 (1997): 728. https://doi. org/10.1016/s0039-128x(97)89519-0. Fraser, Graeme L., Barbara Obermayer-Pietsch, Joop Laven, Georg Griesinger, Axelle Pintiaux, Dirk Timmerman, Bart C. J. M. Fauser et al. “Randomized controlled trial of neurokinin 3 receptor antagonist fezolinetant for treatment of polycystic ovary syndrome.” The Journal of Clinical Endocrinology & Metabolism 106, no. 9 (2021): e3519– e3532. https://doi.org/10.1210/clinem/dgab320. Furtado, Mariana Vargas, Ana Paula Webber Rossini, Raquel Barth Campani, Carolina Meotti, Majorie Segatto, Giovanna Vietta, and Carísi Anne Polanczyk. “Interleukin-18: an independent predictor of cardiovascular events in patients with acute coronary syndrome after 6 months of follow-up.” Coronary Artery Disease 20, no. 5 (2009): 327–331. https://doi.org/10.1097/mca.0b013e32832e5c73. Garg, Akanksha, Bijal Patel, Ali Abbara, and Waljit S. Dhillo. “Treatments targeting neuroendocrine dysfunction in polycystic ovary syndrome (PCOS).” Clinical Endocrinology (2022). https://doi.org/10.1111/cen.14704. Ghaffarzad, Aisa, Reza Amani, Mahzad Mehrzad Sadaghiani, Masoud Darabi, and Bahman Cheraghian. “Correlation of serum lipoprotein ratios with insulin resistance in infertile women with polycystic ovarian syndrome: a case control study.” International Journal of Fertility & Sterility 10, no. 1 (2016): 29. https://doi.org/10.22074/ijfs.2016.4765. Gibson-Smith, Deborah, Mariska Bot, Nadine P. G. Paans, Marjolein Visser, Ingeborg Brouwer, and Brenda W. J. H. Penninx. “The role of obesity measures in the development and persistence of major depressive disorder.” Journal of Affective Disorders 198 (2016): 222–229. https://doi.org/10.1016/j.jad.2016.03.032.

58

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Gjönnaess, Halvard. “Polycystic ovarian syndrome treated by ovarian electrocautery through the laparoscope.” Fertility and Sterility 41, no. 1 (1984): 20–25. https://doi.org/10.1016/ s0015-0282(16)47534-5. Glintborg, Dorte, Marianne Andersen, Bjørn Richelsen, and Jens M. Bruun. “Plasma monocyte chemoattractant protein‐1 (MCP‐1) and macrophage inflammatory protein‐1α are increased in patients with polycystic ovary syndrome (PCOS) and associated with adiposity, but unaffected by pioglitazone treatment.” Clinical Endocrinology 71, no. 5 (2009): 652–658. https://doi.org/10.1111/j.1365-2265.2009.03523.x. Glueck, Charles J., and Naila Goldenberg. “Characteristics of obesity in polycystic ovary syndrome: etiology, treatment, and genetics.” Metabolism 92 (2019): 108–120. https://doi. org/10.1016/j.metabol.2018.11.002. Göbl, Christian S., Johannes Ott, Latife Bozkurt, Michael Feichtinger, Victoria Rehmann, Anna Cserjan, Maike Heinisch et al. “To assess the association between glucose metabolism and ectopic lipid content in different clinical classifications of PCOS.” PLoS One 11, no. 8 (2016): e0160571. https://doi.org/10.1371/journal.pone.0160571. Godoy-Matos, Amélio F., Fernanda Vaisman, Aline P. Pedrosa, Maria L. F. Farias, Laura Maria C. Mendonça, and Maria Fernanda M. C. Pinheiro. “Central-to-peripheral fat ratio, but not peripheral body fat, is related to insulin resistance and androgen markers in polycystic ovary syndrome.” Gynecological Endocrinology 25, no. 12 (2009): 793–798. https:// doi.org/10.3109/09513590903015528. González, Frank, Neal S. Rote, Judi Minium, and John P. Kirwan. “Reactive oxygen speciesinduced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome.” The Journal of Clinical Endocrinology & Metabolism 91, no. 1 (2006): 336–340. https://doi.org/10.1210/jc.2005-1696. González, Frank, Neal S. Rote, Judi Minium, and John P. Kirwan. “Evidence of proatherogenic inflammation in polycystic ovary syndrome.” Metabolism 58, no. 7 (2009): 954–962. https://doi.org/10.1016/j.metabol.2009.02.022. Goodarzi, Mark O., Enrico Carmina, and Ricardo Azziz. “Dhea, dheas and pcos.” The Journal of Steroid Biochemistry and Molecular Biology 145 (2015): 213–225. https://doi. org/10.1016/j.jsbmb.2014.06.003. Goodarzi, Mark O., Ning Xu, and Ricardo Azziz. “Association of CYP3A7* 1C and serum dehydroepiandrosterone sulfate levels in women with polycystic ovary syndrome.” The Journal of Clinical Endocrinology & Metabolism 93, no. 7 (2008): 2909–2912. https:// doi.org/10.1210/jc.2008-0403. Hague, William M., Judith Adams, Christine Rodda, Charles Gd Brook, R. O. S. E. De Bruyn, David B. Grant, and Howard S. Jacobs. “The prevalence of polycystic ovaries in patients with congenital adrenal hyperplasia and their close relatives.” Clinical Endocrinology 33, no. 4 (1990): 501–510. https://doi.org/10.1111/j.1365-2265.1990.tb03887.x. Hajimonfarednejad, Mahdie, Majid Nimrouzi, Mojtaba Heydari, Mohammad Mehdi Zarshenas, Mohammad Javad Raee, and Bahia Namavar Jahromi. “Insulin resistance improvement by cinnamon powder in polycystic ovary syndrome: a randomized double‐blind placebo controlled clinical trial.” Phytotherapy Research 32, no. 2 (2018): 276–283. https://doi. org/10.1002/ptr.5970. Halliwell, Barry. “Reactive oxygen species in living systems: source, biochemistry, and role in human disease.” The American Journal of Medicine 91, no. 3 (1991): S14–S22. https:// doi.org/10.1016/0002-9343(91)90279-7. Hamzavi, Iltefat, Eileen Tan, Jerry Shapiro, and Harvey Lui. “A randomized bilateral ­vehicle-controlled study of eflornithine cream combined with laser treatment versus laser treatment alone for facial hirsutism in women.” Journal of the American Academy of Dermatology 57, no. 1 (2007): 54–59. https://doi.org/10.1016/j.jaad.2006.09.025.

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

59

Han, Ki Hoon, Kyung-Hee Hong, Jae-Hyeong Park, Jesang Ko, Duk-Hyun Kang, Kee-Joon Choi, Myeong-Ki Hong, Seong-Wook Park, and Seung-Jung Park. “C-reactive protein promotes monocyte chemoattractant protein-1—mediated chemotaxis through upregulating CC chemokine receptor 2 expression in human monocytes.” Circulation 109, no.21 (2004): 2566–2571. https://doi.org/10.1161/01.cir.0000131160.94926.6e. Harada, Nobuhiro, Hisamitsu Ogawa, M. Shozu, and K. Yamada. “Genetic studies to characterize the origin of the mutation in placental aromatase deficiency.” American Journal of Human Genetics 51, no. 3 (1992): 666. Retrieved from https://bit.ly/3z4HqhV. Hart, Kaitlin N., William A. Stocker, Nicholas G. Nagykery, Kelly L. Walton, Craig A. Harrison, Patricia K. Donahoe, David Pépin, and Thomas B. Thompson. “Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family.” Proceedings of the National Academy of Sciences 118, no. 26 (2021): e2104809118. https://doi.org/10.1073/pnas.2104809118. Haydardedeoglu, Bulent, Erhan Simsek, Esra B. Kilicdag, and Tayfun Bagis. “Metabolic and endocrine effects of metformin and metformin plus cyclic medroxyprogesterone acetate in women with polycystic ovary syndrome.” International Journal of Gynecology & Obstetrics 105, no. 1 (2009): 32–35. https://doi.org/10.1016/j.ijgo.2008.11.039. Heijnen, E. M. E. W., M. J. C. Eijkemans, E. G. Hughes, J. S. E. Laven, N. S. Macklon, and B. C. J. M. Fauser. “A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome.” Human Reproduction Update 12, no. 1 (2006): 13–21. https:// doi.org/10.1093/humupd/dmi036. Hoffman, David I., Karin Klove, and Rogerio A. Lobo. “The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women.” Fertility and Sterility 42, no. 1 (1984): 76–81. https://doi.org/10.1016/s0015-0282(16)47961-6. Homburg, Roy. “Clomiphene citrate—end of an era? A mini-review.” Human Reproduction 20, no. 8 (2005): 2043–2051. https://doi.org/10.1093/humrep/dei042. Homburg, Roy. “The management of infertility associated with polycystic ovary syndrome.” Reproductive Biology and Endocrinology 1, no. 1 (2003): 1–9. https://doi. org/10.1186/1477-7827-1-109. Hu, Weihong, Jie Qiao, Yan Yang, Lina Wang, and Rong Li. “Elevated C-reactive protein and monocyte chemoattractant protein-1 in patients with polycystic ovary syndrome.” European Journal of Obstetrics & Gynecology and Reproductive Biology 157, no. 1 (2011): 53–56. https://doi.org/10.1016/j.ejogrb.2011.03.015. Iervolino, Matteo, Elisa Lepore, Gianpiero Forte, Antonio Simone Laganà, Giovanni Buzzaccarini, and Vittorio Unfer. “Natural molecules in the management of polycystic ovary syndrome (PCOS): an analytical review.” Nutrients 13, no. 5 (2021): 1677. https:// doi.org/10.3390/nu13051677. Izadi, Azimeh, Sara Ebrahimi, Shabnam Shirazi, Shiva Taghizadeh, Marziyeh Parizad, Laya Farzadi, and Bahram Pourghassem Gargari. “Hormonal and metabolic effects of coenzyme Q10 and/or vitamin E in patients with polycystic ovary syndrome.” The Journal of Clinical Endocrinology & Metabolism 104, no. 2 (2019): 319–327. https://doi. org/10.1210/jc.2018-01221. Joseph, Shaini, Ram Shankar Barai, Rasika Bhujbalrao, and Susan Idicula-Thomas. “PCOSKB: a knowledge base on genes, diseases, ontology terms and biochemical pathways associated with poly cystic ovary syndrome.” Nucleic Acids Research 44, no. D1 (2016): D1032–D1035. https://doi.org/10.1093/nar/gkv1146. Kahsar-Miller, Melissa D., Christa Nixon, Larry R. Boots, Rodney C. Go, and Ricardo Azziz. “Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS.” Fertility and Sterility 75, no. 1 (2001): 53–58. https://doi.org/10.1016/ s0015-0282(00)01662-9.

60

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Kalra, Pramila, Beena Bansal, Piyal Nag, Jitesh K. Singh, Rakesh K. Gupta, Sunil Kumar, Ram Kishore S. Rathore, Vijayalakshmi Bhatia, and Eesh Bhatia. “Abdominal fat distribution and insulin resistance in Indian women with polycystic ovarian syndrome.” Fertility and Sterility 91, no. 4 (2009): 1437–1440. https://doi.org/10.1016/j.fertnstert.2008.06.037. Karabulut, Aysun, Güzin Fidan Yaylali, Semra Demirlenk, Osman Sevket, and Ayhan Acun. “Evaluation of body fat distribution in PCOS and its association with carotid atherosclerosis and insulin resistance.” Gynecological Endocrinology 28, no. 2 (2012): 111–114. https://doi.org/10.3109/09513590.2011.589929. Kaya, Cemil, Recai Pabuccu, Bülent Berker, and Hakan Satıroglu. “Plasma interleukin-18 levels are increased in the polycystic ovary syndrome: relationship of carotid intima-media wall thickness and cardiovascular risk factors.” Fertility and Sterility 93, no. 4 (2010): 1200–1207. https://doi.org/10.1016/j.fertnstert.2008.10.070. Keefe, Candace C., Mildred M. Goldman, Ke Zhang, Nigel Clarke, Richard E. Reitz, and Corrine K. Welt. “Simultaneous measurement of thirteen steroid hormones in women with polycystic ovary syndrome and control women using liquid chromatography-­ tandem mass spectrometry.” PloS One 9, no. 4 (2014): e93805. https://doi.org/10.1371/ journal.pone.0093805. Khodaeifar, Fariba, Seyyed Mohammad Bagher Fazljou, Arash Khaki, Mohammadali Torbati, Elahe Olad Saheb Madarek, Amir Afshin Khaki, Majid Shokoohi, and Amir Hossein Dalili. “Investigating the role of hydroalcoholic extract of Apium graveolens and Cinnamon zeylanicum on metabolically change and ovarian oxidative injury in a rat model of polycystic ovary syndrome.” International Journal of Women’s Health and Reproduction Sciences 7, no. 1 (2019): 92–98. https://doi.org/10.15296/ijwhr.2019.15. Kiconco, Sylvia, Helena J. Teede, Ricardo Azziz, Robert J. Norman, and Anju E. Joham. “The need to reassess the diagnosis of polycystic ovary syndrome (PCOS): a review of diagnostic recommendations from the international evidence-based guideline for the assessment and management of PCOS.” Seminars in Reproductive Medicine 39, no. 03/04 (2021): 071–077. https://doi.org/10.1055/s-0041-1735259. Kim, Jin Ju, and Young Min Choi. “Dyslipidemia in women with polycystic ovary syndrome.” Obstetrics & Gynecology Science 56, no. 3 (2013): 137–142. https://doi.org/10.5468/ ogs.2013.56.3.137. Kort, Daniel H., and Roger A. Lobo. “Preliminary evidence that cinnamon improves menstrual cyclicity in women with polycystic ovary syndrome: a randomized controlled trial.” American Journal of Obstetrics and Gynecology 211, no. 5 (2014): 487–e1-6. https:// doi.org/10.1016/j.ajog.2014.05.009. Kuang, Hongying, Yan Li, Xiaoke Wu, Lihui Hou, Taixiang Wu, Jianping Liu, Ernest Hung Yu Ng, Elisabet Stener-Victorin, Richard S. Legro, and Heping Zhang. “Acupuncture and clomiphene citrate for live birth in polycystic ovary syndrome: study design of a randomized controlled trial.” Evidence-Based Complementary and Alternative Medicine 2013 (2013). https://doi.org/10.1155/2013/527303. Kumar, Ashim, Keslie S. Woods, Alfred A. Bartolucci, and Ricardo Azziz. “Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS).” Clinical Endocrinology 62, no. 6 (2005): 644–649. https://doi.org/10.1111/j.13652265.2005.02256.x. Kumar, D. Rama Nagendra, Krishna G. Seshadri, and Monna Pandurangi. “Effect of metformin-sustained release therapy on low-density lipoprotein size and adiponectin in the South Indian women with polycystic ovary syndrome.” Indian Journal of Endocrinology and Metabolism 21, no. 5 (2017): 679. https://doi.org/10.4103/ijem.ijem_154_17. Legro, Richard S., Allen R. Kunselman, William C. Dodson, and Andrea Dunaif. “Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.” The Journal of Clinical Endocrinology & Metabolism 84, no. 1 (1999): 165–169. https://doi. org/10.1210/jcem.84.1.5393.

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

61

Legro, Richard S., Deborah Driscoll, Jerome F. Strauss III, Janis Fox, and Andrea Dunaif. “Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome.” Proceedings of the National Academy of Sciences 95, no. 25 (1998): 14956–14960. https://doi.org/10.1073/pnas.95.25.14956. Legro, Richard S., Robert G. Brzyski, Michael P. Diamond, Christos Coutifaris, William D. Schlaff, Ruben Alvero, Peter Casson et al. “The pregnancy in polycystic ovary syndrome II study: baseline characteristics and effects of obesity from a multicenter randomized clinical trial.” Fertility and Sterility 101, no. 1 (2014): 258–269. https://doi. org/10.1016/j.fertnstert.2013.08.056. Legro, Richard S., Silva A. Arslanian, David A. Ehrmann, Kathleen M. Hoeger, M. Hassan Murad, Renato Pasquali, and Corrine K. Welt. “Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline.” The Journal of Clinical Endocrinology & Metabolism 98, no. 12 (2013): 4565–4592. https://doi. org/10.1210/jc.2013-2350. Li, Li, Qiong Feng, Ming Ye, Yaojuan He, Aling Yao, and Kun Shi. “Metabolic effect of obesity on polycystic ovary syndrome in adolescents: a meta-analysis.” Journal of Obstetrics and Gynaecology 37, no. 8 (2017): 1036–1047. https://doi.org/10.1080/01443615.201 7.1318840. Li, Mei, Kai Xue, Jing Ling, Fei-Yang Diao, Yu-Gui Cui, and Jia-Yin Liu. “The orphan nuclear receptor NR4A1 regulates transcription of key steroidogenic enzymes in ovarian theca cells.” Molecular and Cellular Endocrinology 319, no. 1–2 (2010): 39–46. https://doi. org/10.1016/j.mce.2010.01.014. Li, Xin, and Ruijin Shao. “PCOS and obesity: insulin resistance might be a common etiology for the development of type I endometrial carcinoma.” American Journal of Cancer Research 4, no. 1 (2014): 73. Retrieved from https://bit.ly/3Pue8im. Li, Yan, Hongli Ma, Yuehui Zhang, Hongying Kuang, Ernest Hung Yu Ng, Lihui Hou, and Xiaoke Wu. “Effect of berberine on insulin resistance in women with polycystic ovary syndrome: study protocol for a randomized multicenter controlled trial.” Trials 14, no. 1 (2013): 1–5. https://doi.org/10.1186/1745-6215-14-226. Lim, Siew S., M. J. Davies, Robert J. Norman, and L. J. Moran. “Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis.” Human Reproduction Update 18, no. 6 (2012): 618–637. https://doi. org/10.1093/humupd/dms030. Liu, Qi, Yuan-jie Xie, Li-hua Qu, Meng-xia Zhang, and Zhong-cheng Mo. “Dyslipidemia involvement in the development of polycystic ovary syndrome.” Taiwanese Journal of Obstetrics and Gynecology 58, no. 4 (2019): 447–453. https://doi.org/10.1016/j. tjog.2019.05.003. Livadas, Sarantis, and Evanthia Diamanti-Kandarakis. “Polycystic ovary syndrome: definitions, phenotypes and diagnostic approach.” Polycystic Ovary Syndrome 40 (2013): 1–21. https://doi.org/10.1159/000341673. Livadas, Sarantis, Christos Pappas, Athanasios Karachalios, Evangelos Marinakis, Nikoleta Tolia, Maria Drakou, Philippos Kaldrymides, Dimitrios Panidis, and Evanthia DiamantiKandarakis. “Prevalence and impact of hyperandrogenemia in 1,218 women with polycystic ovary syndrome.” Endocrine 47, no. 2 (2014): 631–638. https://doi.org/10.1007/ s12020-014-0200-7. Lizneva, Daria, Larisa Suturina, Walidah Walker, Soumia Brakta, Larisa Gavrilova-Jordan, and Ricardo Azziz. “Criteria, prevalence, and phenotypes of polycystic ovary syndrome.” Fertility and Sterility 106, no. 1 (2016): 6–15. https://doi.org/10.1016/j. fertnstert.2016.05.003. Lord, J., R. Thomas, B. Fox, U. Acharya, and T. Wilkin. “The central issue? Visceral fat mass is a good marker of insulin resistance and metabolic disturbance in women with polycystic ovary syndrome.” BJOG: An International Journal of Obstetrics & Gynaecology 113, no. 10 (2006): 1203–1209. https://doi.org/10.1111/j.1471-0528.2006.00973.x.

62

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Lumachi, Franco, and Riccardo Rondinone. “Use of cyproterone acetate, finasteride, and spironolactone to treat idiopathic hirsutism.” Fertility and Sterility 79, no. 4 (2003): 942– 946. https://doi.org/10.1016/s0015-0282(02)04927-0 Lujan, Marla E., Donna R. Chizen, and Roger A. Pierson. “Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies.” Journal of Obstetrics and Gynaecology Canada 30, no. 8 (2008): 671–679. https://doi.org/10.1016/S1701-2163(16)32915-2. Lv, Ping-Ping, Min Jin, Jin-Peng Rao, Jian Chen, Li-Quan Wang, Chang-Chang Huang, SongQing Yang et al. “Role of anti-Müllerian hormone and testosterone in follicular growth: a cross-sectional study.” BMC Endocrine Disorders 20, no. 1 (2020): 1–10. https://doi. org/10.1186/s12902-020-00569-6. Ma, Xiaoting, Emily Hayes, Hen Prizant, Rajesh K. Srivastava, Stephen R. Hammes, and Aritro Sen. “Leptin-induced CART (cocaine-and amphetamine-regulated transcript) is a novel intraovarian mediator of obesity-related infertility in females.” Endocrinology 157, no. 3 (2016): 1248–1257. https://doi.org/10.1210/en.2015-1750. Macut, D., T. Simic, A. Lissounov, M. Pljesa-Ercegovac, I. Bozic, T. Djukic, J. Bjekic-Macut et al. “Insulin resistance in non-obese women with polycystic ovary syndrome: relation to byproducts of oxidative stress.” Experimental and Clinical Endocrinology & Diabetes 119, no. 07 (2011): 451–455. https://doi.org/10.1055/s-0031-1279740. Macut, Djuro, Jelica Bjekić-Macut, and Ana Savić-Radojević. “Dyslipidemia and oxidative stress in PCOS.” Polycystic Ovary Syndrome 40 (2013): 51–63. https://doi. org/10.1159/000341683. Maggs, David G., Thomas A. Buchanan, Charles F. Burant, Gary Cline, Barry Gumbiner, Willa A. Hsueh, Silvio Inzucchi et al. “Metabolic effects of troglitazone monotherapy controlled trial.” in type 2 diabetes mellitus: a randomized, double-blind, placebo-­ Annals of Internal Medicine 128, no. 3 (1998): 176–185. https://doi.org/10.7326/ 0003-4819-128-3-199802010-00002. Maliqueo, Manuel, Teresa Sir-Petermann, Virginia Perez, Bárbara Echiburú, Amanda Ladron de Guevara, Carla Galvez, Nicolás Crisosto, and Ricardo Azziz. “Adrenal function during childhood and puberty in daughters of women with polycystic ovary syndrome.” The Journal of Clinical Endocrinology & Metabolism 94, no. 9 (2009): 3282–3288. https:// doi.org/10.1210/jc.2009-0427. Martinat, Nadine, Pascale Crépieux, Eric Reiter, and Florian Guillou. “Extracellular signalregulated kinases (ERK) 1, 2 are required for luteinizing hormone (LH)-induced steroidogenesis in primary Leydig cells and control steroidogenic acute regulatory (StAR) expression.” Reproduction Nutrition Development 45, no. 1 (2005): 101–108. https://doi. org/10.1051/rnd:2005007. Mayorga, Maritza Perez, Jörg Gromoll, Hermann M. Behre, Claudia Gassner, Eberhard Nieschlag, and Manuela Simoni. “Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype.” The Journal of Clinical Endocrinology & Metabolism 85, no. 9 (2000): 3365–3369. https://doi.org/10.1210/ jcem.85.9.6789 Meera Murugesan B., P. Muralidharan, and R. Hari “Effect of ethanolic seed extract of Caesalpinia bonducella on hormones in mifepristone induced PCOS rats.” Journal of Applied Pharmaceutical Science 10, no. 02 (2020): 072–076. https://doi.org/10.7324/ japs.2020.102012. Miao, Chen-Yun, Xiao-Jie Fang, Yun Chen, and Qin Zhang. “Effect of vitamin D supplementation on polycystic ovary syndrome: a meta-analysis.” Experimental and Therapeutic Medicine 19, no. 4 (2020): 2641–2649. https://doi.org/10.3892/etm.2020.8525. Mikhael, Sasha, Advaita Punjala-Patel, and Larisa Gavrilova-Jordan. “Hypothalamic-pituitaryovarian axis disorders impacting female fertility.” Biomedicines 7, no. 1 (2019): 5. https://doi.org/10.3390/biomedicines7010005.

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

63

Minegish, Takashi, Kazuto Nakamura, Yumi Takakura, Yoshito Ibuki, and Masao Igarashi. “Cloning and sequencing of human FSH receptor cDNA.” Biochemical and Biophysical Research Communications 175, no. 3 (1991): 1125–1130. https://doi.org/10.1016/ 0006-291x(91)91682-3. Misichronis, G., N. A. Georgopoulos, D. J. Marioli, A. K. Armeni, I. Katsikis, A. D. Piouka, A. D. Saltamavros, N. D. Roupas, and D. Panidis. “The influence of obesity on androstenedione to testosterone ratio in women with polycystic ovary syndrome (PCOS) and hyperandrogenemia.” Gynecological Endocrinology 28, no. 4 (2012): 249–252. https:// doi.org/10.3109/09513590.2011.613965. Misso, Marie L., Eliza C. Tassone, Michael F. Costello, Anuja Dokras, Joop Laven, Lisa J. Moran, and Helena J. Teede. “Large-scale evidence-based guideline development engaging the international PCOS community.” Seminars in Reproductive Medicine 36, no. 01 (2018): 028–034. https://doi.org/10.1055/s-0038-1667312. Misso, Marie, Jacqueline Boyle, Robert Norman, and Helena Teede. “Development of evidencedbased guidelines for PCOS and implications for community health.” Seminars in Reproductive Medicine 32, no. 03 (2014): 230–240. https://doi.org/10.1055/s-0034-1371095. Mohammad, Majid Bani, and Abbas Majdi Seghinsara. “Polycystic ovary syndrome (PCOS), diagnostic criteria, and AMH.” Asian Pacific Journal of Cancer Prevention: APJCP 18, no. 1 (2017): 17–21. https://doi.org/10.22034/APJCP.2017.18.1.17. Moini Jazani, Arezoo, Hamidreza Nasimi Doost Azgomi, Alireza Nasimi Doost Azgomi, and Ramin Nasimi Doost Azgomi. “A comprehensive review of clinical studies with herbal medicine on polycystic ovary syndrome (PCOS).” DARU Journal of Pharmaceutical Sciences 27, no. 2 (2019): 863–877. https://doi.org/10.1007/s40199-019-00312-0. Moolhuijsen, Loes M. E., and Jenny A. Visser. “AMH in PCOS: controlling the ovary, placenta, or brain?” Current Opinion in Endocrine and Metabolic Research 12 (2020): 91–97. https://doi.org/10.1016/j.coemr.2020.04.006. Moran, Carlos, Edgardo Garcia-Hernandez, Edgar Barahona, Sandra Gonzalez, and Jose A. Bermudez. “Relationship between insulin resistance and gonadotropin dissociation in obese and nonobese women with polycystic ovary syndrome.” Fertility and Sterility 80, no. 6 (2003): 1466–1472. https://doi.org/10.1016/j.fertnstert.2003.05.010. Moran, Carlos, Eric Knochenhauer, Larry R. Boots, and Ricardo Azziz. “Adrenal androgen excess in hyperandrogenism: relation to age and body mass.” Fertility and Sterility 71, no. 4 (1999): 671–674. https://doi.org/10.1016/s0015-0282(98)00536-6. Moran, Carlos, Monica Arriaga, Gustavo Rodriguez, and Segundo Moran. “Obesity differentially affects phenotypes of polycystic ovary syndrome.” International Journal of Endocrinology 2012 (2012). https://doi.org/10.1155/2012/317241. Moran, Lisa J., Samantha K. Hutchison, Robert J. Norman, and Helena J. Teede. “Lifestyle changes in women with polycystic ovary syndrome.” Cochrane Database of Systematic Reviews 7 (2011). https://doi.org/10.1002/14651858.cd007506.pub2. Morin-Papunen, Laure C., Ilkka Vauhkonen, Riitta M. Koivunen, Aimo Ruokonen, and Juha S. Tapanainen. “Insulin sensitivity, insulin secretion, and metabolic and hormonal parameters in healthy women and women with polycystic ovarian syndrome.” Human Reproduction 15, no. 6 (2000): 1266–1274. https://doi.org/10.1093/humrep/15.6.1266. Mu, L., R. Li, Y. Lai, Y. Zhao, and J. Qiao. “Adipose insulin resistance is associated with cardiovascular risk factors in polycystic ovary syndrome.” Journal of Endocrinological Investigation 42, no. 5 (2019): 541–548. https://doi.org/10.1007/s40618-018-0949-2. Neeland, Ian J., Aslan T. Turer, Colby R. Ayers, Tiffany M. Powell-Wiley, Gloria L. Vega, Ramin Farzaneh-Far, Scott M. Grundy, Amit Khera, Darren K. McGuire, and James A. de Lemos. “Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults.” JAMA 308, no. 11 (2012): 1150–1159. https://doi.org/10.1001/2012. jama.11132.

64

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Nelson, Velen L., Richard S. Legro, Jerome F. Strauss III, and Jan M. McAllister. “Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries.” Molecular Endocrinology 13, no. 6 (1999): 946–957. https://doi. org/10.1210/mend.13.6.0311. Nesby-O’Dell, Shanna, Kelley S. Scanlon, Mary E. Cogswell, Cathleen Gillespie, Bruce W. Hollis, Anne C. Looker, Chris Allen, Cindy Doughertly, Elaine W. Gunter, and Barbara A. Bowman. “Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988–1994.” The American Journal of Clinical Nutrition 76, no. 1 (2002): 187– 192. https://doi.org/10.1093/ajcn/76.1.187. Norman, Robert J. “Obesity, polycystic ovary syndrome and anovulation-how are they interrelated?” Current Opinion in Obstetrics and Gynecology 13, no. 3 (2001): 323–327. https://doi.org/10.1097/00001703-200106000-00013. Norman, Robert J., Didier Dewailly, Richard S. Legro, and Theresa E. Hickey. “Polycystic ovary syndrome.” The Lancet 370, no. 9588 (2007): 685–697. https://doi.org/10.1016/ s0140-6736(07)61345-2. Ovalle, Fernando, and Ricardo Azziz. “Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus.” Fertility and Sterility 77, no. 6 (2002): 1095–1105. https://doi. org/10.1016/s0015-0282(02)03111-4. Özdemir, Suna, Hüseyin Görkemli, Kazim Gezginç, Mustafa Özdemir, and Aysel Kiyici. “Clinical and metabolic effects of medroxyprogesterone acetate and ethinyl estradiol plus drospirenone in women with polycystic ovary syndrome.” International Journal of Gynecology & Obstetrics 103, no. 1 (2008): 44–49. https://doi.org/10.1016/j.ijgo.2008.05.017. Pal, Lubna, Amber Berry, Luisa Coraluzzi, Erin Kustan, Cheryl Danton, Julia Shaw, and Hugh Taylor. “Therapeutic implications of vitamin D and calcium in overweight women with polycystic ovary syndrome.” Gynecological Endocrinology 28, no. 12 (2012): 965–968. https://doi.org/10.3109/09513590.2012.696753. Pan, Jie-Xue, Ya-Jing Tan, Fang-Fang Wang, Ning-Ning Hou, Yu-Qian Xiang, Jun-Yu Zhang, Ye Liu et al. “Aberrant expression and DNA methylation of lipid metabolism genes in PCOS: a new insight into its pathogenesis.” Clinical Epigenetics 10, no. 1 (2018): 1–12. https://doi.org/10.1186/s13148-018-0442-y. Pappalardo, M. A., G. T. Russo, A. Pedone, A. Pizzo, I. Borrielli, G. Stabile, A. C. Artenisio et al. “Very high frequency of the polymorphism for the insulin receptor substrate 1 (IRS1) at codon 972 (glycine972arginine) in Southern Italian women with polycystic ovary syndrome.” Hormone and Metabolic Research 42, no. 08 (2010): 575–584. https://doi. org/10.1055/s-0030-1249020. Pappalardo, M. A., R. Vita, F. Di Bari, M. Le Donne, F. Trimarchi, and S. Benvenga. “Gly972Arg of IRS-1 and Lys121Gln of PC-1 polymorphisms act in opposite way in polycystic ovary syndrome.” Journal of Endocrinological Investigation 40, no. 4 (2017): 367–376. https://doi.org/10.1007/s40618-016-0569-7. Pasquali, Renato, and Alessandra Gambineri. “Therapy of endocrine disease: treatment of hirsutism in the polycystic ovary syndrome.” European Journal of Endocrinology 170, no. 2 (2014): R75–R90. https://doi.org/10.1530/eje-13-0585. Patel, Roshni, and Gaurang Shah. “High-fat diet exposure from pre-pubertal age induces polycystic ovary syndrome (PCOS) in rats.” Reproduction 155, no. 2 (2018): 139–149. https://doi.org/10.1530/rep-17-0584. Pergialiotis, Vasilios, Eftihios Trakakis, Charalampos Chrelias, Nikolaos Papantoniou, and Erifili Hatziagelaki. “The impact of mild hypercholesterolemia on glycemic and hormonal profiles, menstrual characteristics and the ovarian morphology of women with polycystic ovarian syndrome.” Hormone Molecular Biology and Clinical Investigation 34, no. 3 (2018). https://doi.org/10.1515/hmbci-2018-0002.

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

65

Pirotta, Stephanie, Anju J. Joham, Lisa J. Moran, Helen Skouteris, and Siew S. Lim. “Implementation of evidence-based PCOS lifestyle management guidelines: perceived barriers and facilitators by consumers using the theoretical domains framework and COM-B model.” Patient Education and Counseling 104, no. 8 (2021): 2080–2088. https://doi.org/10.1016/j.pec.2021.01.036. Polyzos, Nikolaos P., Maria Tsappi, Davide Mauri, Vedat Atay, Ivan Cortinovis, and Giovanni Casazza. “Aromatase inhibitors for infertility in polycystic ovary syndrome. The beginning or the end of a new era?” Fertility and Sterility 89, no. 2 (2008): 278–280. https:// doi.org/10.1016/j.fertnstert.2007.10.016. Pourghassem Gargari, Bahram, Shiva Houjeghani, Soltanali Mahboob, Laya Farzadi, and Abdolrasoul Safaeian. “Assessment of nutrients intake in polycystic ovary syndrome women compared to healthy subjects.” The Iranian Journal of Obstetrics, Gynecology and Infertility 14, no. 4 (2011): 1–8. Retrieved from https://bit.ly/3aE2wui. Pritts, Elizabeth A. “Letrozole for ovulation induction and controlled ovarian hyperstimulation.” Current Opinion in Obstetrics and Gynecology 22, no. 4 (2010): 289–294. https:// doi.org/10.1097/gco.0b013e32833beebf. Ramadurai, Sivasankari, and Usha Balasundaram. “Rhizomicrobiomics of Caesalpinia bonducella, a wonder plant for PCOS treatment.” Physiology and Molecular Biology of Plants 26, no. 12 (2020): 2453–2463. https://doi.org/10.1007/s12298-020-00915-x. Ramezani Tehrani, Fahimeh, Homeira Rashidi, Mahnaz Bahri Khomami, Maryam Tohidi, and Fereidoun Azizi. “The prevalence of metabolic disorders in various phenotypes of polycystic ovary syndrome: a community based study in Southwest of Iran.” Reproductive Biology and Endocrinology 12, no. 1 (2014): 1–6. https://doi.org/10.1186/14777827-12-89. Rai, S., M. Basheer, H. Ghosh, D. Acharya, and Y. A. Hajam. “Melatonin attenuates free radical load and reverses histologic architect and hormone profile alteration in female rat: an in vivo study of pathogenesis of letrozole induced poly cystic ovary.” Clinical & Cellular Immunology 6 (2015): 1–8. Rani, R., Y. A. Hajam, R. Kumar, R. A. Bhat, S. Rai, and M. A. Rather. “A landscape analysis of the potential role of polyphenols for the treatment of polycystic ovarian syndrome (PCOS).” Phytomedicine Plus 2, no. 1 (2022): 100161. Raperport, Claudia, and Roy Homburg. “The source of polycystic ovarian syndrome.” Clinical Medicine Insights: Reproductive Health 13 (2019): 1179558119871467. https://doi. org/10.1177/1179558119871467. Redmond, Geoffrey P., and Wilma F. Bergfeld. “Diagnostic approach to androgen disorders in women: acne, hirsutism, and alopecia.” Cleveland Clinic Journal of Medicine 57, no. 5 (1990): 423–427. https://doi.org/10.3949/ccjm.57.5.423. Reutrakul, Sirimon, and Eve Van Cauter. “Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes.” Metabolism 84 (2018): 56–66. https://doi.org/10.1016/ j.metabol.2018.02.010. Reynolds, Kristi, Dongfeng Gu, Paul K. Whelton, Xigui Wu, Xiufang Duan, Jingping Mo, Jiang He, and InterASIA Collaborative Group. “Prevalence and risk factors of overweight and obesity in China.” Obesity 15, no. 1 (2007): 10–18. https://doi.org/10.1038/ oby.2007.527. Ridker, Paul M., Julie E. Buring, Nancy R. Cook, and Nader Rifai. “C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women.” Circulation 107, no. 3 (2003): 391–397. https://doi.org/10.1161/01.cir.0000055014.62083.05. Rittmaster, Roger S. “Antiandrogen treatment of polycystic ovary syndrome.” Endocrinology and Metabolism Clinics of North America 28, no. 2 (1999): 409–421. https://doi. org/10.1016/s0889-8529(05)70077-3.

66

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Rizwan, S., S. Ghazanvi, N. Rasheed, and M. I. Ullah. “Association of FTO common RS9939609 polymor-phism with obesity and polycystic ovarian syndrome in Pakistani women.” Journal of Medicinal Research and Biological Studies 1: 101 Abstract Keywords: Polycystic Ovarian Syndrome (2018). Retrieved from https://bit.ly/3c9YaeI. Rizzo, Manfredi, Kaspar Berneis, Martin Hersberger, Ilenia Pepe, Gaetana Di Fede, Giovam Battista Rini, Giatgen A. Spinas, and Enrico Carmina. “Milder forms of atherogenic dyslipidemia in ovulatory versus anovulatory polycystic ovary syndrome phenotype.” Human Reproduction 24, no. 9 (2009): 2286–2292. https://doi.org/10.1093/humrep/dep121. Rodriguez Paris, Valentina, and Michael J. Bertoldo. “The mechanism of androgen actions in PCOS etiology.” Medical Sciences 7, no. 9 (2019): 89. https://doi.org/10.3390/ medsci7090089. Roelfsema, Ferdinand, Petra Kok, Alberto M. Pereira, and Hanno Pijl. “Cortisol production rate is similarly elevated in obese women with or without the polycystic ovary syndrome.” The Journal of Clinical Endocrinology & Metabolism 95, no. 7 (2010): 3318– 3324. https://doi.org/10.1210/jc.2009-2701. Roemheld-Hamm, Beatrix. “Chasteberry.” American Family Physician 72, no. 5 (2005): 821– 824. Retrieved from https://pubmed.ncbi.nlm.nih.gov/16156340/. Roland, Alison V., and Suzanne M. Moenter. “Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: insight from animal models.” Frontiers in Neuroendocrinology 35, no. 4 (2014): 494–511. https://doi.org/10.1016/j.yfrne.2014.04.002. Rojas, Joselyn, Mervin Chávez, Luis Olivar, Milagros Rojas, Jessenia Morillo, José Mejías, María Calvo, and Valmore Bermúdez. “Polycystic ovary syndrome, insulin resistance, and obesity: navigating the pathophysiologic labyrinth.” International Journal of Reproductive Medicine 2014 (2014): 719050. https://doi.org/10.1155/2014/719050 Ross, Russell. “Atherosclerosis—an inflammatory disease.” New England Journal of Medicine 340, no. 2 (1999): 115–126. https://doi.org/10.1056/nejm199901143400207. Rostamtabar, Maryam, Sedigheh Esmaeilzadeh, Mehdi Tourani, Abolfazl Rahmani, Masoud Baee, Fatemeh Shirafkan, Kiarash Saleki, Sajedeh S. Mirzababayi, Soheil Ebrahimpour, and Hamid Reza Nouri. “Pathophysiological roles of chronic low‐grade inflammation mediators in polycystic ovary syndrome.” Journal of Cellular Physiology 236, no. 2 (2021): 824–838. https://doi.org/10.1002/jcp.29912. Rotterdam ESHRE, T. R., & ASRM-Sponsored PCOS Consensus Workshop Group. “Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.” Fertility and Sterility 81, no. 1 (2004): 19–25. https://doi.org/10.1016/j. fertnstert.2003.10.004. Rotterdam ESHRE/ASRM‐Sponsored PCOS Consensus Workshop Group. “Revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS).” Human Reproduction 19, no. 1 (2004): 41–47. https://doi. org/10.1093/humrep/deh098. Rudnicka, Ewa, Michał Kunicki, Anna Calik-Ksepka, Katarzyna Suchta, Anna Duszewska, Katarzyna Smolarczyk, and Roman Smolarczyk. “Anti-Müllerian hormone in pathogenesis, diagnostic and treatment of PCOS.” International Journal of Molecular Sciences 22, no. 22 (2021): 12507. https://doi.org/10.3390/ijms222212507. Sadeu, Jean Clair, and Warren G. Foster. “Cigarette smoke condensate exposure delays follicular development and function in a stage-dependent manner.” Fertility and Sterility 95, no. 7 (2011): 2410–2417. https://doi.org/10.1016/j.fertnstert.2011.03.072. Sam, Susan, Richard S. Legro, Paulina A. Essah, Teimuraz Apridonidze, and Andrea Dunaif. “Evidence for metabolic and reproductive phenotypes in mothers of women with polycystic ovary syndrome.” Proceedings of the National Academy of Sciences 103, no. 18 (2006): 7030–7035. https://doi.org/10.1073/pnas.0602025103.

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

67

Schube, U., M. Nowicki, P. Jogschies, V. Blumenauer, I. Bechmann, and H. Serke. “Resveratrol and desferoxamine protect human OxLDL-treated granulosa cell subtypes from degeneration.” The Journal of Clinical Endocrinology & Metabolism 99, no. 1 (2014): 229– 239. https://doi.org/10.1210/jc.2013-2692. Shaaban, Zahra, Mohammad Reza Jafarzadeh Shirazi, Mohammad Hossein Nooranizadeh, Amin Tamadon, Farhad Rahmanifar, Somayeh Ahmadloo, Amin Ramezani et al. “Decreased expression of arginine-phenylalanine-amide-related peptide-3 gene in dorsomedial hypothalamic nucleus of constant light exposure model of polycystic ovarian syndrome.” International Journal of Fertility & Sterility 12, no. 1 (2018): 43. https://doi. org/10.22074/ijfs.2018.5206. Sharma, P., Y. A. Hajam, R. Kumar, and S. Rai. “Complementary and alternative medicine for the treatment of diabetes and associated complications: a review on therapeutic role of polyphenols.” Phytomedicine Plus 2, no. 1 (2022): 100188. Shim, Youn Young, Bo Gui, Paul G. Arnison, Yong Wang, and Martin J. T. Reaney. “Flaxseed (Linum usitatissimum L.) bioactive compounds and peptide nomenclature: a review.” Trends in Food Science & Technology 38, no. 1 (2014): 5–20. https://doi.org/10.1016/j. tifs.2014.03.011. Sies, Helmut. “Oxidative stress: from basic research to clinical application.” The American Journal of Medicine 91, no. 3 (1991): S31–S38. https://doi.org/10.1016/0002-9343(91)90281-2. Silva, Mauro S. B., and Paolo Giacobini. “New insights into anti-Müllerian hormone role in the hypothalamic–pituitary–gonadal axis and neuroendocrine development.” Cellular and Molecular Life Sciences 78, no. 1 (2021): 1–16. https://doi.org/10.1007/ s00018-020-03576-x. Simic, D. V., J. Mimic-Oka, M. Pljesa-Ercegovac, A. Savic-Radojevic, M. Opacic, D. Matic, B. Ivanovic, and T. Simic. “Byproducts of oxidative protein damage and antioxidant enzyme activities in plasma of patients with different degrees of essential hypertension.” Journal of Human Hypertension 20, no. 2 (2006): 149–155. https://doi.org/10.1038/ sj.jhh.1001945. Simoni, Manuela, and Eberhard Nieschlag. “FSH in therapy: physiological basis, new preparations and clinical use.” Reproductive Medicine Review 4, no. 3 (1995): 163–177. https:// doi.org/10.1017/s0962279900000557. Sirmans, Susan M., and Kristen A. Pate. “Epidemiology, diagnosis, and management of polycystic ovary syndrome.” Clinical Epidemiology 6 (2014): 1. https://doi.org/10.2147/ clep.s37559. Smith, Stacy R., Daniel J. Piacquadio, Brian Beger, and Curt Littler. “Eflornithine cream combined with laser therapy in the management of unwanted facial hair growth in women: a randomized trial.” Dermatologic Surgery 32, no. 10 (2006): 1237–1243. https://doi. org/10.1111/j.1524-4725.2006.32282.x. Somani, Najwa, and Diane Turvy. “Hirsutism: an evidence-based treatment update.” American Journal of Clinical Dermatology 15, no. 3 (2014): 247–266. https://doi.org/10.1007/ s40257-014-0078-4. Spritzer, P. M. Polycystic ovary syndrome. Arquivos Brasileiros de Endocrinologia & Metabologia 58 (2014): 182–187. https://doi.org/10.1590/0004-2730000003051. Steinberger, Emil, Keith D. Smith, and Luis J. Rodriguez-Rigau. “Testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate in hyperandrogenic women.” The Journal of Clinical Endocrinology & Metabolism 59, no. 3 (1984): 471–477. https://doi. org/10.1210/jcem-59-3-471. Stewart, P. M., C. R. W. Edwards, C. H. L. Shackleton, and G. H. Beastall. “5 α-reductase activity in polycystic ovary syndrome.” The Lancet 335, no. 8687 (1990): 431–433. https://doi.org/10.1016/0140-6736(90)90664-q.

68

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Szczuko, Małgorzata, Justyna Kikut, Urszula Szczuko, Iwona Szydłowska, Jolanta NawrockaRutkowska, Maciej Ziętek, Donatella Verbanac, and Luciano Saso. “Nutrition strategy and life style in polycystic ovary syndrome—narrative review.” Nutrients 13, no. 7 (2021): 2452. https://doi.org/10.3390/nu13072452. Szeliga, Anna, Ewa Rudnicka, Marzena Maciejewska-Jeske, Marek Kucharski, Anna Kostrzak, Marta Hajbos, Olga Niwczyk, Roman Smolarczyk, and Blazej Meczekalski. “Neuroendocrine determinants of polycystic ovary syndrome.” International Journal of Environmental Research and Public Health 19, no. 5 (2022): 3089. https://doi. org/10.3390/ijerph19053089. Teede, Helena J., Marie L. Misso, Michael F. Costello, Anuja Dokras, Joop Laven, Lisa Moran, Terhi Piltonen, and Robert J. Norman. “Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.” Human Reproduction 33, no. 9 (2018): 1602–1618. https://doi.org/10.1111/ cen.13795. Themmen, Axel P. N., and Ilpo T. Huhtaniemi. “Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function.” Endocrine Reviews 21, no. 5 (2000): 551–583. https://doi.org/10.1210/ edrv.21.5.0409. Tsouma, Iliana, Evangelia Kouskouni, Stella Demeridou, Maria Boutsikou, Dimitrios Hassiakos, Anthia Chasiakou, Stamatia Hassiakou, Vassiliki Gennimata, and Stavroula Baka. “Lipid lipoprotein profile alterations in Greek infertile women with polycystic ovaries: influence of adipocytokines levels.” in vivo 28, no. 5 (2014): 935–939. Retrieved from https://iv.iiarjournals.org/content/28/5/935. Tsutsumi, Rie, and Nicholas J. G. Webster. “GnRH pulsatility, the pituitary response and reproductive dysfunction.” Endocrine Journal 56, no. 6 (2009): 729–737. https://doi. org/10.1507/endocrj.k09e-185. Unluhizarci, Kursad, Zuleyha Karaca, and Fahrettin Kelestimur. “Role of insulin and insulin resistance in androgen excess disorders.” World Journal of Diabetes 12, no. 5 (2021): 616. https://doi.org/10.4239/wjd.v12.i5.616. Urbanek, Margrit. “The genetics of the polycystic ovary syndrome.” Nature Clinical Practice Endocrinology & Metabolism 3, no. 2 (2007): 103–111. https://doi.org/10.1038/ ncpendmet0400. van Zuuren, Esther J., Zbys Fedorowicz, Ben Carter, and Nikolaos Pandis. “Interventions for hirsutism (excluding laser and photoepilation therapy alone).” Cochrane Database of Systematic Reviews 4 (2015). https://doi.org/10.1002/14651858.cd010334.pub2. Venkatesan, Aradhana M., Andrea Dunaif, and Anne Corbould. “Insulin resistance in polycystic ovary syndrome: progress and paradoxes.” Recent Progress in Hormone Research 56 (2001): 295–308. https://doi.org/10.1210/rp.56.1.295. Venugopal, Senthil Kumar, Sridevi Devaraj, and Ishwarlal Jialal. “Effect of C-reactive protein on vascular cells: evidence for a proinflammatory, proatherogenic role.” Current Opinion in Nephrology and Hypertension 14, no. 1 (2005): 33–37. https://doi. org/10.1097/00041552-200501000-00006. Wallach, Edward E., and Carolyn B. Coulam. “Premature gonadal failure.” Fertility and Sterility 38, no. 6 (1982): 645–655. https://doi.org/10.1016/s0015-0282(16)46688-4. Walters, Kirsty A., Robert B. Gilchrist, William L. Ledger, Helena J. Teede, David J. Handelsman, and Rebecca E. Campbell. “New perspectives on the pathogenesis of PCOS: neuroendocrine origins.” Trends in Endocrinology & Metabolism 29, no. 12 (2018): 841–852. https://doi.org/10.1016/j.tem.2018.08.005. Wang, Jeff G., Richard A. Anderson, George M. Graham III, Micheline C. Chu, Mark V. Sauer, Michael M. Guarnaccia, and Rogerio A. Lobo. “The effect of cinnamon extract on insulin resistance parameters in polycystic ovary syndrome: a pilot study.” Fertility and Sterility 88, no. 1 (2007): 240–243. https://doi.org/10.1016/j.fertnstert.2006.11.082.

Regulation of Hypothalamus-Pituitary-Gonadal Axis and Steroidogenesis

69

Webster, D. E., J. Lu, S.-N. Chen, N. R. Farnsworth, and Z. Jim Wang. “Activation of the μ-opiate receptor by Vitex agnus-castus methanol extracts: implication for its use in PMS.” Journal of Ethnopharmacology 106, no. 2 (2006): 216–221. https://doi. org/10.1016/j.jep.2005.12.025. Willis, Debbie S., Hazel Watson, Helen D. Mason, Ray Galea, Mark Brincat, and Stephen Franks. “Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: relevance to mechanism of anovulation.” The Journal of Clinical Endocrinology & Metabolism 83, no. 11 (1998): 3984–3991. https:// doi.org/10.1210/jcem.83.11.5232. Wuttke, W., H. Jarry, V. Christoffel, B. Spengler, and D. Seidlova-Wuttke. “Chaste tree (Vitex agnus-castus)–pharmacology and clinical indications.” Phytomedicine 10, no. 4 (2003): 348–357. https://doi.org/10.1078/094471103322004866. Xie, Jue, Frada Burstein, Rhonda Garad, Helena J. Teede, and Jacqueline A. Boyle. “Personalized mobile tool AskPCOS delivering evidence-based quality information about polycystic ovary syndrome.” Seminars in Reproductive Medicine 36, no. 01 (2018): 066–072. https://doi.org/10.1055/s-0038-1667156. Xie, Liangzhen, Duojia Zhang, Hongli Ma, Hui He, Qing Xia, Wenjuan Shen, Hui Chang et al. “The effect of berberine on reproduction and metabolism in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized control trials.” Evidence-Based Complementary and Alternative Medicine 2019 (2019). https://doi. org/10.1155/2019/7918631. Yang, Kailin, Liuting Zeng, Tingting Bao, and Jinwen Ge. “Effectiveness of omega-3 fatty acid for polycystic ovary syndrome: a systematic review and meta-analysis.” Reproductive Biology and Endocrinology 16, no. 1 (2018): 1–13. https://doi.org/10.1186/s12958-018-0346-x. Yang, Rui, Shuo Yang, Rong Li, Ping Liu, Jie Qiao, and Yanwu Zhang. “Effects of hyperandrogenism on metabolic abnormalities in patients with polycystic ovary syndrome: a meta-analysis.” Reproductive Biology and Endocrinology 14, no. 1 (2016): 1–10. https:// doi.org/10.1186/s12958-016-0203-8. Yang, Yan, Jie Qiao, Rong Li, and Mei-Zhi Li. “Is interleukin-18 associated with polycystic ovary syndrome?” Reproductive Biology and Endocrinology 9, no. 1 (2011): 1–5. https://doi.org/10.1186/1477-7827-9-7. Yang, Yin, Hui Deng, Tian Li, Min Xia, Chang Liu, Xiao-Qing Bu, Hang Li, Li-Juan Fu, and Zhao-Hui Zhong. “The mental health of Chinese women with polycystic ovary syndrome is related to sleep disorders, not disease status.” Journal of Affective Disorders 282 (2021): 51–57. https://doi.org/10.1016/j.jad.2020.12.084. Yildirim, Basak, Nuran Sabir, and Babur Kaleli. “Relation of intra-abdominal fat distribution to metabolic disorders in nonobese patients with polycystic ovary syndrome.” Fertility and Sterility 79, no. 6 (2003): 1358–1364. https://doi.org/10.1016/s0015-0282(03)00265-6. Yildiz, Bulent O., and Ricardo Azziz. “The adrenal and polycystic ovary syndrome.” Reviews in Endocrine and Metabolic Disorders 8, no. 4 (2007): 331–342. https://doi.org/10.1007/ s11154-007-9054-0. Zhang, Bingqian, Wei Zhou, Yuhua Shi, Jun Zhang, Linlin Cui, and Zi-Jiang Chen. “Lifestyle and environmental contributions to ovulatory dysfunction in women of polycystic ovary syndrome.” BMC Endocrine Disorders 20, no. 1 (2020): 1–7. https://doi.org/10.1186/ s12902-020-0497-6. Zhang, Yan, Lingyan Liu, Tai-Lang Yin, Jing Yang, and Cheng-Liang Xiong. “Follicular metabolic changes and effects on oocyte quality in polycystic ovary syndrome patients.” Oncotarget 8, no. 46 (2017): 80472. https://doi.org/10.18632/oncotarget.19058. Zhang, Yi-fei, Yi-sheng Yang, Jie Hong, Wei-qiong Gu, Chun-fang Shen, Min Xu, Peng-fei Du, Xiao-ying Li, and Guang Ning. “Elevated serum levels of interleukin-18 are associated with insulin resistance in women with polycystic ovary syndrome.” Endocrine 29, no. 3 (2006): 419–423. https://doi.org/10.1385/endo:29:3:419.

70

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Zirlik, Andreas, Shuaib M. Abdullah, Norbert Gerdes, Lindsey MacFarlane, Uwe Schönbeck, Amit Khera, Darren K. McGuire et al. “Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis: results from the Dallas Heart Study.” Arteriosclerosis, Thrombosis, and Vascular Biology 27, no. 9 (2007): 2043–2049. https://doi.org/10.1161/ atvbaha.107.149484.

3

Potential Phytotherapeutic Intervention for the Treatment of Polycystic Ovarian Syndrome Seema Rai, Sushmita Pal, Adyasha Purohit, Sunita Patel, Kshipra Xaxa, and Gunja Roy Guru Ghasidas Vishwavidyalaya

Younis Hajam Ahmad Sant Baba Bhag Singh University

Rajesh Kumar Himachal Pradesh University

CONTENTS 3.1 Introduction..................................................................................................... 72 3.2 PCOS and Reproductive Impairments............................................................ 73 3.3 Therapeutic Drugs in PCOS............................................................................ 74 3.3.1 Oral Contraceptive Pill........................................................................ 74 3.3.1.1 Metformin............................................................................. 74 3.3.1.2 Clomiphene Citrate............................................................... 75 3.4 Phytotherapeutic Interventions in PCOS......................................................... 76 3.4.1 Quercetin............................................................................................. 77 3.4.1.1 Quercetin as Phytotherapeutics............................................ 78 3.4.2 6-Gingerol............................................................................................80 3.4.3 6-Gingerol as Phytotherapeutics.........................................................80 3.4.4 Resveratrol........................................................................................... 81 3.4.4.1 Resveratrol as Phytotherapeutics.......................................... 81 3.5 Conclusion....................................................................................................... 83 Bibliography............................................................................................................. 83

DOI: 10.1201/9781003344728-3

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3.1 INTRODUCTION Nowadays, the most common ovarian disorder is polycystic ovarian syndrome or PCOS. It was first discovered by Stein and Leventhal in 1935 (Leventhal and Cohen, 1951). Hence, it is referred to as Stein–Leventhal syndrome (Leventhal, 1958). It is one of the most common endocrine and metabolic disorders in which the women ovaries produce immature or partially mature eggs in large quantities and develop into ovarian cysts. It occurs mainly in 2%–20% of the reproductive age group (Knochenhauer et al., 1998; Rai et al., 2015; Basheer et al., 2018). Nowadays, the PCOS has become a severe issue. PCOS is a type of secondary amenorrhea (Leventhal, 1958), which includes irregular menstruation or amenorrhea, i.e., absence of menstruation. FSH is responsible for follicular maturation and ovulation. Lack of FSH arrested the growth of antral follicles which causes irregular cycles and anovulation in PCOS women (Doi et al., 2005). Type 2 diabetes, hyperinsulinemia, and glucose intolerance are the metabolic symptoms (Tasali et al., 2008). Physical signs are hirsutism (excessive hair growth on the face), alopecia, overweight, acne, inappropriate male features, oily skin, etc. It occurs in the beginning of adolescence (Teede et al., 2010). Women with PCOS have higher chances of coronary artery diseases and stroke due to high level of LDL cholesterol and low level of HDL (Macut et al., 2013). Hyperandrogenism or malelike features, insulin resistance, and ovulatory dysfunction are the major indications in women with PCOS (Jahan et al., 2018). Women with PCOS exhibit comparatively high emotional distress such as anxiety, depression, poor self-esteem, and reduced quality of life (Coffey et al., 2006; Tasali et al., 2008; Benson et al., 2009; VeltmanVerhulst et al., 2012). Obstructive sleep apnea is also a determinant factor in women with PCOS (Tasali et al., 2008). Dyslipidemia is a common risk factor in women with PCOS. It has been suggested that dyslipidemia, obesity, and hyperinsulinemia may be responsible for PCOSrelated oxidative stress. Due to the presence of excessive adipose tissue and overproduction of reactive oxygen species (ROS) the oxidative stress seems to be increased in women with PCOS. Overproduction of ROS is responsible for the high level of free radicles, such as superoxide radicles and hydrogen peroxide in mitochondria (Macut et al., 2013; Sharma et al., 2022). Low levels of sex hormone binding globulin (SHBG) leads to hyperandrogenemia (Qu and Donnelly, 2020). Increasing oxidative stress leads to an increase in number of cardiovascular diseases in women with PCOS. According to Das and his coworkers, granulosa cell proliferation in women with PCOS is greater than granulosa cell death or apoptosis (Das et al., 2008). Hence, more granulosa cells produce more estrogen in response to FSH stimulation than normal granulosa cells (Erickson et al., 1990). In women with PCOS, antimullerian hormone (AMH) also presents a highlevel output by granulosa cell from preantral and small antral follicles which causes disruptive activity of granulosa cells in women with PCOS (Pigny et al., 2003; Pellatt et al., 2007). In this chapter, we are starting to explore the effects of resveratrol, quercetin, and 6-gingerol on PCOS.

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Phytotherapeutic Intervention for Treatment of PCOS

3.2  PCOS AND REPRODUCTIVE IMPAIRMENTS Rotterdam reported that women with PCOS have higher level of circulating androgen. The aromatase enzyme primarily converts testosterone and androstenedione into estradiol and estrone throughout the steroidogenesis process (Rotterdam, 2003). However, when problems arise with this enzyme, it causes an increase in ovarian androgen production and development of PCOS (Kafali et al., 2004). In women, androgen is mainly produced from the ovary and adrenal glands. In women with PCOS, the ovaries produce up to 60% of androgen and the adrenal gland produces the remaining 40% (Cedars et al., 1992). This excess production of androgen leads to hyperandrogenism. According to Sterling, in normal women without PCOS, the LH and FSH ratio is 5:20 IU/mL, but in women with PCOS, the LH level increases up to 18 IU/ml and the FSH level decreases up to 6 IU/mL. This change can prevent ovulation well and leads to lower pregnancy and higher miscarriage rate. During the early stage of life, LH and FSH are in equal amounts, but 24 hours before ovulation, the LH level increases up to 25–40 IU/mL. After ovulation, the LH levels decreases (Krishnan and Muthusami, 2017). Women with PCOS have an increased risk of impaired glucose tolerance (Rotterdam, 2003). In normal women, the insulin level is 6–15 μIU/mL, but in women with PCOS, the insulin level increases up to 22 μIU/mL (Joshi et al., 2014; Krishnan and Muthusami, 2017), which leads to hyperinsulinemia and causes diabetes mellitus. Women with PCOS also have an elevated level of dehydroepiandrosterone (DHEAS) (Rotterdam, 2004). In women with PCOS, the high

23

24

26 28

25

22 21 20 19 18 17

m

nis

15

5

12

Irr men egular strua l cyc 14

6 7 8 9

FERTILE 16

4

13

11

10

Hype rglyca Infe r tilit

Ovary

lin ce su n In ista s Re

t Ga

in

Obesity hyperinsulinemia

e tiv uc ea str Apn b O ep Sle

FIGURE 3.1  Various physiological impairments involved in PCOS.

Ca rdi o dis vasc ea se ular s

y

Weig h

nd ty a on Alopecia xie i An ress dep

m

tis

u rs

emia

3

le

era

Hyp

Acne

2

Hi

oge ndr

1

PROBABLY INFERTILE

INFERTILE

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Herbal Medicine Applications for Polycystic Ovarian Syndrome

level of insulin may bind with the insulin receptor in the osteoblast cell and reduce bone formation (Krishnan and Muthusami, 2017) (Figure 3.1).

3.3  THERAPEUTIC DRUGS IN PCOS To date, there are several medications that exist for the treatment of PCOS. For patients with PCOS, medical managements such as oral contraceptive pills, metformin, and hormone therapy were introduced (Mihanfar et al., 2021a).

3.3.1 Oral Contraceptive Pill OH CCH

O

Levonorgestrel

Oral contraceptive pills reduce hyperandrogenism and regulate menstrual cycle by suppressing ovulation and preventing cyst formation (Piparva and Buch 2011; Mihanfar et al., 2021). Research evidence suggests a lot of medications for the treatment of PCOS. However, few studies in the literature suggest cardiovascular and breast cancer as side effects of oral contraceptives. Furthermore, there are various allopathic drugs in allopathic medicine to treat PCOS. 3.3.1.1 Metformin CH3 H N

H2N

N CH3

NH

NH

Metformin

Brand: Fortamet, Actoplus met, Janumet, Glycon. Mechanism of action: Previous researchers reported that metformin is primarily used for the treatment of type 2 diabetes and acts as insulin sensitizers. Morley and his coworkers also reported that metformin decreases weight, also decreases the androgen level in blood serum, and improves menstrual irregularities and ovulation (Morley et al., 2017) (Figure 3.2). 3.3.1.1.1  Side Effects of Metformin They all have many sides effects which are evidenced by the use of these drugs in PCOS treatment. Metformin as a PCOS drug causes other diseases such as gastrointestinal disturbance, lactic acidosis, and renal insufficiency (Jahan et al., 2018).

Phytotherapeutic Intervention for Treatment of PCOS

Metformin

75

Hepatic gluconeogenesis

Glucagon

Glycogen

Glucose

FIGURE 3.2  Schematic flowchart of mechanism of action of metformin. Metformin decreases hepatic gluconeogenesis by inhibiting mitochondrial complexes which have downstream effects on cAMP and protein kinase signaling pathways. As a result, glucagon action decreases and circulating insulin and glucose level on ovaries.

3.3.1.2  Clomiphene Citrate It has been reported that clomiphene citrate is an estrogen antagonist and is used for the improvement of ovulation in infertile PCOS women (Macgregor et al., 1968). Rosenfield and Ehrmann (2016) also reported that hyperandrogenism is also treated by clomiphene citrate, thereby reducing hyperinsulinemia because hyperandrogenism is the main factor for hyperinsulinemia (Figure 3.3). OCH2-CH2 -N(C2H5)2

• C6H8O7

Cl •

Clomiphene citrate

3.3.1.2.1  Side Effects of Clomiphene Citrate Congenital abnormalities, such as liver diseases, decrease the quantity and quality of cervical mucus, leads to abnormal development or dysfunction of endometrium (Sereepapong et al., 2000; Sovino et al., 2002), and also leads to mood swings, irritability, and feeling down (Choi et al., 2005) (Figure 3.4). Therefore, clomiphene citrate may not be a suitable drug of choice for long-term PCOS medication (Jahan et al., 2018). Therefore, to treat PCOS, some phytotherapeutic folk medicines need to be explored, as they have been investigated from time to time.

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Herbal Medicine Applications for Polycystic Ovarian Syndrome

Hypothalamus

Clomiphene citrate

GnRH

LH pulse frequency

Estrogen

Progesterone

FIGURE 3.3  Schematic flowchart of the mechanism of action of clomiphene citrate. Clomiphene citrate can increase the LH pulse frequency by increasing the pulsatile secretion of GnRH in hypothalamus, thereby increasing the estrogen level before ovulation and the progesterone level during luteal phase.

Mood swing

Nausea

Vomiting

Congenital abnormalities

Side Effects of Metformin, Clomiphene citrate, Contraceptive Pills

Lactic acidosis

Renal insufficiency Break through bleeding

Liver disease

Irritability Gastrointestinal disturbance

FIGURE 3.4  Schematic diagram showing side effects by using therapeutic medications in PCOS.

3.4  PHYTOTHERAPEUTIC INTERVENTIONS IN PCOS The present scenario, which is related to the various side effects of the therapeutic drugs, such as metformin, clomiphene citrate, contraceptive pills, and so on, inclined the attention of various researchers toward the nutraceuticals/phytoextracts which contain various polyphenols and bioactive compounds for the treatment of PCOS pathogenicity.

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Phytotherapeutic Intervention for Treatment of PCOS

Since ancient times, most of the tribal population use the neutral folk medicine for the treatment of various kind of diseases, including viral infection, inflammation, wound healing, and reproductive disfunction/disorders. In this study, we wish to explore a few plant extracts, such as polyphenols and bioactive compounds, which are widely used to treat PCOS. However, various reports suggest that they are known to have the ability to interfere with different kinds of diseases. It is believed that the phenolic substances from medicinal plants, fruits, and vegetables in diet may play an important role in the protection. Plant polyphenols are dietary antioxidants and act as structural polymers and defense response chemicals (Lin et al., 2016; Rani et al., 2022). These phytotherapeutic drug could be flavonoid and nonflavonoid compounds. The present study explains about one specific flavonoid, i.e., quercetin and nonflavonoids such as 6-gingerol; another phytomolecule which we have considered is the natural polyphenol is in stilbene family, known as resveratrol (Figure 3.5).

3.4.1  Quercetin Flavonoids (i.e., quercetin) are hydrophilic natural glycosides which are present in many plants and foodstuffs (Formica and Regelson, 1995). The most common flavonoids are quercetin and Rutin. Quercetin, the chemical name-3,5,7,3′,4′pentahydroxyflavone, is one of the most common flavanols which is commonly found in fruits and vegetables such as tomato, onion, broccoli, lettuce, grapes, apples, and

Hyperandrogenism, Anovulation, Infertility, Oligoovulation

Oxidative stress, Lipid peroxidation, ROS

Polycystic Ovarian Syndrome

RESVERATROL

QUERCETIN

Polyphenols FIGURE 3.5  Polyphenols in PCOS.

6-GINGEROL

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Herbal Medicine Applications for Polycystic Ovarian Syndrome

blueberries. It was first described by Szent Gyorgyi in 1936 (Formica and Regelson, 1995). It is a nonsteroidal compound and has antioxidant properties. OH OH O

HO

OH OH

O

Structure of quercetin

The present study is based on the effect of quercetin in PCOS. In addition to benefits in PCOS, quercetin exhibits cardiovascular protection, anticancer activity, antidiabatic, anti-inflammatory effect, etc. 3.4.1.1  Quercetin as Phytotherapeutics Quercetin is a potent therapeutic component (Mihanfar et al., 2021a). The metabolic sensors, AMPK and SIRT-1, play an important role in lipid and adipokines metabolism, glycolysis, and oxidative stress but their expression level decreases in PCOS ovarian tissue (Ruderman et al., 2010; Furat Rencber et al., 2018; Tao et al., 2019; Nejabati et al., 2020). Quercetin plays a regulatory role in AMPK and SIRT-1 activation (Iside et al., 2020). Quercetin supplement increases AMPK and SIRT-1 expression as well as increases insulin sensitivity and lipid and adipokines metabolism (Mihanfar et al., 2021b), thereby improving GLUT4 regulation and glycolysis (Pourteymour Fard Tabrizi et al., 2020). Treatment with quercetin in PCOS improves different biochemical and hormonal parameters as well as ovarian histological parameters (Mihanfar et al., 2021a). The granulosa and thecal layer of secondary follicles are thicker in women with PCOS than a healthy woman. However, quercetin ­supplement decreases this thickness of granulosa cell and layer of secondary follicle (Jahan et al., 2018). Jahan and his associates also reported that large-sized cystic f­ollicles are created in women with PCOS instead of secondary and tertiary follicles. These cystic follicles were formed due to excess androgen and disrupted ­folliculogenesis (Wang et al., 2012, Linares et al., 2013). However, quercetin administration decreases this cystic follicle diameter and increases the number of primordial germ cell and primary follicles (Jahan et al., 2018), thereby normalizing the ovarian size and hormonal imbalance and improving hyperandrogenemia (Shah and Patel, 2016). Insulin stimulates ovarian steroidogenesis by inhibiting hepatic SHBG synthesis (Plymate et al., 1988) and both hepatic and ovarian IGFBP synthesis (Poretsky et al., 1996), which regulates the ovarian growth and cyst formation and alters the adrenal steroidogenesis (Poretsky et al., 1999). Insulin also stimulates the ovarian steroidogenesis by binding to its own receptor and IGF1 receptor on granulosa and thecal

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Phytotherapeutic Intervention for Treatment of PCOS

cells of the ovary (Poretsky et al., 1999), which finally leads to the formation of hyperandrogenism and hyperinsulinemia and causes obesity in women with PCOS (Gambineri et al., 2002). However, treatment with quercetin reduces CYP17A1 mRNA expression to prevent excess production of steroidogenic hormones and also decreases ovarian cyst and its weight which finally improves hyperandrogenemia (Shah and Patel, 2016). Quercetin also decreases the total cholesterol level and increases HDL cholesterol (Jeong et al., 2012). In women with PCOS, the blood-glucose level is high due to high activity rate of α-glucosidase enzyme which breaks down the starch and disaccharides to glucose and causes hyperglycemic condition. However, quercetin inhibits the activity of α-glucosidase, which reduces the blood-glucose level (Shikawa et al., 2007; Kim et al., 2011; Jeong et al., 2012). A woman with PCOS exhibits excess level of ROS and free radicals, and a decline in the level of antioxidants causes oxidative stress (Maritim et al., 2003). However, quercetin increases the function of antioxidant enzymes such as hepatic SOD, CAT, and GSH-Px, which protect the cell from oxidative damage (Harman, 1991; Dröge, 2002). Quercetin directly degrades the ROS and free radicals which reduce the oxidative stress in women with PCOS (Hanasaki et al., 1994; Boots et al., 2008) (Figure 3.6). Adipose tissue produce adiponectin, leptin, TNF-α, etc. (Sun et al., 2011). TNF-α and leptin block insulin receptor and IGF-1 receptor tyrosine kinases by inhibiting serine phosphorylation of IRS-1 which causes obese conditions in women with PCOS (Hotamisligil et al., 1996). However, quercetin increases the tyrosine phosphorylation of IRS-1 (Eid and Haddad, 2017) and induces pancreatic β-cell proliferation which leads to increase in the insulin level (Gurav et al., 2018). On the other hand, adiponectin enhances insulin sensitivity (Mamaghani et al., 2009; Cui et al., 2017) but its level is low in women with PCOS because testosterone concentration is higher in women

cholesterol STAR protein pregnenolone

progesterone Dihydroepiandrosterone 3β HSD

Quercetin

Androstenedione Theca cell

17β HSD Blood vessel

3β HSD

Estrone

Estradiol Aromatase CYP19 Testosterone Quercetin

17β HSD

Androstenedione Granulosa cell

FIGURE 3.6  Effects of quercetin on steroidogenesis during PCOS.

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Herbal Medicine Applications for Polycystic Ovarian Syndrome

with PCOS which exerts negative feedback on adiponectin secretion (Rezvan et al., 2017). Therefore, it decreases insulin sensitivity and increases insulin resistance condition in women with PCOS. However, quercetin increases adiponectin production by decreasing TNF α synthesis through the inhibition of NF-κβ (Min et al., 2007). Shah and Patel reported that correction of dyslipidemia decreased plasma concentrations of cholesterol, reduced triglyceride, LDL, and VLDL levels, and increased the HDL level due to the administration of quercetin (Shah and Patel, 2016). Hong and his associates reported that quercetin decreases the serum glucose level to maintain glucose homeostasis and reduces body weight by decreasing the production of steroidogenic enzymes such as 3β-HSD and 17-β HSD (Hong et al., 2018). Antiobesity action of quercetin reduces adipogenesis and lipogenesis by decreasing the expression of PPARγ, SREBP, and fatty acid synthase in adipocytes, thereby reducing body fat and protecting against weight gain (Ahn et al., 2008; Aguirre et al., 2011).

3.4.2 6-Gingerol Ginger rhizome, commonly known as ginger, contains pungent phenolic substances 6-gingerol (Kim et al., 2005). The chemical name of 6-gingerol is – (1-[4′-hydroxy3′-methoxyphenyl]5-hydroxy-3-decanone). It is the ginger extract in natural aromatic polyphenol. It is the most bioactive compound of ginger, having different biological properties such as anticancer, antioxidant, antiatherosclerosis, anti-inflammation, antiplatelet aggression, and antifungal properties (Pournaderi et al., 2017a). O

OH

HO O

Structure of 6-gingerol

3.4.3 6-Gingerol as Phytotherapeutics In women with PCOS, high-pituitary sensitivity to hypothalamic GnRH and higher pulse frequency of GnRH increases the production of LH over FSH (Polska et al., 2011). A rise in level produced more androgen from thecal cells which causes hyperandrogenism in PCOS patients (Moret et al., 2009). Rahmanian et al. reported that 6-gingerol suppresses gonadotropin secretion by its effect on pituitary-gonadal axis which in turn decreases the release of FSH and LH (Rahmanian et al., 2012). Khaki and his coresearchers reported that 6-gingerol decreases the testosterone levels by reducing the blood-glucose and insulin level (Khaki et al., 2014). Androgens are synthesized into estrogen by cytochrome p450 aromatase enzyme. 6-Gingerol hampers this pathway and reduces the estrogen level (Li et al., 2013). Prostaglandins are responsible for gonadotropin synthesis. Pournaderi and his coresearchers reported that 6-gingerol inhibits the synthesis of arachidonic acid and prostaglandins by inhibiting cyclooxygenase and lipoxygenase pathways, thereby normalizing the hormonal imbalance and decreasing the gonadotropin level.

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Phytotherapeutic Intervention for Treatment of PCOS

3.4.4 Resveratrol Resveratrol (trans-3,5,4′-tryhydroxystilbene) is a natural polyphenol of stilbene family and is synthesized from phenylalanine (Fernández-Mar et al., 2012). It can be extracted from the skin and seeds of grapes, peanuts and their derivatives, barriers, dark chocolate, and the derivatives of red wine, rose wine, and white wine (Fernández-Mar et al., 2012). Its concentration is higher in red wine (1.90 mg/l) than white wine (0.13 mg/l) and rose wine (0.41 mg/l) (Romero-Pérez et al., 1996; Carando et al., 1999; Landrault et al., 2002; Stervbo et al., 2006). It has two isomeric forms: cis and trans-resveratrol. The trans-resveratrol is found in grapevines which is the main component of stilbene family of phenolic compound. It has anticarcinogenic, antiproliferative, anti-inflammatory, and antioxidant properties (Wong et al., 2010). OH HO

OH

Structure of Resveratrol

3.4.4.1  Resveratrol as Phytotherapeutics Resveratrol is a nonflavonoid polyphenol. This phytoestrogen exhibits antidiabetic, antioxidant, anti-inflammatory (Furat Rencber et al., 2018) and chemopreventive properties (Ortega et al., 2012). Yet not much research has been done regarding the role of resveratrol in reproductive function such as PCOS. Ortega and associates reported that resveratrol protects the granulosa cell, embryonic cell, and erythroleukemia cells from apoptosis (Ortega et al., 2012). In theca-interstitial cell, LH binds with LH receptor which converts cholesterol to pregnenolone and then ovarian androgen (i.e. androstenedione and some testosterone), which then diffuses to granulosa cell where they convert into estrogen by aromatase enzyme (Hillier et al., 1994). However, in the granulosa cell of PCOS, women have little or no aromatase (P450) activity; therefore E2 production decreases (Erickson et al., 1990). In women with PCOS, theca cell produces more testosterone than the normal theca cell because of high levels of LH concentration. The resveratrol supplement inhibits mRNA expression of Cyp17a1 (rate-limiting enzyme in androgen biosynthesis pathway) in theca cells, thereby decreasing the excessive production of ovarian androgen or steroidogenesis from thecal cells (Ortega and Duleba, 2015; Mansour et al., 2021). Resveratrol can inhibit theca cell proliferation and increase the growth of granulosa cell (Mansour et al., 2021). As a result, the estrogen level can return to its normal condition. Hence, ultimately decline the total testosterone quantity and DHEAS level and improve ovulation in women with PCOS. Granulosa cells in women with PCOS also produced an increased amount of AMH from preantral and small antral follicles but there was no effect in AMH expression after giving resveratrol supplement (Ortega et al., 2012). Two factors of insulin resistance, i.e., enlarged adipocytes and decreased lipolytic activity, are associate with PCOS (Faulds et al., 2003; Mannerås-Holm et al., 2011). Resveratrol reduce lipogenesis and increase release of free fatty acid (FFA) and

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induce lipolysis by decreasing lipogenic enzyme activity and by stimulating adipose triglyceride lipase (ATGL) (Alberdi et al., 2011; Lasa et al., 2012). These adipose triglyceride lipases hydrolyze triglyceride to form diglyceride and FFA (Lasa et al., 2012), hence decrease fat mass gain and reduce adiposity by resveratrol supplement (Benrick et al., 2013). Resveratrol supplement shows no effect on the circulating level of SHBG and lipid metabolism in PCOS patients (Mansour et al., 2021). Wong and coresearchers reported that resveratrol counteracts antiapoptotic effects of insulin and oxidative stress (Wong et al., 2010). Insulin and moderate oxidative stress stimulate theca-interstitial cell of ovaries to grow excessively (Duleba et al., 1997; Duleba et al., 2004). Hence, the ovaries are enlarged in women with PCOS women (Hughesdon, 1982). But resveratrol inhibits excess theca-interstitial cell proliferation by inducing apoptosis through increasing caspase 3/7 activity and DNA fragmentation (Joe et al., 2002; Jiang et al., 2005). Resveratrol also inhibits the growth of theca cell by increasing the insulin sensitivity and decreasing insulin resistance and oxidative stress (Baur et al., 2006; Ortega et al., 2012). Resveratrol supplement can reduce body weight and obesity by reducing inflammatory markers (IL-1β, IL-6, TNF-α), adipocyte proliferation, lipogenesis, and promoting adipocyte apoptosis, lipolysis, and fatty acid oxidation (Christenson et al., 2016). According to Ortega and his coworkers, vascular endothelial growth factor (VEGF) is a key proangiogenic factor involved in the regulation of follicular maturation in granulosa cell which is activated by HIF1 genes and present at high level in women with PCOS (Stelzer et al., 2016). LH stimulates VEGF expression in the granulosa cell of the ovaries (Artini et al., 2003). As the LH level is higher in women with PCOS, higher VEGF expression is found in women with PCOS which gets negative impact on follicular maturation and decreases the ability of fertilization (de Leo et al., 2016). According to Bahramrezaie and his associates, resveratrol supplement can decrease VEGF mRNA and protein expression by decreasing HIF1 expression and by reducing the LH level in women with PCOS (Bahramrezaie et al., 2019; Ortega et al., 2012) (Figure 3.7). OH HO

RESVERATROL OH

Polycystic ovarian syndrome

Oxidative stress

VEGF expression

Lipogenesis

Steroidogenesis Adiposity

Obesity Insulin resistance

Estrogen

Normal Ovulation FIGURE 3.7  Schematic diagram showing effect of resveratrol in PCOS management.

Phytotherapeutic Intervention for Treatment of PCOS

83

3.5 CONCLUSION PCOS is a complex metabolic and reproductive disorder with many complications, such as anovulation, diabetes, cardiovascular, so on. Numerous synthetic or allopathic drugs are available for the treatment of PCOS but they all have various side effects following long-term administration. Therefore, pure plant-derived bioactive compounds such as resveratrol, quercetin, and 6-gingerol could be the safest alternatives with higher therapeutic potential for PCOS management. This review has led to establish that these bioactive compounds may regulate and reverse PCOS to normal ovulation/reproductive cyclicity/menstrual cycles and other associated metabolic disorders. However, before reaching to any conclusion further, clinical investigations are required to standardize the pharmacological properties of these herbal remedies to be employed for the treatment of PCOS, or as an adjuvant therapy to make it beneficial for humans to examine the therapeutic potential.

BIBLIOGRAPHY Aguirre, L, Arias, N, Macarulla, M T, Gracia, A, & Portillo, M P (2011). Beneficial effects of quercetin on obesity and diabetes. The Open Nutraceuticals Journal, 4(1), 189–198. Ahn, J, Lee, H, Kim, S, Park, J, & Ha, T (2008). The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signalling pathways. Biochemical and Biophysical Research Communications, 373(4), 545–549, https://doi.org/10.1016/j.bbrc.2008.06.077. Alberdi, G, Rodríguez, V M, Miranda, J, Macarulla, M T, Arias, N, Andrés-Lacueva, C, & Portillo, M P (2011). Changes in white adipose tissue metabolism induced by resveratrol in rats. Nutrition & Metabolism, 8(1), 1–7, https://doi.org/10.1186/1743-7075-8-29. Artini, P G, Monti, M, Cristello, F, Matteucci, C, Bruno, S, Valentino, V, & Genazzani, A R (2003). Vascular endothelial growth factor in females of reproductive age. Gynecological Endocrinology: The Official Journal of the International Society of Gynecological Endocrinology, 17(6), 477–492, https://doi.org/10.1080/09513590312331290418. Bahramrezaie, M, Amidi, F, Aleyasin, A, Saremi, A T, Aghahoseini, M, Brenjian, S, Khodarahmian, M, & Pooladi, A (2019). Effects of resveratrol on VEGF & HIF1 genes expression in granulosa cells in the angiogenesis pathway and laboratory parameters of polycystic ovary syndrome: a triple-blind randomized clinical trial. Journal of Assisted Reproduction and Genetics, 36(8), 1701–1712, https://doi.org/10.1007/s10815-019-01461-6. Basheer, M, Rai, S, Ghosh, H, & Hajam, Y A (2018). Protective role of seed extract of Tephrosia purpurea in letrozole induced polycystic ovary syndrome in Wistar rats. Journal of Biological Sciences, 18(8), 458–467. Baur, J, Pearson, K, & Price, N (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 444, 337–342. Benrick, A, Maliqueo, M, Miao, S, Villanueva, J A, Feng, Y, Ohlsson, C, Duleba, A J, & StenerVictorin, E (2013). Resveratrol is not as effective as physical exercise for improving reproductive and metabolic functions in rats with dihydrotestosterone-induced polycystic ovary syndrome. Evidence-Based Complementary and Alternative Medicine, https:// doi.org/10.1155/2013/964070. Benson, S, Hahn, S, Tan, S, Mann, K, Janssen, O E, Schedlowski, M, & Elsenbruch, S (2009). Prevalence and implications of anxiety in polycystic ovary syndrome: results of an internet-based survey in Germany. Human Reproduction, 24(6), 1446–1451, https://doi. org/10.1093/humrep/dep031. Boots, A W, Haenen, G R M M, & Bast, A (2008). Health effects of quercetin: from antioxidant to nutraceutical. European Journal of Pharmacology, 585(2–3), 325–337, https://doi. org/10.1016/j.ejphar.2008.03.008.

84

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Carando, S, Teissedre, P L, Waffo-Teguo, P, Cabanis, J C, Deffieux, G, & Merillon, J M (1999). High-performance liquid chromatography coupled with fluorescence detection for the determination of trans-astringin in wine. Journal of Chromatography A, 849(2), 617–620. Cedars, M I, Steingold, K A, de Ziegler, D, Lapolt, P S, Chang, R J, & Judd, H L (1992). Long-term administration of gonadotropin-releasing hormone agonist and dexamethasone: assessment of the adrenal role in ovarian dysfunction. Fertility and Sterility, 57(3), 495–500, https://doi.org/10.1016/s0015-0282(16)54890-0. Choi, S H, Shapiro, H, Robinson, G E, Irvine, J, Neuman, J, Rosen, B, Murphy, J, & Stewart, D (2005). Psychological side-effects of clomiphene citrate and human menopausal gonadotrophin. Journal of Psychosomatic Obstetrics and Gynaecology, 26(2), 93–100, https:// doi.org/10.1080/01443610400022983. Christenson, J, Whitby, S J, Mellor, D, Thomas, J, McKune, A, Roach, P D, & Naumovski, N (2016). The effects of resveratrol supplementation in overweight and obese humans: a systematic review of randomized trials. Metabolic Syndrome and Related Disorders, 14(7), 323–333, https://doi.org/10.1089/met.2016.0035. Coffey, S, Bano, G, & Mason, H D (2006). Health-related quality of life in women with polycystic ovary syndrome: a comparison with the general population using the Polycystic Ovary Syndrome Questionnaire (PCOSQ) and the Short Form-36 (SF-36). Gynaecological Endocrinology, 22(2), 80–86. Cui, Z, Sheng, T, Wang, Y, Zhou, W, Wang, W, Jin, Y, Jin, Y, Zhang, Z, Jin, X, & Yang, K (2017). Association between single nucleotide polymorphisms (SNPs) in the gene of ADP-ribosylation factor-like 15 (ARL15) and type 2 diabetes (T2D) in Korean Chinese population in Yanbian, China. International Journal of Diabetes in Developing Countries, 37(2), 124–128, https://doi.org/10.1007/s13410-015-0391-3. Das, M, Djahanbakhch, O, Hacihanefioglu, B, Saridogan, E, Ikram, M, Ghali, L, Raveendran, M, & Storey, A (2008). Granulosa cell survival and proliferation are altered in polycystic ovary syndrome. Journal of Clinical Endocrinology & Metabolism, 93(3), 881–887, https://doi.org/10.1210/jc.2007-1650. de Leo, V, Musacchio, M C, Cappelli, V, Massaro, M G, Morgante, G, & Petraglia, F (2016). Genetic, hormonal and metabolic aspects of PCOS: an update. Reproductive Biology and Endocrinology, 14(1), https://doi.org/10.1186/s12958-016-0173-x. Doi, S A R, Al-Zaid, M, Towers, P A, Scott, C J, & Al-Shoumer, K A S (2005). Irregular cycles and steroid hormones in polycystic ovary syndrome. Human Reproduction, 20(9), 2402–2408, https://doi.org/10.1093/humrep/dei093. Dröge, W (2002). Free radicals in the physiological control of cell function. Physiological Reviews, 82(1), 47–95, https://doi.org/10.1152/physrev.00018.2001. Duleba, A, Spaczynski, R Z, Olive, D L, & Behrman, H R (1997). Effects of insulin and insulin-like growth factors on proliferation of rat ovarian theca-interstitial cells. Biology of Reproduction, 56(4), 891–897. Duleba, A J, Foyouzi, N, Karaca, M, Pehlivan, T, Kwintkiewicz, J, & Behrman, H R (2004). Proliferation of ovarian theca-interstitial cells is modulated by antioxidants and oxidative stress. Human Reproduction, 19(7), 1519–1524, https://doi.org/10.1093/humrep/deh299. Eid, H, & Haddad, P (2017). The antidiabetic potential of quercetin: underlying mechanisms. Current Medicinal Chemistry, 24(4), 355–364. Erickson, G F, Magoffin, D A, Cragun, J R, & Chang, R J (1990). The effects of insulin and insulin-like growth factors-I and-II on estradiol production by granulosa cells of polycystic ovaries. Journal of Clinical Endocrinology and Metabolism, 70(4), 894–902. Faulds, G, Rydé N M, Ek, I, Wahrenberg, H, & Arner, P (2003). Mechanisms behind lipolytic catecholamine resistance of subcutaneous fat cells in the polycystic ovarian syndrome. The Journal of Clinical Endocrinology & Metabolism, 88(5), 2269–2273, https://doi. org/10.1210/jc.2002-021573.

Phytotherapeutic Intervention for Treatment of PCOS

85

Fernández-Mar, M I, Mateos, R, García-Parrilla, M C, Puertas, B, & Cantos-Villar, E (2012). Bioactive compounds in wine: resveratrol, hydroxytyrosol and melatonin: a review. Food Chemistry, 130(4), 797–813. Formica, J V, & Regelson, W (1995). Review of the biology of quercetin and related bioflavonoids. Food and Chemical Toxicology, 33(12), 1061–1080. Furat Rencber, S, Kurnaz Ozbek, S K, Eraldemır, C, Sezer, Z, Kum, T, Ceylan, S, & Guzel, E (2018). Effect of resveratrol and metformin on ovarian reserve and ultrastructure in PCOS: an experimental study. Journal of Ovarian Research, 11(1), 1–16, https://doi. org/10.1186/s13048-018-0427-7. Gambineri, A, Pelusi, C, Vicennati, V, Pagotto, U, & Pasquali, R (2002). Review obesity and the polycystic ovary syndrome. International Journal of Obesity, 26, 883–896, https:// doi.org/10.1038=sj.ijo=0801994. Gurav, M, Bhise, S, & Warghade, S (2018). Effect of quercetin on beta cell regeneration. Asian Journal of Pharmacy and Pharmacology, 4(2), 214–221, https://doi.org/10.31024/ ajpp.2018.4.2.19. Knochenhauer, E S, Key, T J, Kahsar-Miller, M, Waggoner, W, Boots, L R, & Azziz, R (1998). Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. The Journal of Clinical Endocrinology and Metabolism, 83(9), 3078–3082, https://academic.oup.com/jcem/ article/83/9/3078/2865186. Hanasaki, Y, Ogawa, S, & Fuku, S (1994). The correlation between active oxygens scavenging and antioxidative effects of flavonoids. Free Radical Biology & Medicine, 16(6) 845–850. Harman, D (1991). The aging process: major risk factor for disease and death. Proceedings of the National Academy of Sciences, 88(12), 5360–5363. Hillier, S G, Whitelaw, P F, & Smyth, C D (1994). Follicular oestrogen synthesis: the “twocell, two-gonadotrophin” model revisited. Molecular and Cellular Endocrinology, 100(1–2), 51–54. Hong, Y, Yin, Y, Tan, Y, Hong, K, Jiang, F, & Wang, Y (2018). Effect of quercetin on biochemical parameters in letrozole-induced polycystic ovary syndrome in rats. Tropical Journal of Pharmaceutical Research, 17(9), 1783–1788, https://doi.org/10.4314/tjpr. v17i9.15. Hotamisligil, G S, Peraldi, P, Budavari, A, Ellis, R, White, M F, Spiegelman, B M (1996). IRS-1 mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α and obesity-induced insulin resistance. Science, 271(5249), 665–670. Hughesdon, P E (1982). Morphology and morphogenesis of the Stein-Leventhal ovary and of so-called “hyperthecosis”. Obstetrical & Gynecological Survey, 37(2), 59–77. Iside, C, Scafuro, M, Nebbioso, A, & Altucci, L (2020). SIRT1 activation by natural phytochemicals: an overview. Frontiers in Pharmacology, 11, 1225, https://doi.org/10.3389/ fphar.2020.01225. Jahan, S, Abid, A, Khalid, S, Afsar, T, Ain, Q U, Shaheen, G, Almajwal, A, & Razak, S (2018). Therapeutic potentials of quercetin in management of polycystic ovarian syndrome using letrozole induced rat model: a histological and a biochemical study. Journal of Ovarian Research, 11(1), 1–10, https://doi.org/10.1186/s13048-018-0400-5. Jeong, S M, Kang, M J, Choi, H N, Kim, J H, & Kim, J I (2012). Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice. Nutrition Research and Practice, 6(3), 201–207, https://doi.org/10.4162/ nrp.2012.6.3.201. Jiang, H, Zhang, L, Kuo, J, Kuo, K, Gautam, S C, Groc, L, Rodriguez, A I, Koubi, D, Hunter, T J, Corcoran, G B, Seidman, M D, & Levine, R A (2005). Resveratrol-induced apoptotic death in human U251 glioma cells. Molecular Cancer Therapeutics, 4(4), 554–561, http://aacrjournals.org/mct/article-pdf/4/4/554/1870417/554-561.pdf.

86

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Joe, A K, Liu, H, Suzui, M, Vural, M E, Xiao, D, Weinstein, I B, & Of Medicine, D (2002). Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clinical Cancer Research, 8(3), 893–903, http://aacrjournals.org/clincancerres/article-pdf/8/3/893/2302892/ df0302000893.pdf. Joshi, B, Mukherjee, S, Patil, A, Purandare, A, Chauhan, S, & Vaidya, R (2014). A crosssectional study of polycystic ovarian syndrome among adolescent and young girls in Mumbai, India. Indian Journal of Endocrinology and Metabolism, 18(3), 317–324, https://doi.org/10.4103/2230-8210.131162. Kafali, H, Iriadam, M, Ozardali, I, & Demir, N (2004). Letrozole-induced polycystic ovaries in the rat: a new model for cystic ovarian disease. Archives of Medical Research, 35(2), 103–108, https://doi.org/10.1016/j.arcmed.2003.10.005. Khaki, A, Khaki, A A, Hajhosseini, L, Golzar, F S, & Ainehchi, N (2014). The anti-oxidant effects of ginger and cinnamon on spermatogenesis dys-function of diabetes rats. African Journal of Traditional, Complementary and Alternative Medicines, 11(4), https://doi. org/10.4314/ajtcam.v11i4.1. Kim, E C, Min, J K, Kim, T Y, Lee, S J, Yang, H O, Han, S, Kim, Y M, & Kwon, Y G (2005). [6]-Gingerol, a pungent ingredient of ginger, inhibits angiogenesis in vitro and in vivo. Biochemical and Biophysical Research Communications, 335(2), 300–308, https://doi. org/10.1016/j.bbrc.2005.07.076. Kim, J H, Kang, M J, Choi, H N, Jeong, S M, Lee, Y M, & Kim, J I (2011). Quercetin attenuates fasting and postprandial hyperglycemia in animal models of diabetes mellitus. Nutrition Research and Practice, 5(2), 107–111, https://doi.org/10.4162/nrp.2011.5.2.107. Krishnan, A, & Muthusami, S (2017). Hormonal alterations in PCOS and its influence on bone metabolism. Journal of Endocrinology, 232 (2), R99–R113, https://doi.org/10.1530/ JOE-16-0405. Landrault, N, Larronde, F, Delaunay, J C, Castagnino, C, Vercauteren, J, Merillon, J M, Gasc, F, Cros, G, & Teissedre, P L (2002). Levels of stilbene oligomers and astilbin in French varietal wines and in grapes during noble rot development. Journal of Agricultural and Food Chemistry, 50(7), 2046–2052. Lasa, A, Schweiger, M, Kotzbeck, P, Churruca, I, Simón, E, Zechner, R, & Portillo, M d P (2012). Resveratrol regulates lipolysis via adipose triglyceride lipase. Journal of Nutritional Biochemistry, 23(4), 379–384. Leventhal, M L (1958). The Stein-Leventhal syndrome. American Journal of Obstetrics and Gynecology, 76(4), 825–838, https://doi.org/10.1016/0002-9378(58)90019-X. Leventhal, M L, & Cohen, M R (1951). Bilateral polycystic ovaries the Stein syndrome. American Journal of Obstetrics and Gynecology, 61(5), 1034–1046, https://doi. org/10.1016/0002-9378(51)90305-5. Li, M, Chen, P-Z, Yue, Q-X, Li, J-Q, Chu, R-A, Zhang, W, & Wang, H (2013). Pungent ginger components modulate human cytochrome P450 enzymes in vitro. Acta Pharmacologica Sinica, 34(9), 1237–1242, https://doi.org/10.1038/aps.2013.49. Lin, D, Xiao, M, Zhao, J, Li, Z, Xing, B, Li, X, Kong, M, Li, L, Zhang, Q, Liu, Y, Chen, H, Qin, W, Wu, H, & Chen, S (2016). An overview of plant phenolic compounds and their importance in human nutrition and management of type 2 diabetes. Molecules, 21(10), 1374, https://doi.org/10.3390/molecules21101374. Linares, R, Hernández, D, Morán, C, Chavira, R, Cárdenas, M, Domínguez, R, & MoralesLedesma, L (2013). Unilateral or bilateral vagotomy induces ovulation in both ovaries of rats with polycystic ovarian syndrome. Reproductive Biology and Endocrinology, 11(1), 1–9, https://doi.org/10.1186/1477-7827-11-68. Macgregor, A H, Johnson, J E, & Bunde, C A (1968). Further clinical experience with clomiphene citrate. Fertility and Sterility, 19(4), 616–622.

Phytotherapeutic Intervention for Treatment of PCOS

87

Macut, D, Pfeifer, M, Yildiz, B O, & Diamanti-Kandarakis, E (eds) (2013). Polycystic Ovary Syndrome: Novel Insights into Causes and Therapy. Front Horm Res series. Basel: Karger, 2013, vol. 40, pp. 51–63. https://doi.org/10.1159/000342244Mamaghani, F, Zarghami, N, Maleki, M J, Moghaddam M, & Pourhassan F (2009). Variation of adiponectin levels in normal and obese subjects: possible correlation with lipid profiles. International Journal of Endocrinology and Metabolism, 7(3), 170–178. Mannerås-Holm, L, Leonhardt, H, Kullberg, J, Jennische, E, Odé, A, Ran Holm, G, Hellströ, M, Lö, L, Olivecrona, G, Stener-Victorin, E, & Lö, M (2011). Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. The Journal of Clinical Endocrinology & Metabolism, 96(2), E304–E311, https://doi. org/10.1210/jc.2010-1290. Mansour, A, Samadi, M, Sanginabadi, M, Gerami, H, Karimi, S, Hosseini, S, Shirzad, N, Hekmatdoost, A, Mahdavi-Gorabi, A, Mohajeri-Tehrani, M R, & Qorbani, M (2021). Effect of resveratrol on menstrual cyclicity, hyperandrogenism and metabolic profile in women with PCOS. Clinical Nutrition, 40(6), 4106–4112, https://doi.org/10.1016/j.clnu.2021.02.004. Maritim, A C, Sanders, R A, & Watkins, J B (2003). Diabetes, oxidative stress, and antioxidants: a review. Journal of Biochemical and Molecular Toxicology, 17(1), 24–38, https:// doi.org/10.1002/jbt.10058. Mihanfar, A, Nouri, M, Roshangar, L, & Khadem-Ansari, M H (2021a). Polyphenols: natural compounds with promising potential in treating polycystic ovary syndrome. Reproductive Biology, 21(2), 100500, https://doi.org/10.1016/j.repbio.2021. Mihanfar, A, Nouri, M, Roshangar, L, & Khadem-Ansari, M H (2021b). Therapeutic potential of quercetin in an animal model of PCOS: possible involvement of AMPK/SIRT-1 axis. European Journal of Pharmacology, 900, https://doi.org/10.1016/j.ejphar.2021.174062. Min, Y D, Choi, C H, Bark, H, Son, H Y, Park, H H, Lee, S, Park, J W, Park, E K, Shin, H I, & Kim, S H (2007). Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-κB and p38 MAPK in HMC-1 human mast cell line. Inflammation Research, 56(5), 210–215, https://doi.org/10.1007/s00011-007-6172-9. Moret, M, Stettler, R, Rodieux, F, Gaillard, R C, Waeber, G, Wirthner, D, Giusti, V, Tappy, L, & Pralong, F P (2009). Insulin modulation of luteinizing hormone secretion in normal female volunteers and lean polycystic ovary syndrome patients. Neuroendocrinology, 89(2), 131–139, https://doi.org/10.1159/000160911. Morley, L C, Tang, T, Yasmin, E, Norman, R J, & Balen, A H (2017). Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews, (11), 1465–1858. https://doi.org/10.1002/14651858.CD003053.pub6 Nejabati, H R, Samadi, N, Shahnazi, V, Mihanfar, A, Fattahi, A, Latifi, Z, Bahrami-asl, Z, Roshangar, L, & Nouri, M (2020). Nicotinamide and its metabolite N1-methylnicotinamide alleviate endocrine and metabolic abnormalities in adipose and ovarian tissues in rat model of polycystic ovary syndrome. Chemico-Biological Interactions, 324, 109093, https://doi.org/10.1016/j.cbi.2020.109093. Ortega, I, & Duleba, A J (2015). Ovarian actions of resveratrol. Annals of the New York Academy of Sciences, 1348(1), 86–96, https://doi.org/10.1111/nyas.12875. Ortega, I, Wong, D H, Villanueva, J A, Cress, A B, Sokalska, A, Stanley, S D, & Duleba, A J (2012). Effects of resveratrol on growth and function of rat ovarian granulosa cells. Fertility and Sterility, 98(6), 1563–1573. Pellatt, L, Hanna, L, Brincat, M, Galea, R, Brain, H, Whitehead, S, & Mason, H (2007). Granulosa cell production of anti-Müllerian hormone is increased in polycystic ovaries. The Journal of Clinical Endocrinology and Metabolism, 67(3), 460–464, https://doi. org/10.1210/jc.2006-1582.

88

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Pigny, P, Merlen, E, Robert, Y, Cortet-Rudelli, C, Decanter, C, Jonard, S, & Dewailly, D (2003). Elevated serum level of anti-mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. The Journal of Clinical Endocrinology & Metabolism, 88(12), 5957–5962, https://doi.org/10.1210/ jc.2003-030727. Piparva, K G, & Buch, J G (2011). Deep vein thrombosis in a woman taking oral combined contraceptive pills. Journal of Pharmacology & Pharmacotherapeutics, 2(3), 185. Plymate, S R, Matej, L A, Jones, R E, & Friedl, K E (1988). Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. The Journal of Clinical Endocrinology and Metabolism, 67(3), 460–464. Polska, E, Lewiński, A, Lewandowski, K C, Cajdler-Łuba, A, Salata, I, & Bieńkiewicz, M (2011). The utility of the gonadotrophin releasing hormone (GnRH) test in the diagnosis of polycystic ovary syndrome (PCOS). Endokrynologia Polska, 62(2), 120–128. Poretsky, L, Cataldo, N A, Rosenwaks, Z, & Giudice, L C (1999). The insulin-related ovarian regulatory system in health and disease. Endocrine Reviews, 20(4), 535–582, https://doi. org/10.1210/edrv.20.4.0374. Poretsky, L, Chandrasekher, Y A, Bai, C, Liu, H C, Rosenwaks, Z, & Giudice, L (1996). Insulin receptor mediates inhibitory effect of insulin, but not of insulin-like growth factor (IGF)-I, on IGF binding protein 1 (IGFBP-1) production in human granulosa cells. The Journal of Clinical Endocrinology & Metabolism, 81(2), 493–496, https://academic. oup.com/jcem/article/81/2/493/2649361. Pournaderi, P S, Yaghmaei, P, Khodaei, H, Noormohammadi, Z, & Hejazi, S H (2017a). The effects of 6-gingerol on reproductive improvement, liver functioning and cyclooxygenase-2 gene expression in estradiol valerate – induced polycystic ovary syndrome in Wistar rats. Biochemical and Biophysical Research Communications, 484(2), 461–466, https://doi.org/10.1016/j.bbrc.2017.01.057. Pourteymour Fard Tabrizi, F, Hajizadeh-Sharafabad, F, Vaezi, M, Jafari-Vayghan, H, Alizadeh, M, & Maleki, V (2020). Quercetin and polycystic ovary syndrome, current evidence and future directions: a systematic review. Journal of Ovarian Research, 13(1), 1–10, https:// doi.org/10.1186/s13048-020-0616-z. Qu, X, & Donnelly, R (2020). Sex hormone-binding globulin (Shbg) as an early biomarker and therapeutic target in polycystic ovary syndrome. International Journal of Molecular Sciences, 21, 1–17, https://doi.org/10.3390/ijms21218191. Rahmanian, F, Jahromi, V H K, & Kargar, H (2012). The effects of ginger hydroalcoholicextract on spermatogenesis process and hormone-pituitary-gonadal axis in immature mice. Journal of Natural Science, Biology and Medicine, 10(3), 915–922. Rai, S, Basheer, M, Ghosh, H, Acharya, D, & Hajam, Y A (2015) Melatonin attenuates free radical load and reverses histologic architect and hormone profile alteration in female rat: an in vivo study of pathogenesis of letrozole induced poly cystic ovary. Clinical & Cellular Immunology, 6, 1–8. Rani, R, Hajam, Y A, Kumar, R, Bhat, R A, Rai, S, & Rather, M A (2022) A landscape analysis of the potential role of polyphenols for the treatment of polycystic ovarian syndrome (PCOS). Phytomedicine Plus, 2(1), 100161. Rezvan, N, Moini, A, Janani, L, Mohammad, K, Saedisomeolia, A, Nourbakhsh, M, GorganiFiruzjaee, S, Mazaherioun, M, & Hosseinzadeh-Attar, M J (2017). Effects of quercetin on adiponectin-mediated insulin sensitivity in polycystic ovary syndrome: a randomized placebo-controlled double-blind clinical trial. Hormone and Metabolic Research, 49(2), 115–121, https://doi.org/10.1055/s-0042-118705.

Phytotherapeutic Intervention for Treatment of PCOS

89

Romero-Pérez, A I, Lamuela-Raventós, R M, Waterhouse, A L, & de La Torre-Boronat, M C (1996). Levels of cis-and trans-resveratrol and their glucosides in white and rosé Vitis vinifera wines from Spain. Journal of Agriculture and Food Chemistry, 44(8), 2124–2128. Rosenfield, R L, & Ehrmann, D A (2016). The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocrine Reviews, 35(5), 467–520. Ruderman, N B, Xu, X J, Nelson, L, Cacicedo, J M, Saha, A K, Lan, F, & Ido, Y. (2010). AMPK and SIRT1: a long-standing partnership? American Journal of Physiology Endocrinology Metabolism, 298, 751–760. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised (2003). Consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction. 2004 Jan; 19(1), 41–47. Sereepapong, W, Suwajanakorn, S, Triratanachat, S, Sampatanukul, P, Pruksananonda, K, Boonkasemsanti, W, & Reinprayoon, D (2000). Effects of clomiphene citrate on the endometrium of regularly cycling women. Fertility and Sterility, 73(2), 287–291. Shah, K N, & Patel, S S (2016). Pharmaceutical biology phosphatidylinositide 3-kinase inhibition: a new potential target for the treatment of polycystic ovarian syndrome. Pharmaceutical Biology, 54(6), 975–983, https://doi.org/10.3109/13880209.2015.1091482. Sharma, P, Hajam, Y A, Kumar, R, & Rai, S (2022) Complementary and alternative medicine for the treatment of diabetes and associated complications: a review on therapeutic role of polyphenols. Phytomedicine Plus, 2(1), 100188. Shikawa, A I, Amashita, H Y, Iemori, M H, Nagaki, E I, Imoto, M K, Kamoto, M O, Suji, H T, Nawaz, A, Emon, M, Ohammadi, A M, & Atori, Y N (2007). Characterization of inhibitors of postprandial hyperglycemia from the leaves of Nerium indicum. Journal of Nutritional Science and Vitaminology, 53(2), 166–173. Sovino, H, Sir-Petermann, T, & Devoto, L (2002). Clomiphene citrate and ovulation induction. Reproduction Biomedicine Online, 4(3), 303–310. Stelzer, G, Rosen, N, Plaschkes, I, Zimmerman, S, Twik, M, Fishilevich, S, Iny Stein, T, Nudel, R, Lieder, I, Mazor, Y, Kaplan, S, Dahary, D, Warshawsky, D, Guan-Golan, Y, Kohn, A, Rappaport, N, Safran, M, & Lancet, D (2016). The GeneCards suite: from gene data mining to disease genome sequence analyses. Current Protocols in Bioinformatics, 54(1), 1–30, 1.30.1–1.30.33, https://doi.org/10.1002/cpbi.5. Stervbo, U, Vang, O, & Bonnesen, C (2006). Time-and concentration-dependent effects of resveratrol in HL-60 and HepG2 cells. Cell Proliferation, 39(6), 469–493. Sun, K, Kusminski, C M, & Scherer, P E (2011). Adipose tissue remodeling and obesity. The Journal of Clinical Investigation, 121(6), 2094–2101, https://doi.org/10.1172/JCI45887. Tao, X, Cai, L, Chen, L, Ge, S, & Deng, X (2019). Effects of metformin and exenatide on insulin resistance and AMPKα-SIRT1 molecular pathway in PCOS rats. Journal of Ovarian Research, 12(1), 86, https://doi.org/10.1186/s13048-019-0555-8. Tasali, E, van Cauter, E, Hoffman, L, & Ehrmann, D A (2008). Impact of obstructive sleep apnea on insulin resistance and glucose tolerance in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 93(10), 3878–3884, https:// doi.org/10.1210/jc.2008-0925. Teede, H, Deeks, A, & Moran, L (2010). Open access review polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Medicine, 8(1), 1–10, http://www.biomedcentral.com/1741-7015/8/41.

90

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Veltman-Verhulst, S M, Boivin, J, Eijkemans, M J C, & Fauser, B J C M (2012). Emotional distress is a common risk in women with polycystic ovary syndrome: a systematic review and meta-analysis of 28 studies. Human Reproduction Update, 18(6), 638–651, https:// doi.org/10.1093/humupd/dms029. Wang, F, Yu, B, Yang, W, Liu, J, Lu, J, & Xia, X (2012). Polycystic ovary syndrome resembling histopathological alterations in ovaries from prenatal androgenized female rats. Journal of Ovarian Research, 5(1), 1–7, https://doi.org/10.1186/1757-2215-5-15. Wong, D H, Villanueva, J A, Cress, A B, & Duleba, A J (2010). Effects of resveratrol on proliferation and apoptosis in rat ovarian theca-interstitial cells. Molecular Human Reproduction, 16(4), 251–259, https://doi.org/10.1093/molehr/gaq002.

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Polycystic Ovarian Syndrome (PCOS) The “Green Healers” an Ayurvedic Eye Shikhar Deep, Ashvani Kumar Srivastav, Sangeeta Rai, and Radha Chaube Banaras Hindu University

CONTENTS 4.1 Introduction.....................................................................................................92 4.2 Etiology of Polycystic Ovary Syndrome......................................................... 93 4.3 Symptoms of Polycystic Ovary Syndrome......................................................94 4.4 Management of PCOS..................................................................................... 95 4.4.1 Allopathic Therapy.............................................................................. 95 4.4.1.1 Combined Oral Contraceptive Pills (COCPs)....................... 95 4.4.1.2 Clomiphene Citrate...............................................................96 4.4.1.3 Tamoxifen.............................................................................96 4.4.1.4 Metformin (Side Effects)......................................................96 4.4.1.5 Letrozole (Side Effects).........................................................96 4.4.2 Treatment of PCOS through Medicinal Plants and Herbs..................97 4.4.2.1 Mentha spicata (Spearmint).................................................97 4.4.2.2 Cinnamomum sp. (Cinnamon)..............................................97 4.4.2.3 Camellia sinensis (Green Tea)..............................................97 4.4.2.4 Aloe barbadensis (Aloe Vera)............................................... 98 4.4.2.5 Actaea racemosa (Black Cohosh).........................................99 4.4.2.6 Ocimum sp. (Holy Basil).......................................................99 4.4.2.7 Linum usitatissimum (Flaxseed)........................................ 100 4.4.2.8 Curcuma longa (Curcumin)................................................ 100 4.4.2.9 Vitex agnus-castus (Chaste Berry)..................................... 100 4.4.2.10 Sesamum indicum (Sesame Seeds)..................................... 101 4.4.2.11 Cucurbita pepo (Pumpkin Seeds)....................................... 102 4.4.2.12 Trigonella foenum (Fenugreek).......................................... 103 4.4.2.13 Trifolium pretense (Red Clover)......................................... 103 4.4.2.14 Foeniculum vulgare (Fennel Seeds)................................... 104 4.5 Conclusion..................................................................................................... 105 Bibliography........................................................................................................... 105 DOI: 10.1201/9781003344728-4

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4.1 INTRODUCTION Polycystic ovarian syndrome (PCOS) is an alarming endocrinopathy, which has certain biochemical and/or clinical manifestations, viz hyperandrogenism, oligo-/ anovulation, and polycystic ovarian morphology (PCOM). PCOM is defined as the presence of at least 12 antral follicles, each having a diameter ranging from 2 to 9 mm in the entire ovary and/or an ovarian volume of more than 10 mL (Paixao et al., 2017). According to the widely accepted criterion of PCOS classification, i.e., the Rotterdam criteria-2003 (Rotterdam, 2004), any patient bearing any two of the three manifestations is said to be suffering from PCOS (Hoffman et al., 2016; Yii et al., 2009). The prevalence of this syndrome ranges from 5% to 20% (Azzia et al., 2016) and the current incidence of occurrence of PCOS is increasing day by day due to the deteriorating lifestyle of the youth. It is very common in adolescence, soon after puberty. Also, its prevalence is so high that it is affecting two in every ten women in India as observed in a study conducted by the PCOS society (Khanage et al., 2019). PCOS is also referred to as Stein–Leventhal syndrome since it was first reported by them in 1935. Different criteria for diagnosing PCOS in adolescents have been suggested by Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group on the women’s health aspect of PCOS from those used for adults. According to its suggestion, all the essential elements of the Rotterdam criteria, wherein after 2 years of menarche/primary amenorrhea, oligomenorrhea ought to be present at 16 years of age, polycystic ovaries on ultrasonography, along with increased ovarian volume (>10 cm3), and hyperandrogenemia should be present (Fauser et al., 2012) (Figure 4.1). There seems to be a link between PCOS and autoimmune diseases since in these patients an increased prevalence of autoimmune thyroiditis, goiters, and antithyroid antibodies has been reported (Kachuei et al., 2012). According to recent reports, 50%–70% of PCOS patients are obese (Sunesh and Shaw, 2018). It has got several significant clinical implications including reproductive (hyperandrogenism, hirsutism, infertility), metabolic (impaired glucose tolerance, insulin resistance, type 2 diabetes mellitus, adverse cardiovascular risk profiles), and psychological features (increased anxiety and depression along with the worsened quality of life) (Himelein and Thatcher, 2006; Sharma et al., 2022). There occurs an increased risk of type II diabetes with the occurrence of PCOS (it has been reported that women suffering from PCOS have ten times greater risk of developing type II diabetes (Nidhi et al., 2011); one in five women have been found to develop diabetes before the age of 40 (Azziz et al., 2005)); gestational diabetes, hypertension, and gynecological cancers especially endometrial cancer (Williams et al., 2013; Yii et al., 2009). It stands out to be the most prevailing cause of anovulatory infertility (Gorry et al., 2006). PCOS has been linked to both genetic and environmental factors (Yii et al., 2009). Coming on to the inheritance pattern of PCOS, it is found to be a polygenic and autosomal-dominant disease. Moreover, PCOS is most likely to pass down between subfertile females and fertile carrier males (Azziz et al., 2011). It has been observed that in the offspring of women with PCOS, there occurs hyperinsulinemia, which is one of the associated clinical manifestations of the syndrome, long before the onset of puberty, thereby asserting the part of family history (Ibáñez et al., 2009).

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Drugs Usage

Genetic Predisposition

PCOS

Lethargic Lifestyle

Obesity

FIGURE 4.1  Pathogenic factors causing PCOS.

Secretion of leptin, adiponectin, and cytokines from the adipose tissues of obese patients results in the interference with the insulin signaling pathway, thereby leading to insulin resistance (IR) and hyperinsulinemia. Also, as a result of IR and the resulting increase in the insulin level, i.e., hyperinsulinemia, there occurs an increase in the GnRH pulse frequency, hence leading to an elevated LH/FSH ratio (Basheer et al., 2018; BurtSolorzano et al., 2012; Rai et al., 2015). Elevated LH secretion by insulin may cause infertility or miscarriage via improper oocyte maturation. In other words, in women suffering from PCOS, there occurs altered ovarian function, mainly because of hyperandrogenism and uplifted level of luteinizing hormone (LH) (Imani et al., 2002), thus resulting in multiple cysts (Frank et al., 2008). Hypothalamicpituitary-ovarian (HPO) axis and adrenal glands too have a role in the genesis of PCOS to some extent. With the help of biochemical studies, it has been found that women with PCOS have lower tyrosine levels; thus amino acids too have a role to play (Oliva et al., 2019).

4.2  ETIOLOGY OF POLYCYSTIC OVARY SYNDROME The exact cause of PCOS has not yet been determined. Still, hereunder are certain probable causative factors in the generation of PCOS:

1. Genetic predisposition 2. Hyperstimulated state of the adrenals in childhood 3. Elevated insulin level (hyperinsulinemia)

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4. Use of oral contraceptive pills 5. Hormonal disparity 6. Anxiety/stress/strain (Khanage et al., 2019) 7. Family history of infertility (Chakraborty, 2022) 8. Obesity 9. Unhealthy food habits (consumption of junk food) 10. Lack of exercise 11. Family history of PCOS 12. Exposure to endocrine disruptive chemicals (EDCs).

Usage of personal care products such as deodorants, hair dyes, perfumes, and other grooming ingredients, although seeming hygienic, are EDCs which are one of the main culprits behind the rising instances of PCOS (Boberg et al., 2010; Ozen and Darcan, 2011; Rani et al., 2022; Yang et al., 2015). Moreover, these days the cravings for canned and packaged foods have seemingly increased; these packaged products contain Bisphenol A (BPA), which gets accumulated over a long period of time, hence leading to reproductive issues such as PCOS, etc. (Coster and Larebeke, 2012; Konieczna et al., 2015; Noonan et al., 2011).

4.3  SYMPTOMS OF POLYCYSTIC OVARY SYNDROME The common symptom of PCOS is an-/oligo-ovulation. One of the major symptoms of PCOS is insulin resistance, which further leads to hyperinsulinemia and may lead to type II diabetes mellitus (Sirmans and Pate, 2013; Teede et al., 2010). Higher risk of early onset cardiovascular disease is also found in PCOS patients. Due to the altered sex-steroids levels, there are chances of development of “sleep apnea” (i.e., a sleep disorder characterized by repeated starts and stops in breathing) (Tasali et al., 2008) (Figure 4.2). As already mentioned, the clinical and/or biochemical manifestations of PCOS are as follows:

1. Hirsutism (abnormal hair growth on skin and face) 2. Acne 3. Absence of regular periods (Wijeyaratne et al., 2011) 4. Androgenic alopecia, i.e., male pattern baldness (Azziz et al., 2016) 5. Darkening of skin (Acanthosis nigricans) 6. Menstrual pain 7. Ovarian cysts (seen via ultrasonography) (Khanage et al., 2019) 8. Elevated androgen level in the blood serum (mainly testosterone and dihydrotestosterone) 9. Metabolic comorbidities.

One of the major etiologies of PCOS is hyperandrogenism. It can also result from several other reasons, such as late onset of congenital adrenal hyperplasia, hyperprolactinemia, hyperthecosis, Cushing’s syndrome, hypothyroidism, along with adrenal

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Endometrial Hyperplasia

Hyperandrog -enemia

PCOS

Infertility

Androgenic Alopecia

Hirsutism

Acne

FIGURE 4.2  Pathophysiologies associated with PCOS.

and ovarian tumors (especially androgen-secreting tumors). All of these come under the category of PCOS’ differential diagnosis (Fauser et al., 2012).

4.4  MANAGEMENT OF PCOS PCOS is not curable to date. The clinical treatments are just to govern the symptoms associated with PCOS. Presently, there are three management alternatives for PCOS, viz

1. Conventional allopathic remedies 2. Herbal/ayurvedic curatives 3. Lifestyle and dietary moderation.

4.4.1 Allopathic Therapy 4.4.1.1  Combined Oral Contraceptive Pills (COCPs) These is an amalgamation of estrogen and progesterone, which primarily aims at enhancing sex hormone binding globulin (SHBG) levels, which in turn decreases the free testosterone and ovarian androgen production (Moghetti and Toscano, 2006). The task force and endocrine society have recommended the usage of combined therapy with hormonal contraceptives to manage the long-term symptoms of PCOS, as in hyperandrogenism, amenorrhea, or other intricacies in the menstrual cycle (Cappelli et al., 2017). There are certain drugs that help instigate ovulation in PCOS patients. Some of them are mentioned in the following section.

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4.4.1.2  Clomiphene Citrate When ovulation-induction is taken into consideration, clomiphene citrate is thought to be the first line agent in this regard. It’s the prime choice of drug treatment. It is a nonsteroidal, ovulation-inducing, and antagonist of estrogen receptors. It stimulates FSH secretion from the pituitary, hence stimulating ovarian-follicles growth. It is the drug of choice since it is economical and with fewer side effects (at elevated doses, clomiphene citrate produces certain side effects, as in enhanced rate of multiple gestations, etc.) and requires less monitoring (Legro et al., 2007). 4.4.1.3 Tamoxifen It also causes ovarian stimulation by obstructing the estrogen receptors present in the hypothalamus. It is an alternative to clomiphene citrate (CC); also, the mechanism of action of tamoxifen is the same as that of CC (Dhaliwal et al., 2011). Certain aromatase inhibitors (Letrozole and anastrozole) are very potent in ovulation induction. There are some antidiabetic agents or insulin-sensitizing agents, as in metformin, triazolidinediones, pioglitazone (Actos, EliLilly), etc. are also used for ovulationinduction in patients suffering from PCOS. Bailareon et al. have shown that treatment with these insulin-sensitizing agents/drugs results in an increased ovulation frequency and also ameliorates hyperandrogenemia (a clinical manifestation of PCOS), that too in non-obese women with PCOS who seem to have normal insulin sensitivity. These allopathic drugs have got some side effects which are mentioned below: 4.4.1.4  Metformin (Side Effects) It is associated with initial gastrointestinal (GI)-disturbance, including diarrhea and nausea (Du et al., 2012). It carries a little risk of lactate acidosis (most common in women with imperfectly controlled diabetes and diminished/damaged renal function). Other side effects include: – Deficiency of Vitamin B12 (Kumthekar et al., 2012) – Peripheral neuropathy (Bell, 2010) – Hepatotoxicity (Miralles-Linares et al., 2012) Some other side effects associated with this drug are fatigue, dizziness, somnolence, muscular pain, breathing discomfort (labored breathing), bradycardia/arrhythemia, abdominal pain, nausea, etc. (Nasri and Rafieian-kopaei, 2014). Orlistat which inhibits lipase activity has been found to reduce fat absorption from the intestine. Also, it is correlated with BMI (Body Mass Index) reduction in women with PCOS, but there occurs controversies on the effect of orlistat on insulin sensitivity (Dimanti-Kandarakis et al., 2007). 4.4.1.5  Letrozole (Side Effects) On the administration of Letrozole, it was reported that letrozole’s administration to infertile women led to babies with congenital anomalies, especially cardiac and

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locomotor anomalies. Hence, its use is “off-label” in some countries for research purposes (Biljan et al., 2005; Kar, 2013). Hence, we have reported the side effects of only certain drugs, although there are many more to be enumerated, which is afar the scope of this chapter.

4.4.2 Treatment of PCOS through Medicinal Plants and Herbs 4.4.2.1  Mentha spicata (Spearmint) It belongs to the family Lamiaceae. It has been found that it has got an antiandrogenic effect, since after 1 month of its administration the total and free testosterone was found to be decreased. Also, it led to decrement in the degree of hirsutism (Grant, 2010) (Figure 4.3). 4.4.2.2  Cinnamomum sp. (Cinnamon) It belongs to the family Lauraceae. It has been found to ameliorate insulin sensitivity and also decrease insulin resistance. It does so by increasing PI3-K (phosphatidyl inositol 3-kinase) activity in the pathway involved in insulin signaling cascade (Figure 4.4). 4.4.2.3  Camellia sinensis (Green Tea) Belonging to the family of Theaceae, green tea has a variety of beneficial roles to play, as in; it is used as a herbal remedy for weight loss, it modulates the level of

FIGURE 4.3  Mentha spicata (spearmint): (a) flowers and (b) leaves (Muhhamad et al., 2018).

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gonadotropins, and helps to reduce insulin resistance. It also improves ovarian morphology and reduces ovarian cysts (Ghafurniyan et al., 2015). It has been found that potent antioxidants present in the green tea called catechins are accountable for lowering the levels of hormones, responsible for the genesis of ovarian cysts and related manifestations (Figure 4.5). 4.4.2.4  Aloe barbadensis (Aloe Vera) It belongs to the family Liliaceae. Aloe vera gel formulation has been reported to exert a protective role against PCOS, and it is performed via alteration in the steroidogenic activity since aloe vera gel acts directly on steroidogenic enzymes like3βHSD and 17βHSD. It basically decreases their activities, thereby driving the way toward estradiol formation. Not only this, aloe vera gel has been found to include

FIGURE 4.4  Cinnamomum sp. (cinnamon) (Khanage et al., 2019).

FIGURE 4.5  Camellia sinensis (green tea).

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phytosterols and phytophenols, which are assumed to be the active components in the control of hyperglycemic condition and in the modulation of the steroidogenic pathway (Ghagane et al., 2022; Khanage et al., 2019; Zeng et al., 2022) (Figure 4.6). 4.4.2.5  Actaea racemosa (Black Cohosh) Black cohosh belongs to the buttercup family. It has been found to have a powerful endocrine effect. This is so because it contains certain phytochemicals which help in the suppression of LH (luteinizing hormone) secretion. It has also been found to be useful in the management of hormonal disturbances such as mood swings, excessive menstrual cramps, and menopause (PMS) (Dehghan et al., 2012). It has also been reported that black cohosh has a role in inducing ovulation in women with PCOS (Bency et al., 2016). In pristine times Actaea racemosa was well known to be the women’s medication associated with parturition and the menstrual cycles. It was found to be efficacious in treating amenorrhe, leucorrhea, dysmenorrhea, and other menstrual and uterine conditions (Shari, 2009). There are certain side effects associated with this herb, such as gastrointestinal issues, muscle pain, headache, dizziness, and vaginal spotting (Figure 4.7). 4.4.2.6  Ocimum sp. (Holy Basil) It belongs to the family Lamiaceae. It is bestowed with excellent antioxidant property. Tulsi has been found to have antiandrogenic properties which are effective in the treatment of PCOS. It also moderates the insulin level and is hence helpful in diabetes management as well (Khanage et al., 2019). It is also used in opposition to

FIGURE 4.6  Aloe barbadensis (aloe vera).

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numerous ailments and holds promising results in the management of obesity and its related comorbidities (Satpathy et al., 2016) (Figure 4.8). 4.4.2.7  Linum usitatissimum (Flaxseed) As member of the Linaceae family, its powder has been associated with promising impacts on PCOS patients. It results in reducing androgen levels and hirsutism. Also, a significant improvement is found in reduction of obesity and insulin and serum concentration of free and bound testosterone (Nowak et al., 2007) (Figure 4.9). 4.4.2.8  Curcuma longa (Curcumin) Curcumin belongs to the Zingiberaceae family. Curcumin’s effect is akin of clomiphene citrate’s (CC) action, extensively used for the purpose of ovulation induction in patients suffering from PCOS (Khanage et al., 2019). Not only this, it causes a decrement in the androgen level (Figure 4.10). 4.4.2.9  Vitex agnus-castus (Chaste Berry) Belonging to the family Lamiaceae, it has got a prominent role in the stimulation and stabilization of the functions of the hypophysis (pituitary) and a promising effect

FIGURE 4.7  Actaea racemosa (black cohosh) (Khanage et al., 2019).

FIGURE 4.8  Ocimum sp. (holy basil).

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FIGURE 4.9  Linum usitatissimum (flaxseed) (Khanage et al., 2019).

FIGURE 4.10  Curcuma longa (curcumin).

on amenorrhea, anovulation, and pelvic pain, which are the symptoms of PCOS. Since time immemorial, it has been used for the treatment of hormonal regulation/­ imbalances (Goswami et al., 2012; Westphal et al., 2006). It is not affiliated with significant side effects but it has been reported to cause dizziness, stomach issues, and rashes. It is not advisable for pregnant women, or for women who are taking birth control pills, since it affects the hormones (Khanage et al., 2019) (Figure 4.11). 4.4.2.10  Sesamum indicum (Sesame Seeds) It belongs to the Pedaliaceae family. The black seeds of sesame have been found to cause a decrement in the level of testosterone, an increment in insulin absorption, and also aid in the regulation of menstruation. Its fats are healthy and aid in the regulation of serum glucose concentration. Alongwith this, it also holds certain minerals,

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such as zinc, calcium, magnesium, abundant lignans, vitamins B1 and B6, and ­phytosterols – all of which help in the proper balance of the hormones (Ghasemzadeh et al., 2013; Goswami et al., 2012) (Figure 4.12). 4.4.2.11  Cucurbita pepo (Pumpkin Seeds) It belongs to the Cucurbitaceae family. One of the symptoms of PCOS is dyslipidemia. So for this particular symptom, one of the treatment options can be the use of pumpkin seeds since it is a good source of omega-3 fatty acids which aid in the management of high cholesterol and also manages the elevated level of insulin (hyperinsulinemia), prevalent in the patients with PCOS. It additionally contains beta-sitosterol which is responsible for the removal of excess androgens (testosterone) and also for the treatment of acne, hirsutism, and weight gain, which are the clinical manifestation of PCOS (Reddy et al., 2016; Szczuko et al., 2017) (Figure 4.13).

FIGURE 4.11  Vitex agnus-castus (chaste berry) (Khanage et al., 2019).

FIGURE 4.12  Sesamum indicum (sesame seeds) (Khanage et al., 2019).

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4.4.2.12  Trigonella foenum (Fenugreek) It has been reported that fenugreek (belonging to the Fabaceae family) has got antidiabetic and cholesterol-reducing effects and lowers insulin resistance in PCOS patients (Hassanzatech et al., 2013). There are certain soluble fibers present in fenugreek, which help decrease the blood glucose level (postprandial) by reducing the enzymatic digestion and absorption of carbohydrates (Hassanzatech et al., 2013; Swaroop et al., 2015). On the administration of fenugreek on premenopausal women, it was reported that there occurred 46% decrement in cyst size as well as 71% of the women with irregular periods reverted to the normal (regular) menstrual cycle (Swaroop et al., 2015). Hence, its use is recommended for women with polycystic ovarian morphology and irregular menstrual cyclicity (Hassanzatech et al., 2013; Swaroop et al., 2015) (Figure 4.14). 4.4.2.13  Trifolium pretense (Red Clover) It belongs to the family Fabaceae. Because of its detoxifying properties, it is used for blood purification and for the treatment of acne, which is one of the symptoms of

FIGURE 4.13  Cucurbita pepo (Khanage et al., 2019).

FIGURE 4.14  Trigonella foenum (fenugreek).

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PCOS. The main component of red clover is its phytochemical isoflavones, because of which it is used for its medicinal activity (Holden et al., 2014). It has also been found to increase the level of progesterone in the body. There is certain aftermath associated with the use of this herb, which is muscular spasm, cephalalgia, puke, occasional vaginal bleeding, rashes, nausea, etc. Also, its utilization must circumvent in certain conditions, such as endometriosis, ovarian cancer, breast cancer, or in cases of pregnant/breast-feeding females. This is so because this herb increases the progesterone level which might deteriorate the above mentioned conditions (Abbasian and Ghanbari, 2017) (Figure 4.15). 4.4.2.14  Foeniculum vulgare (Fennel Seeds) It belongs to the Apiaceae family. Fennel is regarded as a phytoestrogen (Karampoor et al., 2014; Sadrefozalayi and Farokhi, 2014). Its traditional use suggests using in the treatment of anovulation/infertility. Apart from this, it has got a significant potential to treat PCOS, because of its antioxidant, anti-inflammatory, antihirsutism, antiandrogenic, and estrogenic properties (Karampoor et al., 2014; Khanage et al., 2019; Zeng et al., 2022) (Figure 4.16).

FIGURE 4.15  Trifolium pretense (red clover) (Khanage et al., 2019).

FIGURE 4.16  Foeniculum vulgare (fennel seeds).

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4.5 CONCLUSION Nowadays, PCOS is becoming a prevalent disorder, with lifetime complications in the women of reproductive age. Since PCOS is a complex disorder and its severity varies in different individuals, the treatment should be tailored according to the symptoms faced by the patient. Also, there are certain comorbidities associated with PCOS, i.e., there are increased chances of developing cardiovascular diseases and hypertension apart from the regular symptoms such as anovulation and infertility. When it comes to the use of herbal remediation, it can be contemplated to have good effects in the evolution of efficacious therapeutic agents for treating PCOS. There are certain healthy practices that can be adopted in the daily routine in order to avoid conditions like PCOS, such as making certain lifestyle changes, as in regular exercising, having a balanced and healthy diet, abstaining from too much of dairy products and junk food, making efforts to lose weight, and improving the insulin sensitivity. Also, in case of markedly obese individuals, for sustained weight loss, bariatric surgery is the best choice. Since there are numerous aftermath of allopathic medicines, these days the trend to use natural antioxidants and anti-inflammatory agents, which help in the regulation of metabolism, hyperinsulinemia, and dyslipidemia, which are the common comorbidities associated with PCOS, has increased. There are certain medications which are used to regulate the menstrual cycles, embolden ovulation and insulin resistance, hyperandrogenism, and obesity-associated PCOS. The medicinal plants which have been reviewed in this chapter have got multidimensional beneficial effects on the polycystic ovarian syndrome, including hyperandrogenism, insulin resistance, oligo/amenorrhea, and obesity. Hence, more preclinical and clinal studies are expected to explore the ascendency of herbal medicines in PCOS. This chapter helps understand the effectiveness of medicinal plants for better treatment and management of the polycystic ovarian syndrome.

BIBLIOGRAPHY Abbasian Z. and Ghanbari A. “Hydroalcoholic extract of red clove (Trifolium pretense) improves hormonal balances after induction of polycystic ovary syndrome in rats.” In 22 nd National Congress on Medica basic Sciences and Knowledge based Production (Iran: Iran’s Scientific Community Laboratory, 2017). Alu’datt M. H., Rababah T., Alhamad M. N., Gammoh S., Al-Mahasneh M. A., Tranchant C. C, and Rawshdeh M. “Pharmaceutical, nutraceutical and therapeutic properties of selected wild medicinal plants: Thyme, spearmint, and rosemary.” In Therapeutic, Probiotic, and Unconventional Foods, pp. 275–290. Academic Press, 2018. Azziz R., Carmina E., Chen Z. et al. “Polycystic ovary syndrome”, Nat. Rev. Disease Primers. (2016): 2: 16057. https://doi.org/10.1038/nrdp.2016.57. Azziz R., Dumesic D. and Goodarzim M. “Polycystic ovary syndrome: an ancient disorder?”, Fertil. Steril. (2011): 95: 1544–1548. https://doi.org/10.1016/j.fertnstert.2010.09.032. Azziz R., Martin C., Hoq I., Badamgaray E. and Song P. “Health care related economic burdeof the polycystic ovary syndrome during the reproductive life span”, J. Clin. Endocrinol. Meta. (2005): 90(8): 4650–4658. https://doi.org/10.1210/jc.2005-0628. Basheer, M., Rai, S., Ghosh, H. and Hajam, Y. A. “Protective role of seed extract of Tephrosia purpurea in letrozole induced polycystic ovary syndrome in wistar rats.” J. Biol. Sci. (2018): 18(8): 458–467.

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Bell D. S. “Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy”, South. Med. J. (2010): 103: 265–267. https://doi.org/10.1097/ SMJ.0b013e3181ce0e4d. Bency B. T., Smitha R., Remya K., Shebina R. P. and Azeem A. K. “Polycystic ovarian syndrome: therapeutic potential of herbal remedies - a review”, Int. J. Herb. Med. (2016): 4(5): 91–96. Biljan M. M., Hemmings R. and Brassard N. “The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins”, Fertil. Steril. (2005): 84: 595. https://doi.org/10.1016/j.fetnstert.2005.07.230. Boberg J., Tazvig C., Christiansen S. and Hass U. “Possible endocrine disrupting effects of parabens and their metabolites”, Reprod. Toxicol. (2010): 30: 301–312. https://doi. org/10.1016/j.reprotox.2010.03.011. BurtSolorzano C. M., Beller J. P., Abshire M. Y., Collins J. S., McCartney C. R. and Marshall J. C. “Neuroendocrine dysfunction in polycystic ovary syndrome”, Steroids (2012): 77(4): 332–337. Cappelli V., Musacchio M. C., Bulfoni A., Morgante G. and De Leo V. “Natural molecules for the therapy of hyperandrogenism and metabolic disorders in PCOS”, Eur. Rev. Med. Pharmacol. Sci. (2017): 21(2 suppl. 1): 15–29. Chakraborty K. “Therapeutic implication of Aloe barbadensis Mill. (aloe vera) for the management of polycystic ovarian syndrome (PCOS): a systematic review”. J. Biochem. Int. (2022): 9(1): 22–26. Coster S. D. and Larebeke N. V. “Endocrine-disrupting chemicals: associated disorders and mechanisms of action”, J. Environ. Public Health. (2012): 713696. https://doi. org/10.1155/2012/713696. Dehghan A., Esfandiari A. and Bigdeli S. M. “Alternative treatment of ovarian cysts with Tribulus terrestris extract: a rat model”, Reprod. Domest. Anim. (2012): 47(1): 12–15. https://doi.org/10.1111/j.1439-0531.2011.01877.x. Dhaliwal L. K., Suri V., Gupta K. R. and Sahdev S. “Tamoxifen: an alternative ot clomiphene in women with polycystic ovary syndrome”, J. Hum. Reprod. Sci. (2011): 4(2): 76–79. https://doi.org/10.4103/0974-1208.86085. Dimanti-Kandarakis E., Katsikis I., Piperi C., Alexandraki K. and Panidis, D. “Effects of longterm orlistat treatment on serum levels of advanced glycation end products in women with polycystic ovary syndrome”, Clin. Endocrinol. (2007): 66: 103–109. https://doi. org/10.1111/j.1365-2265.2006.02693.x. Du Q., Wang Y. J., Yang S. et al. “A systematic review and meta-anlysis of randamized controlled trials comparing pioglitazone versus metformin in the treatment of polycystic ovary syndrome”, Curr. Med. Res. Opin. (2012): 28(5): 723–730. https://doi.org/10.118 5/03007995.2012.681636. Fauser B. C. J. M., Tarlatzis B. C. and Rebaretal R. W. “Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-sponsored 3rd PCOS Consensus Workshop Group”, Fertil. Steril. (2012): 97(1): 28.e25–38.e25. https:// doi.org/10.1016/j.fertnstert.2011.09.024. Frank S., Stark J. and Hardy K. “Follicle dynamics and anovulation in polycystic ovary syndrome”, Hum. Reprod. Update. (2008): 14(4): 367–378. https://doi.org/10.1093/ humupd/dmn015. Ghafurniyan H., Azarnia M., Nabinni M. and Karimzadeh L. “The effect of green tea extract on reproductive improvement in estradiol volerate-induced polycystic ovarian syndrome in rat”, Iran. J. Phanr. Res. (2015): 14(4): 1215–1233. Ghagane S. C., Toragall M. M., Akbar A. and Hiremath M. “Effect of aoe vera (Barbadensis mill) on letrozole induced polycystic ovarian syndrome in Swiss Albino mice”, J. Hum. Reprod. Sci. (2022): 15(2): 126–132. https://doi.org/10.4103/jhrs.jhrs_22_22.

PCOS—The “Green Healers”

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Ghasemzadeh A., Farzadi L., Khari A. and Ahmadi S. K. “Effect of Allium cepa seeds ethanolic extract on experimental polycystic ovary syndrome (PCOS) apoptosis induced by estradiol-valerate”, Life Sci. (2013): 10(suppl. 4): 170–175. Gorry A., White D. M. and Franks, S. “Infertility in polycystic ovary syndrome”, Endocrine. (2006): 30(1): 27–33. https://doi.org/10.1385/ENDO:30:1:27. Goswami P. K., Khale A. and Ogale S. “Natural remedies for polycystic ovarian syndrome (PCOS): a review”, Int. J. Pharm. Phytopharm. Res. (2012): 1(6): 396–402. Grant P. “Spearmint herbal tea has significant anti-androgen effects in polycystic ovarian syndrome. A randomized controlled trial”, Phytother. Res. (2010): 24(2): 186–188. https:// doi.org/10.1002/ptr.2900. Hassanzatech B. M., Emani S. A., Mousavifar N., Esmaily H. A., Mahmoudi M. and Mohammad P. A. H. “Evaluation of fenugreek (Trigonella foenum-graceum L.), effects seeds extraction on insulin resistanc on women with polycystic ovarian syndrome”, Iran. J. Pharm. Res. (2013): 12(2): 475–484. Himelein M. J. and Thatcher S. S. “Depression and body image among women with polycystic ovary syndrome”, J. Health Psychol. (2006): 11(4): 613–625. https://doi. org/10.1177/1359105306065021. Hoffman B. L., Schorge J.O., Bradshaw K. D., Halvorson L. M., Schaffer J. I. and Corton M.M. (Eds.). Williams Gynecology, 3e. McGraw Hill, 2016. https://obgyn.mhmedical. com/content.aspx?bookid=1758§ionid=118165489 Holden S., Davis R. and Yeh G. “Pregnant women’s use of complementary & alternative medicine in the United State”, J. Alter. Compl. Med. (2014): 20(5): 120–129. https://doi. org/10.1089/acm.2014.5319. Ibáñez L., Díaz R., López-Bermejo A. and Marcos M. V. “Clinical spectrum of premature pubarche: links to metabolic syndrome and ovarian hyperandrogenism”, Rev. Endocr. Metab. Disord. (2009): 10(1): 63–76. https://doi.org/10.1007/s11154-008-9096. Imani B., Eijkemans M. J. C., TeVelde E. R. and Fauser B. C. J. M. “A nomogram to predict the probability of live birth afer clomiphene citrate induction of ovulation in normogonadotropicoligoamenorrheicinfertility”, Fertil. Steril. (2002). https://doi.org/10.1016/ S0015-0282(01)02929-6. Kachuei M., Jafari F., Kachuei A. and Keshteli A. H. “Prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome”, Arch. Gynecol. Obstet. (2012): 285: 863–856. https://doi.org/10.1007/s00404-011-2040-5. Kar S. “Current evidence supporting “letrozole” for ovulation induction”, J. Hum. Reprod. Sci. (2013): 6: 93–98. https://doi.org/10.4103/0974-1208.117166. Karampoor P., Azarnia M., Mirabolghasemi G. and Alizadeh F. “The effect of hydroalcoholic exract of fennel (Foeniculum vulgare) seed on serum levels of sexual hormones in female wistar rats with polycystic ovarian syndrome (PCOS)”, J. Arak Univ. Med. Sci. (2014): 17(5): 70–78. Khanage S. G., Subhash T. Y. and Bhaiyyasaheb I. R. “Herbal drugs for the treatment of polycystic ovary syndrome (PCOS) and its complications”, Pharm. Res. (2019): 2(1): 5–13. Konieczna A., Rutkowska A. and Rachon D. “Health risk of exposure to bisphenol A (BPA)”, Rocz. PanstwowegoZakladuHig. (2015): 66: 5–11. Kumthekar A. A., Gidwani H. V. and Kumthekar A. B. “Metformin associated B12 deficiency”, J. Assoc. Physicians India. (2012): 60: 58–60. Legro R. S., Barnhart H. X., Schlaff W. D., et al. “Clomiphene, metformain, or both for infertilityl in the polycystic ovary syndrome”, N. Engl. J. Med. (2007): 356: 551–566. https:// doi.org/10.1056/NEJMoa063971. Miralles-Linares, F., Puerta-Fernandez, S., Bernal-Lopez, M. R., Tinahones, F. J., Andrade, R. J. and Gomez-Huelgas, R. “Metformin-induced hepatotoxicity”, Diabetes Care (2012): 103: 265–267. https://doi.org/10.2337/dc11-2306.

108

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Moghetti P. and Toscano V. “Treatment of hirsutism and acne in hyperandrogenism”, Best. Pract. Res. (2006): 20: 221–234. https://doi.org/10.1016/j.beem.2006.03.003. Nasri H. and Rafieian-kopaei M. “Metformin: current knowledge”, J. Res. Med. Sci. (2014): 19: 658–664 (Accessed 17 February 2015). Nidhi R., Padmalatha V., Nagarathn, R. and Amritanshu R. “Prevalence of polycystic ovarian syndrome in Indian adolescents”, J. Pediatr. Adolesc. Gynecol. (2011): 24(4): 223–227. https://doi.org/10.1016/j.jpag.2011.03.002. Noonan G. O., Ackerman L. K. and Begley T. H. “Concentration of bisphenol A in highly consumed canned foods on the U. S. Market”, J. Agric. Food Chem. (2011): 59: 7178–7185. https://doi.org/10.1021/jf201076f. Nowak D. A., Snyder, D. C., Brown, A. J. and Demark-Wahnefried, W. “The effect of flaxseed supplementation on hormonal levels associated with polycystic ovarian syndrome: a case study”, Curr. Top. Nutraceutical Res. (2007): 5(4): 177–181. Oliva M. M., Zuev V., Lippa A., Carra M. C. and Lisi F. “Efficacy of the synergic action of myoinositol, tyrosine, selenium and chromium in women with PCOS”, Eur. Rev. Med. Pharm. Sci. (2019): 23: 8687–8694. https://doi.org/10.26355/eurrev_201910_19186. Ozen S. and Darcan S. “Effects of environmental endocrine disruptors on pubertal development”, J. Clin. Res. Pediatr. Endocrinol. (2011): 3: 1–6. https://doi.org/10.4274/jcrpe. v3i1.01. Paixao L., Ramos R. B., Lavarda A., Morsh D. M. and Spritzer P. M. “Animal models of hyperandrogenism and ovarian morphology changes as features of polycystic ovary syndrome: a systematic review”, Reprod. Biol. Endocrinol. (2017): 15(10): 12. https://doi. org/10.1186/s12958-017-0231-z. Rai, S., Basheer, M., Ghosh, H., Acharya, D. and Hajam, Y. A. “Melatonin attenuates free radical load and reverses histologic architect and hormone profile alteration in female rat: an in vivo study of pathogenesis of letrozole induced poly cystic ovary”, Clin. Cell. Immunol. (2015): 6: 1–8. Rani, R., Hajam, Y. A., Kumar, R., Bhat, R. A., Rai, S. and Rather, M. A. “A landscape analysis of the potential role of polyphenols for the treatment of polycystic ovarian syndrome (PCOS)”, Phytomed. Plus. (2022): 2(1): 100161. Reddy S. P., Nazia B., Sumith M. and Bakshi V. “Beneficial effect of curcumin in letrozole induced polycystic ovary syndrome”, Asian Pac. J. Repr. (2016): 5(2): 116–122. https:// doi.org/10.1016/j.apjr.2016.01.006. Rotterdam ESHRE/ASRM – Sponsored PCOS Consensus Workshop. “Revised 2003 consensus on diagnostic criteria and long-term health risks related to polyucystic ovary syndrome (PCOS)”, Hum. Reprod. (2004): 19: 41–47. https://doi.org/10.1093/humrep/ deh098. Sadrefozalayi S. and Farokhi F. “Effect of the aquous extract of Foeniculum vulgare (fennel) on the kidney in experimental PCOS female rats”, Avicenna J. Phytomed. (2014): 4(2): 110–117. Satpathy S., Das N., Bandyopadhyay D., Mahapatra S. C., Sahu D. S. and Meda M. “Effect of tulsi (Ocimum sanctum Linn.) supplementation on metabolic parameters and liver enzymes in young overweight and obese subjects”, Ind. J. Clin. Biochem. (2016). https:// doi.org/10.1007/s12291-016-0615-4.. Shari L. “A review of the effectiveness of Cimicifuga racemosa (Black cohosh) for the symptoms of menopause”, J. Women’s Health. (2009): 7(5): 525–529. Sharma, P., Hajam, Y. A., Kumar, R. and Rai, S. “Complementary and alternative medicine for the treatment of diabetes and associated complications: a review on therapeutic role of polyphenols”, Phytomed. Plus. (2022): 2(1): 100188. Sirmans S. M. and Pate K. A. “Epidemiology, diagnosis, and management of polycystic ovary syndrome”, Clin. Epidemiol. (2013): 6: 1–13. https://doi.org/10.2147/CLEP.S37559.

PCOS—The “Green Healers”

109

Sunesh Kumar H. and Shaw B. Textbook of Gynaecology, Seventeenth Edition, Kumar S., Padubidri V. G. & Daftary, S. N. (Eds.) (New Delhi: Elsevier, 2018): 314. Swaroop A., Jaipuriar A. S., Gupta S. K., Bagchi M., Kumar P., Presuss H. G., et al. “Efficacy of a novel tenugreek seed extract (Trigonella foenum-graecum, Furocyst TM) in polycystic ovary syndrome (PCOS)”, Int. J. Med. Sci.(2015): 12(10): 825–31. https://doi. org/10.7150/ijms.13024. Szczuko M., Zapalowska-chwyc M., Maciejeswska D., Drozd A., Starczewski A. and Stachowska E. “Significant improvement of selected mediators of inflammation in phenotypes of women with PCOS after reduction and low GI diet”, Mediat. Inflamm. (2017): 5489523. https://doi.org/10.1155/2017/5489523. Tasali E., Van Cauter E. and Ehrmann D. A. “Polycystic ovary syndrome and obstructive sleep apnea”, Sleep Med. (2008): 3: 37–46. https://doi.org/10.1016/j.jsmc.2007.11.001. Teede H., Deeks L., Moran E., Diamanti-Kandarakis C., Kouli A., Bergiele et al. “Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan”, BMC Med. (2010): 8: 41. https://doi.org/10.1186/1741-7015-8-41. Wang J. G. and Anderson R. A. “The effect of cinnamon extract on insulin resistance parameters in polycystic ovary syndrome: a pilot study”, Fertil. Steril. (2007): 88(1): 240–243. https://doi.org/10.1016/j.fertnstert.2006.11.082. Westphal L. M., Polan M. L. and Trant, A. S. “Double-blind, placebo-controlled study of fertility blend: a nutritional supplement for improving fertility in women”, Clin. Exp. Obstet. Gynecol. (2006): 33(4): 205–208. Wijeyaratne C. N., Seneviratne R. D. A., Dahanayakeetal S. “Phenotype and metabolic profile of South Asian women with polycystic ovary syndrome (PCOS): results of a large database from a specialist endocrine clinic”, Hum. Reprod. (2011): 26(1): 202–213. https:// doi.org/10.1093/humrep/deq310. Williams R. M., Ong K. K. and Dunger D. B. “Polycystic ovarian syndrome during puberty and adolescence”, Mol. Cell. Endocrinol. (2013): 373(1): 61–67. https://doi.org/10.1016/j. mce.2013.01.005. Yang O., Kim H. L., Weon J. I., Seo Y. R. “Endocrine-disrupting chemicals: review of toxicological mechanisms using molecular pathway analysis”, J. Cancer Prev. (2015): 20: 12–24. https://doi.org/10.15430/JCP.2015.20.1.12. Yii M. F., Lim C. E. D., Luo X., Wong W. S. F., Cheng N. C. L. and Zhan X. “Polycystic ovarian syndromeinadolescence”, Gynecol. Endocrinol. (2009): 25(10): 634–639. https:// doi.org/10.1080/09513590903015551. Zeng L. H., Rana S., Hussain L., Asif M., Mehmood M. H., Imran I., Younas A., Mandy A., Joufi F. A. and Abed S. N. “Polycystic ovary syndrome: a disorder of reproductive age, its pathogenesis, and a discussion on the emerging role of herbal remedies”, Front. Pharmacol. (2022): 13 Article 874914: 1–16. https://doi.org/10.3389/fphar.2022.874914.

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Concept of Polycystic Ovarian Syndrome Anti-PCOS Plants in the Unani System of Medicines Neha Salaria, Indu Kumari, Neeraj, Diksha Pathania, and Rajesh Kumar Arni University

CONTENTS 5.1 Introduction................................................................................................... 112 5.2 Brief Account on PCOS................................................................................. 114 5.3 Principles of Unani Medicine........................................................................ 116 5.3.1 Arkan or Anasir (Element)................................................................ 116 5.3.2 Mizaj (Temperament)........................................................................ 116 5.3.3 Akhlat (Humors-Body Fluids)........................................................... 116 5.3.4 Aaza (Organs).................................................................................... 117 5.3.5 Arwah (Spirits).................................................................................. 117 5.3.6 Quwa.................................................................................................. 117 5.3.7 Afa’l (Functions)................................................................................ 117 5.4 Different Plants and Their Utilization in Unani Medicine System............... 118 5.4.1 Melissa officinalis.............................................................................. 118 5.4.2 Azadirachta indica............................................................................ 120 5.4.3 Abrusprecatorius............................................................................... 120 5.4.4 Tephrosia purpurea........................................................................... 120 5.4.5 Trigonella foenum-graecum.............................................................. 120 5.4.6 Linumusitatissimum.......................................................................... 121 5.4.7 Mentha spicata.................................................................................. 121 5.4.8 Cinnamomum zeylanicum................................................................. 121 5.4.9 Camellia sinensis............................................................................... 122 5.4.10 Nigella sativa..................................................................................... 122 5.5 Challenges in the System of Unani Medicines.............................................. 122 5.6 Conclusion..................................................................................................... 124 Bibliography........................................................................................................... 124

DOI: 10.1201/9781003344728-5

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5.1 INTRODUCTION Since ancient times, the Unani System of Medicine has provided promotive, preventative, and curative healthcare (Naaz and Noman, 2016). This is based on plant, animal, and mineral-derived medicine compounds. More than a thousand medicines from all three natural sources are described alphabetically in the text of Advia (pharmacology) (Ansari and Nasreen, 2019). Unani medications are grouped into three types based on their origin: plant-derived drugs, such as fruit, stem, bark, leaves, extract, flower, seed, gum, resin, root, and so on. Mineral source medications include nonmetals, metals, and metal ores, in their native state, whereas animal origin pharmaceuticals include tissues, animal glands, along with some animal poisons. Unani pharmacotherapy is built on plant-based medications (Husain et al., 2021; Rani et al., 2022). In the Unani medical philosophy, medications are classified depending on their activities, such as tonic, aphrodisiac, purgatives, concoctive, exhilarants, blood purifiers, and so on. A review of Unani literature indicated that a variety of herbs and plants can work as an effective medicine that can be utilized in various dose forms to cure a variety of diseases. It is also a key component in blood purifier formulas (Ansari and Nasreen, 2019). The Unani System of Medicine was created by Arabs into a sophisticated medical science built on the foundation of Buqrat (Hippocrates) and Jalinoos (Galen) (Ansari et al., 2017). Since then, the term “Unani Medicine” has been used as Greco-Arab Medicine. This approach is founded on Hippocrates’ notion of four humors, including black bile, yellow bile, blood, in addition to phlegm, as well as the four attributes of live human body states such as cold, damp, dry, and heated (Husain et al., 2010). The Greek theories were transformed into seven principles (Umoor-e-Tabbiya), which were composed of the following: temperament (Mizaj), organs (Aaza), spirit (Arwah), functions (Afaal), humors (Akhlat), element (Arkan), and capacities (Qowa) (Singh et al., 2021). The Unani System of Medicine is an acknowledged effective replacement for addressing the requirements of the global population in terms of health care, according to the World Health Organization (WHO). Alternative medicine is practiced all around the world (Hongal et al., 2014). The Unani physician believes that the human body’s health is maintained by a force called as Tabiyat or Quwwat-e-Mudabbira (medicatrix naturae), which was bestowed upon it by its creator. The idea of Tabiyat is far broader than the concept of the body’s immune system. It governs, regulates, and restores the physiological functions of the body and aids in the body’s immunity and resistance to various illnesses. Disease results from the suppression of this gifted potential. As a result, the physician’s responsibility is to employ methods/treatments that promote the body’s own intrinsic healing response (Tabiyat) (Kausar et al., 2021). This is accomplished by activating the Hararat-e-Ghariziya (Body Vital Force), which is diminished in a diseased individual, putting him vulnerable to environmental and pathological stresses (Azfar et al., 2020). Some find it difficult to accept the usage of traditional medications as a type of treatment in a biotechnology era as well as gene editing, tailored therapies supported by computers. However, we forget that until a few decades ago, all medications were derived from natural sources (Newman and Gordon, 2012). Even today, it is believed

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that a quarter of all medications recommended in industrialized nations hold substances obtained from plants, either directly or indirectly, and among the 252 medicines. A total of 11% classified as basic as well as necessary by WHO are solely originated with flowering plants (Raskin et al., 2002). In the 25 years before 2007, over half of all approved medications filed globally were natural compounds or their artificial derivatives. The WHO has identified 21,000 plants used for medical reasons across the world. About 2,500 of these species are present in India, 150 of them are economically beneficial exploited on a substantial basis. India is the world’s leading producer of medicinal plants and is known as a botanical paradise (Dwivedi and Swarnali, 2013). There are numerous medical conditions for which standard therapies are inadequate. The majority of today’s medications only have one active component that works against one specific biological target. The intricacy of the human body makes this method seem oversimplified (Kim et al., 2015). In many investigations, the scientific perspective still reflects reductionist reasoning. It doesn’t have a comprehensive vision, despite the fact that it has given us useful cellular information. Beginning in the early years of the second millennium, this strategy began to change. Studies on health have recently adopted a more thorough and holistic methodology. The world’s traditional medical systems frequently utilize holistic strategies for treating patients’ health (Costantini et al., 2014). Traditional medicine, in contrast to modern medicine, uses pharmaceuticals that are frequently multicomponent and, thus, multitarget (Kim et al., 2015). In the practice of medicine, one of the areas where doctors have trouble treating patients is when a syndrome develops with a group of symptoms that are tied to one another and to a particular condition. The polycystic ovarian syndrome (PCOS), which can afflict up to 17.8% of women of reproductive age, is one of these syndromes. A comprehensive strategy is necessary for the medical management of this issue (Arentz et al., 2014). Stein–Leventhal syndrome is another name for PCOS. A complex endocrine and metabolic disorder is which impacts a woman’s menstrual cycle, hormone production, fertility, insulin production, circulatory system, and attractiveness (Sharma et al., 2022). It affects between 5% and 10% of premenopausal women (Escobar-Morreale, 2018). This disorder causes a variety of symptoms in women, including irregular or nonexistent menstrual periods, an increase in the number of tiny follicles in the ovary, abnormal hair growth, and acne. Furthermore, metabolic syndrome manifests in PCOS women as glucose intolerance, insulin resistance, hypertension, dyslipidemia, higher risk of DM type 2, cardiovascular problems, and an increased incidence of endometrial cancer (Rai et al., 2015; Basheer et al., 2018; Wekker et al., 2020). The National Institute of Health (NIH) organized a committee of specialists in 1990 to describe PCOS as ovulatory failure with clinical evidence of hyperandrogenism (Lizneva et al., 2016). Marz Akyas Khusytur Rehm, which is an Arabic translation of PCOS, is the Unani word for PCOS. Unani doctors have classified this illness under the areas of amenorrhea, obesity, phlegmatic sickness, and liver problems (Sina, 2010; Shaikh et al., 2021). The ailment has not been characterized under the word PCOS in the Unani system of medicine, as the disease was just recently classified a century ago. The disease’s description can be comparable to what several Unani physicians have described under the heads of Ehtebas Tams and uqr (Khan et al., 2019). The major cause of the sickness, according to

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Hippocrates, is humoral dysfunction (Akhlat). Ehtebas Tams is caused by the dominance of Khiltebalgham, which increases blood viscosity. The primary foundation for the Unani notion of PCOS is khiltebalgham’s predominance (phlegm). Due to the liver’s inability to convert chyme into blood, instead it transforms into phlegmatic blood or tenacious phlegm, the Mizaj Barid (abnormal cold temperament) of the liver has been referenced in classical writings as having the potential to cause aberrant phlegm production. Balgham Mayi, thinner-than-normal kind of phlegm that can build up in sacs to produce cysts, is one of the aberrant varieties of phlegm (Firdose et al., 2016). Phlegm production has also been linked to other common PCOS symptoms such amenorrhea, oligomenorrhoea, and obesity. Therefore, it is asserted that PCOS results from an excess of phlegm in the body, which causes ovarian cyst formation, obesity, and amenorrhea (Firdose and Shameem, 2016; Athar et al., 2018). According to Ibn Sina and Majusi, one of the causes of Ehtebas Tams issue Mizaj Barid of Rehm and Samanemufrat (obesity) (Viquar and Munawwar, 2021). Obesity induces blood channel constriction which lowers blood circulation, and Sue Mizaj Barid produces a rise in the viscosity of the humors. In this group, Unani doctors described different disorders such as Qillate Tams, Ehtebase Tams, and uqr. Because PCOS is characterized by symptoms of amenorrhea, infertility, obesity, and hirsutism, various descriptions of the aforementioned conditions can be found in Unani literature in the description of Sue mizajmukhtalif of quwatetauleedmani in women; primarily, Sue Mizaj Barid causes uqr by tooleehtebasemani (chronic anovulation) (Saman et al., 2015). Galen goes on to say that if a woman’s mizaj shifts toward masculinity, she may develop characteristics such as male pattern hair growth, hoarseness of voice, and so on. The reasons of female infertility owing to obesity and PCOS identified by current studies are very similar to the characteristics of Uqr in Unani medicine (Khan and Wajeeha, 2019).

5.2  BRIEF ACCOUNT ON PCOS Hyperandrogenic anovulation (HA), also known as polycystic ovarian syndrome (PCOS), is a prolonged, complicated, moreover the prevalent endocrine illness seen in women of reproductive age (Azziz et al., 2016). It is an important matter of public health. Stein and Leventhal first identified polycystic ovarian syndrome (PCOS) in 1953 as an oligomenorrhea and polycystic ovary syndrome that was sporadically characterized by acne, hirsutism, and fatness (Azziz and Eli, 2016). The National Institutes of Health (NIH) made the first effort at diagnosis of PCOS in 1990 and used oligo or anovulation and hyperandrogenism (HA) as the two criteria after ruling out other comparable illnesses (Lujan et al., 2008). PCOS gained its name since the morphology of an ovarian USG scan seems to be a large number of cysts dispersed throughout the ovary, which are, in fact, immature follicles. These follicles develop from primordial follicles, but no development occurs since it is prevented at the start of an antral stage due to the defective PCOS ovarian physiology. On a USG scan, the follicles appear to be a “necklace” and are evident along the ovarian perimeter. The LH/FSH ratio rises in PCOS women due to the increasing regularity of hypothalamic GnRH pulses (Kitzinger and Jo, 2002). Nonetheless, the precise reason behind PCOS is yet unidentified, it is most contingent on many factors. There is no main causative

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component that adequately explains the range of anomalies in polycystic ovary syndrome (Ehrmann, 2005). The two main hormonal imbalances that cause PCOS are insulin resistance (IR) and hyperandrogenism, weight, environment, lifestyle, and genetic inheritance also play a role (Conway et al., 2014). Oligo/Amenorrhea, clinical or endocrine symptoms of hyperandrogenemia, and polycystic ovaries are all features of polycystic ovarian disorder. Menstrual difficulties, which frequently result in 73%–75% of cases of infertility, abdominal obesity (30%–70%), and 10% of type 2 diabetes are the most prevalent anomalies linked to PCOS (Wołczyński and Zgliczyński, 2012). However, the health hazards linked with PCOS go well beyond addressing these symptoms and most likely last into menopause and into the postmenopausal years (Cooney and Dokras, 2018). A lower quality of life as well as higher incidence of anxiety and depression is both experienced by women with PCOS. Up to 70% of affected women go years without a diagnosis or experience significant delays before the illness is discovered. Women exhibit a variety of traits, including reproductive (disordered menstruation, hirsutism, infertility, and pregnancy problems) (Boomsma et al., 2006) and psychological (stress, anxiety, body image along with degraded lifestyle quality) issues (Teede et al., 2010) as well as major metabolic characteristics (Cardiovascular risk factors, prediabetes, type 2 diabetes, insulin resistance, as well as metabolic syndrome). Patients with PCOS may not share all of their symptoms, and if the woman gains weight, the manifestation may alter over time and develop worse. It is believed that PCOS is a hereditary illness caused by genetic differences that emerge in a multifaceted genetic trait. Because it can run in families, polycystic ovary may occur without any obvious symptoms. The prevalence of metabolic syndrome is significant among the parents and siblings of PCOS-affected women (Kahsar-Miller et al., 2001). Because of its effectiveness in the target tissues, insulin plasma levels increase (Teede et al., 2013). In addition to interfering with ovulation, this excess insulin may influence the ovaries by increasing the production of androgen (a male hormone). This may cause masculinization in the form of male pattern hair growth or loss in addition to acne vulgaris in females. The use of insulin sensitizers like metformin or gloxazones in the treatment of PCOS has been made possible by the discovery that insulin resistance is the underlying cause of the condition. This discovery has sparked a new discussion among medical professionals and scientists worldwide (Sangeeta, 2012). Young females are being diagnosed with PCOS at disturbingly high rates. Every other girl is complaining having unpredictable cycles, having acne, or having too much hair growth. Teenage girls who have PCOS experience enormous stress throughout their lives, even after marriage. Since PCOS is generally misunderstood worldwide, raising awareness seems essential. Increased awareness, early symptom detection, and a multidisciplinary approach are required for PCOS diagnosis. Health-care professionals must educate the public in order to address and assess this morbid endocrinopathy. By doing this, the public will be well-versed on the disease’s symptoms, making it simpler for patients to report the condition as soon as possible. PCOS demands attention since it is the most ignored condition and because females need to understand the importance of the disorder’s presentation and effects because it has become necessary (Tang et al., 2006).

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5.3  PRINCIPLES OF UNANI MEDICINE On the basis of Unani literature, tabiyat is regarded as our body’s supreme planner who establishes a healthy internal environment and gets us ready to confront disease. The tabiyat can be regarded as the totality of an individual’s structural, functional, and psychological characteristics. A man is less likely to get sick if his tabiyat is strong; conversely, if it weakens, a man is more likely to get sick. The tabiyat is made up of seven principles known as Umoore Tabaiyah. The seven natural and fundamental parts of the human body, known as Umoore Tabaiyah, are said to be responsible for both sustaining the human body’s functioning as well as the preservation of health, according to the Unani discipline. A person would die if any one of these components were lost. These are listed below:

5.3.1 Arkan or Anasir (Element) The main constituents of the body are said to be Arkan (plural: Rukn) by the Unani System of Medicine. The four Arkan elements make up every creation in the natural world (elements). These four substances—Hawa (air), Naar (fire), Arz along with Ma (water), are also present in the human body (earth). Each of these substances has a natural binary quality, such as fire being warm and dried, air being warm and moist, the chilly and drenched water and earth being dry as well as wintry. Four of these substances are actually four different states of matter, with gases designated by the acronym Hawa, Ma used for water substances, Arz intended for solid substances, and Nar for substances that have been converted into thermal energy.

5.3.2 Mizaj (Temperament) When these four elements mix in various amounts to form different creations in the universe, their opposing qualities interact with one another and give rise to new qualities in the compound that are distinct from the inherent features of the contributing components. This fresh feature emerged in its Mizaj constituent (Temperament). Thus, everything in this universe has a distinct personality in line with the tasks that must be carried out by that composite body. In order to fulfill the best abilities that other species cannot possess, the human being has been endowed with the best temperament and the best combination of constituent parts.

5.3.3 Akhlat (Humors-Body Fluids) The four main body fluids of a human are obtained from food, different enzymes, and hormones. These fluids—SAFRA for yellow bile, DAM for blood, SAUDA for Black bile along with BALGHAM for phlegm, which are formed via initiating varying proportions of the four arkan—are the four types of bile mentioned above, Sauda is chilly and arid, Balgham is damp and chilly, Dam is steamy and soggy, as well as Safra is warm and arid in temperament. The dominance of a specific khilt (humor) in a man’s physique is an expression of his mizaj. So, depending on the predominance of Dam, Balgham, Safra, or Sauda, man could be Balghami (phlegmatic), Safravi

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(choleric), or Saudavi (melancholic), Damvi (sanguineous). The theory of humors known as Nazariya Akhlat states that in the human body, there are four humors. As long as these humors are kept in balance, the health is sustained according to their number along with quality; illness only appears when the quantity and/or quality of these akhlat are out of balance. The normal mizaj of a person changes to a temperamental sickness when the four humors are not in the proper balance. Different approaches are used in Unani medicine as a form of treatment to reverse the condition and restore the normal mizaj.

5.3.4 Aaza (Organs) These are many organs within the human body, along with its state of health or illness of any one of them can affect how the body as a whole is feeling. Aaza have been divided into two groups in Unani medicine as follows: (1) Baseetah or Aaza e Mufridah (basic organs: tissues along with cells) (2) Aliyah or Aaza e Murakkebah (compound organs – organs and membrane).

5.3.5 Arwah (Spirits) The word “Arwah,” singular “Ruh,” refers to these elements that the body gets by the air we breathe, which is essential to life and without which life cannot exist. These are given prominence in the diagnosis and treatment of sickness because they are thought to be the source of life. They are transporters of various powers according to what the physicians of Unani have said.

5.3.6  Quwa Every living thing must do specific tasks in order to maintain life. These activities require a certain amount of power to be carried out. In order to sustain life and pass down generations, every human being is born with one of three forms of power, according to Unani medicine. The three faculties that make up the human body are Quwa Tabaiyah (natural faculty), Quwa Nafsania (psychic and mental faculty), and Quwa Haywaniya (important faculty). Each and every organ is equipped with a power that allows it to carry out the physiological tasks that are exclusive to that organ. The body’s Quwa tabaiyah (natural faculties) supports nutrition, development, and reproduction while also eliminating waste materials to ensure the survival of both individuals and species. The main organ of this quawat is the liver. The mental faculties, also known as Quwanafsania, are responsible for the body’s intellectual, sensory, and motor functioning. The brain is this quwat’s main organ. Quwahaywania (vital faculties) are those that give an organ life so that it can get quwatnafsania to carry out various life-giving activities. The main organ of this faculty is the heart.

5.3.7 Afa’l (Functions) These consist of how the body’s various organs move and perform. It is crucial to make sure that all of the body’s organs are in good physical condition and are

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carrying out their respective functions correctly in order to sustain overall health (Kabeeruddin, 1954; AHSI 2010; Majoosi, 2010; Sina, 2010; Zaidi and Hasan, 2011).

5.4 DIFFERENT PLANTS AND THEIR UTILIZATION IN UNANI MEDICINE SYSTEM Man has long used plants to relieve pain, treat illnesses, and bring comfort from health issues. A number of studies indicated that ancient people and old societies throughout history used several medicinal plants to aid in the treatment of illness states. Some natural harmful chemicals were reported in ancient medical history based on human attempts, experiments, and blunders (Nagaoka et al., 2012). It is noteworthy to note that global perception has not yet completely shifted, and individuals with little resources and living in rural places continue to employ herbal cures as part of their traditional therapeutic systems (Sofowora, 1996). Needless to say, the usage of medicinal plants has been a long-standing practice in all societies across the world. The Unani medicine system, like other traditional systems of medicine, is recognized by WHO as an alternate way of treatment. Several formulations in the Unani medical philosophy that use diverse plants have been thoroughly recorded. Several studies have shown that these plants are capable to heal a variety of illnesses. Table 5.1 lists numerous plants and parts of them that have been used to cure diverse dysfunctions in PCOS patients. An attempt has been made to investigate the usage and potential of Unani herbs for PCOS therapy.

5.4.1  Melissa officinalis Melissa officinalis has been referenced in the Unani medical system for a variety of purposes (Bhat et al., 2012). It offers healing qualities for cardiovascular disorders, which are a prevalent symptom in PCOS women. It is also known as bee balm since the term Melissa is derived from a Greek word that means bee, and melissa has a strong affinity to bees, therefore the name. Badrangboya, taragarbha in Persian, MufarrehalqhalbUtrajulRaihath, WarqehabaqeRauhawi in Arabic, Billi lotan in Hindi, Mountain balm, sweet balm, or Lemon balm in English are various names for this plant (Joukar and Asadipour, 2015; Shakeri et al., 2016). Melissa officinalis leaf contains triterpenes (ursolic and oleanolic acids), monoterpenoid aldehydes, sesquiterpenes, tannins, and monoterpene glycosides, as well as flavonoids (quercitrin and rhamnocitrin), polyphenolic chemicals (rosmarinic acid, caffeic acid, and protocatechuic acid), along with essential oils (citral) (luteolin) (Uwineza et al., 2022). Research on Melissa officinalis L. (lemon balm) leaf extract revealed that it contains more than 5% hydroxycinnamic acid, which has antianxiety benefits (Ghazizadeh et al., 2021). Aqueous and methanolic extracts of the complete Nepeta hindostana herb were also examined for their antidiabetic and antioxidant properties in rats with alloxan and OGTT-induced diabetes. They discovered that treating experimental animal models with Nepeta hindostana aqueous and methanolic extracts (100, 200, and 400 mg/kg) for 7 days effectively reduced blood glucose levels and protected against hyperglycemic and alloxan-induced oxidative stress. According to this study, its hypolipidemic action may constitute a preventive mechanism against the development of atherosclerosis (Kainsa et al., 2015).

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TABLE 5.1 Medicinal Plants and Their Parts Utilized in the Unani Medical System to Treat PCOS S. No. 1. 2. 3.

Plant Name

Utilization

Plant Part

References

Diabetes control Diuretic Antioxidant, antimicrobial

Leaves Leaves Roots

Vadivel et al. (2011) Johnson et al. (2021) Sharma (2013)

4.

Pongamia pinnata Tephrosia purpurea Saccharum spontaneum Tribulus terrestris

Induces ovulation

5.

Mentha spicata

6. 7.

Glycyrrhiza glabra Paeonia lactiflora

Amanullah et al. (2021) Arumugam et al. (2010) Salim et al. (2018) Ahmad et al. (2013)

8.

Saraca indica

Antiandrogenic, lowers testosterone Lowers testosterone Improves ovulation, increases the production of progesterone Cures internal bleeding, menorrhagia, menometrorrhagia

Roots and fruits Leaf

9.

Saw palmetto

10.

Withania somnifera

11.

Gymnema sylvestre

12.

Pergularia daemia

13.

Withania somnifera

14.

Tribulus terrestis

15.

Cinnamomum zeylanicum

Cures genitourinary disturbances An energy and longevity tonic Diuretic characteristics are also present Antiandrogenic and menstrual irregularity regularizer Enhances insulin sensitivity Normalizing PCOS hormonal levels Normalizing menstrual abnormalities and establishing a regular estrous cycle Follicular development is improved PCOS hormone regulation Normalize hormone levels, promote regular ovulation, and minimize ovarian cysts Anti-androgenic, normalize folliculogenesis and menstrual cyclicity disruptions Enhances insulin sensitivity

Roots Roots

Leaves, flowers, bark, and seeds Berries

Saha et al. (2012)

Roots, leaves and seeds

Saiyed et al. (2016)

Leaves

Singh et al. (2008)

Leaves

Brahmam et al. (2018)

Bark and roots

Uddin et al. (2012)

Fruit, leaves, and root

Pachiappan et al. (2020)

Bark and leaves

Zaki et al. (2019)

Gilani (2005)

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5.4.2  Azadirachta indica Azadirachta indica, referred to as Neem, is a member of the Meliaceae family and has been widely utilized in the treatment and prevention of numerous ailments in Chinese, ayurvedic, as well as in Unani systems of medicine (Reddy and Neelima, 2022). A. indica has a variety of components, containing limonoids, – sitosterol, nimbin, nimbidin, and quercetin and it plays a key role in the treatment of diseases such as cancer, diabetes, ulcers, arthritis, and fungal as well as bacterial infections by modulating many pathways (Rahmani et al., 2018). Quercetin is a polyphenolic flavonoid rich in fresh A. indica leaves that has been shown to be effective in the treatment of inflammation, hypertension, mood disorders, obesity, antioxidant, and gastrointestinal protective function (Sabitha et al., 2021). It has been discovered previously that quercetin, a natural plant chemical, had a therapeutic impact in an animal model of PCOS by inhibiting phosphoinositide-3 kinase (PI3K). It has been discovered that PI3K regulates androgen production in the ovary. PI3K inhibition may be a viable target in the therapy of PCOS (Patel et al., 2021). As a result, Azadirachtaindica has the ability to restore hormonal balance in PCOS women.

5.4.3  Abrusprecatorius The use of Abrusprecatorius to treat various symptoms of PCOS is widely established in the Unani system of medicine (Amtul, 2018). It is a woody climber that can be discovered in the Himalayas, the plains of India, Sri Lanka, and other hot countries. The leaves of Abrusprecatorius are employed to treat roughness of the voice and aphthous ulcers of the mouth, as well as externally for skin conditions such as leukoderma in addition to eczema, and are also suggested as a treatment for balding (Rahmatullah et al., 2010). Many regions of the world use its juice as a blood cleanser (Das et al., 2012).

5.4.4  Tephrosia purpurea Tephrosia purpurea is a Fabaceae family flowering plant native to the Indian subcontinent (Palbag et al., 2014). It is utilized as a solo drug or as a component in multiple Unani formulations used to manage a variety of bodily health conditions treated by the Unani medical system. It has numerous functions, including those of a blood purifier, diuretic, digestive aid, laxative, resolvent, and antidote. It is used to treat syphilis, gonorrhea, leprosy, pruritus, inflammation, hemorrhoids, and skin disorders. Tephrosia purpurea has analgesic, hepatoprotective, immunomodulatory, antidiabetic, antibacterial, antioxidant, antileishmanial, anticarcinogenic, as well as antilipid peroxidative properties (Ansari and Nasreen, 2019).

5.4.5  Trigonella foenum-graecum Trigonella foenum-graecum (Hulba) is an essential medicinal crop grown mostly in Indian states of Himachal Pradesh, Bihar, Panjab, as well as Kashmir. In India, it is produced as a winter season crop (Khan et al., 2015). The plant is a 1–2 feet

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long annual herb with seed pods that are long and narrow sickle-shaped, leaves, and flowers. Hulbah is commonly used to treat diabetes (Zameer et al., 2018), Ihtebase-BaulwaHaiz (Ammenorrhoea) (Bhatia et al., 2015), Istisqaa (ascites), Yerqaan (Jaundice), Zof-e-Meda (Gastric upset), Nafakh-e-Shikam (Flatulence) (Koupý et al., 2015), Qulanj (Intestinal colic), Qillatud Dam (Anemia), and Izm-e- (Incontinence) (Chourasiya et al., 2019).

5.4.6  Linumusitatissimum Linumusitatissimumis a perennial that only has a height of 60–120 cm. It has terminal panicles of tiny blue, bluish violet, or white flowers. The fruits are capsular, with five cells bearing two seeds each. The plant is regarded to be one of the earliest cultivated crops, with cultivation evidence extending back thousands of years (Umer et al., 2017). Alsi is a tiny herb seed that is commonly planted alongside wheat in the Unani School of medicine. It stands around 36 inches tall. It has a narrow stem, branches, and leaves. The blossoms are a lovely bluish color (Leena et al., 2016). Linseed supplementation resulted in a substantial improvement in menstrual cycle frequency, reduction in ovarian volume, and number of follicles in polycystic ovaries, and no change in body weight, blood sugar levels, or hirsutism in a prospective, open label, interventional research (Ebrahimi et al., 2017). The favorable impact of flaxseed powder (FSP) might be related to a decrease in the levels of insulin, LH, estrogen, and testosterone which contribute to follicular maturation, as well as antiinflammatory effects, which contribute to a decrease in ovarian volume. Flaxseeds appear to be a suitable source for future PCOS treatment development given the improvement in ovarian function and menstrual cycle (Ebrahimi et al., 2021).

5.4.7  Mentha spicata Mentha is a Labiatae family member, comes originally from Eastern Asia and comes in two varieties: Mentha spicata Labiatae (spicata) as well as Mentha piperita Labiatae (peppermint) (Naghibi et al., 2022). M. spicata Labiatae is 30–100 cm long and odoriferous. Its leaves are smooth or grey-haired. Its blooms are light blue and form a tall and slender spike at the branches’ tips (Akdoğan et al., 2007). M. spicata has a volatile oil content of 0.21%–2.1%, carvone content of 29%–74%, limonene content of 4%–24%, and cineole content of 3%–18%. M. spicata’s most essential ingredient is carvone. It prefers dampness and gloomy environments. M. spicata increases LH and FSH levels while decreasing testosterone levels. As a result, it has the potential to treat hirsutism in PCOS patients (Akdogan et al., 2004).

5.4.8  Cinnamomum zeylanicum Cinnamon (Cinnamomum zeylanicum of the Lauraceae family) contains insulinstimulating effects (Patel et al., 2012). Polyphenols and procyanidins have been found in cinnamon. This substance controls insulin-stimulated glucose absorption and glycogen synthesis. Cinnamon extracts enhanced insulin sensitivity in PCOS women. Cinnamon extract’s polyphenols and procyanidins are responsible for the

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hypoglycemic impact using insulin signaling pathway stimulator (Anderson et al., 2004). Cinnamon has been used in conjunction with other therapies to treat PCOS in a number of trials. Cinnamon has also exhibited improvement menstrual cyclicity and metabolic dysfunction in people with PCOS. Cinnamon supplementation enhanced menstrual cyclicity and was found to be beneficial in the treating polycystic ovarian syndrome (Dou et al., 2018).

5.4.9  Camellia sinensis The leaves and buds of Camellia sinensis are used to make green tea. It nearly ranks as the most popular in the beverage planet. Camellia sinensis includes a high concentration of catechins. Catechins are powerful antioxidants that work equally in vivo and in vitro (Sharangi, 2009). Furthermore, green tea includes vitamins and minerals that boost the antioxidant capacity of this kind of tea (Cabrera et al., 2006). Recent human research reveals that Camellia sinensis offers several health advantages, including a lower risk of cardiovascular disease and certain malignancies, blood pressure regulation (weight reduction), antiviral and antibacterial activity, and involvement in antidiabetic methods (through intestinal amylase inhibitor and saliva that minimizes starch deterioration) (Khan and Mukhtar, 2013). It is also antiinflammatory, antifibrotic, and antimutagenic, UV radiation protection is another benefit, promotes bone mineral density, lowers cholesterol, triglycerides, in addition to decreasing insulin resistance (Ghafurniyan et al., 2014). Green tea has long been used to help regulate blood sugar levels in the body. Type 1 diabetes may be prevented by drinking green tea and decrease its course once it has established, according to animal research. Type 1 diabetes patients generate insufficient or no insulin, an enzyme that transforms glucose (sugar), carbohydrates, along with added nutrients as energy. Green tea might be beneficial with glucose balance in the body and is beneficial in the treatment of PCOS (Yin et al., 2019).

5.4.10  Nigella sativa Nigella sativa seeds have long been employed in traditional medical systems, notably the Unani School of medicine (Abdulelah and Zainal, 2007). Nigella sativa seeds have antibacterial and antifungal qualities, as well as being menstrual regulators and milk enhancers, and used to treat a range of inflammatory and infectious diseases in Iranian traditional medicine (Hussain et al., 2016). Compounds identified from N.  sativa, such as thymoquinone, t-anethole, carvacrol, and 4-terpinol, show free radical scavenging, antioxidant, and anti-inflammatory activities. It works by lowering testosterone levels as well as insulin levels. It also improves graafian follicles while decreasing cystic follicles (Cascella et al., 2017).

5.5  CHALLENGES IN THE SYSTEM OF UNANI MEDICINES • To ensure the stability and brightness of the Unani system’s future, several requirements and difficulties must be met by its proponents and practitioners. It is important to comprehend these two types of obstacles, internal and external.

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• Internal obstacles include people’s laid-back attitudes, inferiority complexes, the growing trend of sacrificing larger interests for personal ones, disagreements and conflicts over inconsequential issues, a lack of unity, a lack of interest in and effort put into acquiring knowledge and learning, shortcuts for obtaining material comforts and resources, the search for covert ways to meet worldly needs, and lack of unity. The future of this system and its practitioners depends on its practitioners taking on these difficulties headon and eliminating its flaws, limitations, and barriers. • The general public seems to be losing interest in this therapy technique. If there are any individuals who struggle to resuscitate, sustain, and advance this system, they do not seem to be the representatives of the current generation. The Unani medical system’s inadequate and failing educational system is the primary cause of this. • When it comes to the history of this science, more focus is placed on the dates of birth and death of well-known Hakeems, their dynasty, etc., but very little attention is given to their creative output, groundbreaking research, and invaluable contributions. • External difficulties for this system’s future are also very significant. For ages, the arts and sciences of Islam and the East have gone through cycles of ascendance and decline. Because of their innate strength and their direct connection to human life, including its needs and aspirations, moral and cultural formation, and training, they are still alive today. One of those sciences is the Unani medical system. • Despite being woefully inadequate, any fairly modest technical and financial support given by the government to Unani institutions—whether it be to preserve the idea of democracy, to comply with vote politics, or as a result of the unmatched sacrifices, selfless services, nationalism, and patriotism of prominent figures in the world of Unani medicines—should be viewed as a blessing because at no time in its history has the science of Unani medicine been as effective. • Even worse, neither the teachers nor the students of this science have the motivation or capability to benefit in any way from the paltry support and patronage. Although the policy and decision makers in our nation do not wish to completely abandon the Unani system, they are working behind the scenes to eliminate its status as an independent and exclusive science and integrate it into ayurveda or one of its departments. Even some of the system’s supporters are being exploited as a tool for this goal. • In some ways, compared to ayurveda, the Unani system of medicine is a more flawless science from a scientific standpoint. Its methods for making diagnoses and prescribing treatments, as well as its core values and philosophy, are entirely dissimilar from those of ayurveda. Unani scholars and practitioners emphasize that the ayurvedic and Unani systems differ fundamentally from one another. But regrettably, under pressure from the aforementioned conspiracy, our experienced and senior doctors told the media that there wasn’t much of a difference between Unani and ayurveda. This system suffers from the bad attitude and way of thinking of our own people.

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• Our senior and master physicians helped to establish and improve the Unani system of medicine, which is our past legacy, by their selfless service and willingness to use their skill and knowledge to ease the sufferings and ails of God’s slaves. They did not receive sponsorship or help from the government. Understanding the risks that lie in wait for the Unani medical system’s future is crucial, and we must follow in the steadfast footsteps of our forerunners in medicine as we advance.

5.6 CONCLUSION Despite extensive research being done on PCOD over the past 50 years, we still know very little about its intricate etiology. However, there is a lot that we now know about this disease’s effects and diagnosis. The ultimate goal of all gynecologists is to provide positive treatment for women’s reproductive health. In order to enhance the quality of life, alternative therapy procedures have been used. Idrarhaiz, Tadeelmizaj, weight loss, and specific medications like insulin sensitizers are among the Unani remedies that may be employed as therapy alternatives for this complex disease. The imprecise diagnostic criteria and enormous intricacy of this syndrome’s characteristics make them one of its most difficult elements. Effective PCOS prevention, mitigation, palliation, and treatment are made possible by the three medical systems. In comparison to allopathic medical systems, Unani treatments show positive outcome with few to no adverse effects. According to the patient’s preference, any regimen from the three therapies may be chosen. The ayurvedic and Unani medical systems have slow reactions while treating PCOS, while allopathic treatment exhibits speedy results. They are promising candidates in order to treat PCOS since they generally have few adverse consequences and low toxicity. However, experimental investigations have only been done on a fewer numeral of Unani remedies, on a small number of patients, with varying dosages and lengths of treatment. Therefore, it is advised that future studies use a bigger sample size and last longer to demonstrate the effectiveness and safety of Unani medications in the treatment of secondary amenorrhea in PCOD patients. Future study on the genetics and pathophysiology of PCOS will be necessary to identify both effective prevention strategies and therapeutic approaches.

BIBLIOGRAPHY Abdulelah, H. A. A., and B. A. H. Zainal-Abidin. “In vivo anti-malarial tests of Nigella sativa (black seed) different extracts.” Am J Pharmacol Toxicol 2, no. 2 (2007): 46–50. AHSI, Jurjani. “Zakheera Khwarzam Shahi.” New Delhi: Idara kitab-us-shifa 10 (2010): 64–69. Ahmad, Feroz, and Nahida Tabassum. “Effect of 70% ethanolic extract of roots of Paeonia officinalis Linn. on hepatotoxicity.” Journal of Acute Medicine 3, no. 2 (2013): 45–49. Akdogan, Mehmet, M. Ozguner, G. Aydin, and O. Gokalp. “Investigation of biochemical and histopathological effects of Mentha piperita Labiatae and Mentha spicata Labiatae on liver tissue in rats.” Human & Experimental Toxicology 23, no. 1 (2004): 21–28.

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Akdoğan, Mehmet, Mehmet Numan Tamer, Erkan Cüre, Medine Cumhur Cüre, Banu Kale Köroğlu, and Namik Delibaş. “Effect of spearmint (Mentha spicata Labiatae) teas on androgen levels in women with hirsutism.” Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives 21, no. 5 (2007): 444–447. Amanullah, Khan Zeeshan, Fahmeeda Zeenat, Wasim Ahmad, Shaihba Firoz, and Ansari Naeela. “A comprehensive review on a Unani medicinal plant: Tribulus terrestris Linn.” International Journal of Herbal Medicine 9, no. 1 (2021): 23–28. Amtul, Zareen. “Nature’s medicines to treat epileptic seizures.” Studies in Natural Products Chemistry 56 (2018): 129–150. Anderson, Richard A., C. Leigh Broadhurst, Marilyn M. Polansky, Walter F. Schmidt, Alam Khan, Vincent P. Flanagan, Norberta W. Schoene, and Donald J. Graves. “Isolation and characterization of polyphenol type-A polymers from cinnamon with insulin-like biological activity.” Journal of Agricultural and Food Chemistry 52, no. 1 (2004): 65–70. Ansari, Mushir, and Nasreen Jahan. “Tephrosia purpurea (L.) Pers. (Sarphuka, Wild Indigo): an important drug of Unani system of medicine.” Discovery Phytomedicine 6 (2019): 61–69. Ansari, Shabnam, Qamar Alam Khan, Rubi Anjum, Aisha Siddiqui, and Kamar Sultana. “Fundamentals of Unani system of medicine-a review.” European Journal of Biomedical and Pharmaceutical Science 4 (2017): 219–223. Arentz, Susan, Jason Anthony Abbott, Caroline Anne Smith, and Alan Bensoussan. “Herbal medicine for the management of polycystic ovary syndrome (PCOS) and associated oligo/amenorrhoea and hyperandrogenism; a review of the laboratory evidence for effects with corroborative clinical findings.” BMC Complementary and Alternative Medicine 14, no. 1 (2014): 1–19. Arumugam, P., P. Ramamurthy, and A. Ramesh. “Antioxidant and cytotoxic activities of lipophilic and hydrophilic fractions of Mentha spicata L. (Lamiaceae).” International Journal of Food Properties 13, no. 1 (2010): 23–31. Athar, Khan Saba Mohd, Ismath Shameem, Sahibole Suhail, and Siddiqui Aafreen. “Concept of infertility among obese women in Unani system of medicine-a review.” International Journal of Ayurvedic and Herbal Medicine, 8, no. 2 (2018): 3163–3179. Azfar, Mohd, Mohd Saleem, and Yusuf Jamal. “Study of sleep, wake pattern in healthy individuals with reference to different Mizaj.” International Journal of Unani and Integrative Medicine 4, no. 1 (2020): 14–17. Azziz, Ricardo, and Eli Y. Adashi. “Stein and Leventhal: 80 years on.” American Journal of Obstetrics and Gynecology 214, no. 2 (2016): 247.e1–247.e11. https://doi.org/10.1016/j. ajog.2015.12.013 Azziz, Ricardo, Enrico Carmina, ZiJiang Chen, Andrea Dunaif, Joop S. E. Laven, Richard S. Legro, Daria Lizneva, Barbara Natterson-Horowtiz, Helena J. Teede, and Bulent O. Yildiz. “Polycystic ovary syndrome.” Nature Reviews Disease Primers 2, no. 1 (2016): 1–18. Basheer, M., Rai, S., Ghosh, H., and Hajam, Y. A. “Protective role of seed extract of Tephrosia purpurea in letrozole induced polycystic ovary syndrome in wistar rats.” Journal of Biological Sciences 18, no. 8 (2018), 458–467. Bhat, Jalal Uddin, Qudsia Nizami, Mohammad Aslam, Asia Asiaf, Shiekh Tanveer Ahmad, and Shabir Ahmad Parray. “Antiepileptic activity of the whole plant extractof Melissa officinalis in swiss albino mice.” International Journal of Pharmaceutical Sciences and Research 3, no. 3 (2012): 886. Bhatia, Harpreet, Yash Pal Sharma, R. K. Manhas, and Kewal Kumar. “Traditional phytoremedies for the treatment of menstrual disorders in district Udhampur, J&K, India.” Journal of Ethno Pharmacology 160 (2015): 202–210.

126

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Boomsma, C. M., M. J. C. Eijkemans, E. G. Hughes, G. H. A. Visser, B. C. J. M. Fauser, and N. S. Macklon. “A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome.” Human Reproduction Updates 12, no. 6 (2006): 673–683. Brahmam, P., K. Sunita, and B. Hari Babu. “Phytochemical investigation of plants Limoniaacidissima (L.) and Pergulariadaemia (L.) from Prakasam district, Andhra Pradesh, India.” EJBPS 5, no. 5 (2018): 977–983. Cabrera, Carmen, Reyes Artacho, and Rafael Giménez. “Beneficial effects of green tea—a review.” Journal of the American College of Nutrition 25, no. 2 (2006): 79–99. Cascella, Marco, Giuseppe Palma, Antonio Barbieri, Sabrina Bimonte, Nagoth Joseph Amruthraj, Maria Rosaria Muzio, Vitale Del Vecchio, Domenica Rea, Michela Falco, Antonio Luciano, Claudio Arra, and Arturo Cuomo. “Role of Nigella sativa and its constituent thymoquinone on chemotherapy-induced nephrotoxicity: evidences from experimental animal studies.” Nutrients 9, no. 6 (2017): 625. https://doi.org/10.3390/ nu9060625 Chourasiya, Anand, Rakesh Kumar Sahu, and Mohd Azaz Khan. “Anti-anemic and haemopoietic evaluation of Trigonella foenum-graecum (Fenugreek) in rodent model.” Journal of Drug Delivery and Therapeutics 9, no. 4-s (2019): 332–337. Conway, Gerard, Didier Dewailly, Evanthia Diamanti-Kandarakis, Héctor F. EscobarMorreale, Stephen Franks, Alessandra Gambineri, Fahrettin Kelestimur, Djuro Macut, Dragan Micic, Renato Pasquali, Marija Pfeifer, Duarte Pignatelli, Michel Pugeat, Bulent O Yildiz. “The polycystic ovary syndrome: a position statement from the European Society of Endocrinology.” European Journal of Endocrinology 171, no. 4 (2014): P1– P29. https://doi.org/10.1530/EJE-14-0253 Cooney, Laura G., and Anuja Dokras. “Beyond fertility: polycystic ovary syndrome and longterm health.” Fertility and Sterility 110, no. 5 (2018): 794–809. Costantini, Susan, Giovanni Colonna, and Giuseppe Castello. “A holistic approach to study the effects of natural antioxidants on inflammation and liver cancer.” Advances in Nutrition and Cancer 159 (2014): 311–323. Das, Trishna, Shanti Bhushan Mishra, Dipankar Saha, and Shivani Agarwal. “Ethnobotanical survey of medicinal plants used by ethnic and rural people in Eastern Sikkim Himalayan region.” African Journal of Basic & Applied Sciences 4, no. 1 (2012): 16–20. Dou, Lei, Yahong Zheng, Lu Li, Xiaowei Gui, Yajuan Chen, Meng Yu, and Yi Guo. “The effect of cinnamon on polycystic ovary syndrome in a mouse model.” Reproductive Biology and Endocrinology 16, no. 1 (2018): 1–10. Dwivedi, Chandraprakash, and Swarnali Daspaul. “Antidiabetic herbal drugs and polyherbal formulation used for diabetes: a review.” Journal of Phytopharmacology 2, no. 3 (2013): 44–51. Ebrahimi, Faraneh Afshar, Mansooreh Samimi, Fatemeh Foroozanfard, Mehri Jamilian, Hossein Akbari, Elham Rahmani, Shahnaz Ahmadi, Mohsen Taghizadeh, Mohammad Reza Memarzadeh, and Zatollah Asemi. “The effects of omega-3 fatty acids and vitamin E co-supplementation on indices of insulin resistance and hormonal parameters in patients with polycystic ovary syndrome: a randomized, double-blind, placebo-­ controlled trial.” Experimental and Clinical Endocrinology & Diabetes 125, no. 06 (2017): 353–359. Ebrahimi, Babak, Zohreh Nazmara, Negar Hassanzadeh, Atousa Yarahmadi, Neda Ghaffari, Fatemeh Hassani, Amirreza Liaghat, Leila Noori, and Gholamreza Hassanzadeh. “Biomedical features of flaxseed against different pathologic situations: a narrative review.” Iranian Journal of Basic Medical Sciences 24, no. 5 (2021): 551. Ehrmann, David A. “Polycystic ovary syndrome.” The New England Journal of Medicine 352 no. 12 (2005): 1223–1236. Escobar-Morreale, Héctor F. “Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment.” Nature Reviews Endocrinology 14, no. 5 (2018): 270–284.

Anti-PCOS Plants in the Unani System of Medicines

127

Firdose, Kouser Fathima, and Ismath Shameem. “An approach to the management of poly cystic ovarian disease in Unani system of medicine: a review.” International Journal of Applied Research 2, no. 6 (2016): 585–590. Ghafurniyan, Habibeh, Mohammad Nabiuni, and Latifeh Karimzadeh. “The effect of green tea on IL-6 and CRP level in model of polycystic ovary syndrome as an inflammation state.” International Journal of Cellular & Molecular Biotechnology 2014 (2014): 1–12. Ghazizadeh, Javid, Saeed Sadigh‐Eteghad, Wolfgang Marx, Ali Fakhari, Sanaz Hamedeyazdan, Mohammadali Torbati, Somaiyeh Taheri‐Tarighi, Mostafa Araj‐khodaei, and Mojgan Mirghafourvand. “The effects of lemon balm (Melissa officinalis L.) on depression and anxiety in clinical trials: a systematic review and meta‐analysis.” Phytotherapy Research 35, no. 12 (2021): 6690–6705. Gilani, Anwarul Hassan. “Trends in ethnopharmacology.” Journal of Ethnopharmacology 100, no. 1–2 (2005): 43–49. Hongal, Sudhir, Nilesh Arjun Torwane, Goel Pankaj, B. R. Chandrashekhar, and Abhishek Gouraha. “Role of Unani system of medicine in management of orofacial diseases: a review.” Journal of Clinical and Diagnostic Research: JCDR 8, no. 10 (2014): ZE12. Husain, Ahmad, G. D. Sofi, Tajuddin Tajuddin, Raman Dang, and Nilesh Kumar. “Unani system of medicine-introduction and challenges.” Medical Journal of Islamic World Academy of Sciences 18, no. 1 (2010): 27–30. Husain, Mohd Kashif, Goli Penchala Pratap, Mokhtar Alam, Ghazala Javed, and Munawwar Husain Kazmi. “Botany, traditional uses and pharmacology of Bukkun Booti-Phyla nodiflora (L.) Greene: an underexposed botanical drug of AYUSH-Unani system.” International Journal of Research in Pharmaceutical Sciences 12, no. 2 (2021): 1009–1019. Hussain, Deena A. S., and M. Musharraf Hussain. “Nigella sativa (black seed) is an effective herbal remedy for every disease except death-a prophetic statement which modern scientists confirm unanimously: a review.” Advancement in Medicinal Plant Research 4, no. 2 (2016): 27–57. Johnson, D. Benito, R. Sivasakthi, M. V. Nazzneen, and R. Venkatanarayanan. “Evaluation of anti-ulcer activity of Tephrosia purpurea linnpers leaf extract in wistar rats.” Research Journal of Pharmacognosy and Phytochemistry 13, no. 4 (2021): 174–178. Joukar, Siyavash, and Haleh Asadipour. “Evaluation of Melissa officinalis (Lemon Balm) effects on heart electrical system.” Research in Cardiovascular Medicine 4, no. 2 (2015): e27013–e27013. Kabeeruddin, Mohd. Kulliyat-e-Nafisi. New Delhi: Idarakitabul shifa (1954): 404–415. Kahsar-Miller, Melissa D., Christa Nixon, Larry R. Boots, Rodney C. Go, and Ricardo Azziz. “Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS.” Fertility and Sterility 75, no. 1 (2001): 53–58. Kainsa, Sushma, and Randhir Singh. “Chemical constituents, antihyperglycemic and antioxidant effects of Nepeta hindostana whole herb in alloxan and OGTT induced diabetes in rats.” Journal of Chemical and Pharmaceutical Research 7, no. 9 (2015): 920–932. Kausar, Firdaus, Kunwar Mohammad Yusuf Amin, Showkeen Bashir, Athar Parvez, and Pervaiz Ahmad. “Concept of ʻIhtiraqʼ in Unani medicine–a correlation with oxidative stress, and future prospects.” Journal of Ethnopharmacology 265 (2021): 113269. Khan, Abiha Ahmad, and Wajeeha Begum. “Efficacy of darchini in the management of polycystic ovarian syndrome: a randomized clinical study.” Journal of Herbal Medicine 15 (2019): 100249. Khan, Naghma, and Hasan Mukhtar. “Tea and health: studies in humans.” Current Pharmaceutical Design 19, no. 34 (2013): 6141–6147. Khan, Qamar Alam, Asim Ali Khan, Shabnam Ansari, and Umar Jahangir. “Hulbah (Trigonella foenum graecum): a review.” IJP 2, no. 7 (2015): 315–319.

128

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Kim, Hyun Uk, Jae Yong Ryu, Jong Ok Lee, and Sang Yup Lee. “A systems approach to traditional oriental medicine.” Nature Biotechnology 33, no. 3 (2015): 264–268. Kitzinger, Celia, and Jo Willmott. “‘The thief of womanhood’: women’s experience of polycystic ovarian syndrome.” Social Science & Medicine 54, no. 3 (2002): 349–361. Koupý, David, Hana Kotolová, and Rudá Kučerová. “Effectiveness of phytotherapy in supportive treatment of type 2 diabetes mellitus II. Fenugreek (Trigonella foenumgraecum).” Ceska a Slovenskafarmacie: casopis Ceske farmaceutickespolecnosti a Slovenskefarmaceutickespolecnosti 64, no. 3 (2015): 67–71. Leena, Hameed, Farooq Ahsana Dar, and Qureshi Tasneem. “Polycystic ovarian syndrome: a review on Unani verses modern medicine.” 59, no. 2 (2016): 54–71. Lizneva, Daria, Larisa Suturina, Walidah Walker, Soumia Brakta, Larisa Gavrilova-Jordan, and Ricardo Azziz. “Criteria, prevalence, and phenotypes of polycystic ovary syndrome.” Fertility and Sterility 106, no. 1 (2016): 6–15. Lujan, Marla E., Donna R. Chizen, and Roger A. Pierson. “Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies.” Journal of Obstetrics and Gynaecology Canada 30, no. 8 (2008): 671–679. Majoosi, A. B. A. “Kamilus Sana (Urdu translated by Kantoori GH), vol II.” Idarae Kitab-usShifa, New Delhi 2 (2010): 464–474. Naaz, Farah, and Noman Khan. “Medical tourism in India: perspective of Unani medicine.” Journal of AYUSH:-Ayurveda, Yoga, Unani, Siddha and Homeopathy 5, no. 3 (2016): 52–60. Nagaoka, So I., Terry J. Hassold, and Patricia A. Hunt. “Human aneuploidy: mechanisms and new insights into an age-old problem.” Nature Reviews Genetics 13, no. 7 (2012): 493–504. Naghibi, Farzaneh, Mahmoud Mosaddegh, Saeed Mohammadi Motamed, and Abdolbaset Ghorbani. “Labiatae family in folk medicine in Iran: from ethnobotany to pharmacology.” Iranian Journal of Pharmaceutical Research 4, no. 2 (2022): 63–79. Newman, David J., and Gordon M. Cragg. “Natural products as sources of new drugs over the 30 years from 1981 to 2010.” Journal of Natural Products 75, no. 3 (2012): 311–335. Pachiappan, Sudhakar, Kothai Ramalingam, and Arul Balasubramanian. “A review on phytomedicine and their mechanism of action on PCOS.” International Journal of Current Research and Review 12, no. 23 (2020): 81. Palbag, Satadru, Bijay Kr Dey, and Narendra Kumar Singh. “Ethnopharmacology, phytochemistry and pharmacology of Tephrosia purpurea.” Chinese Journal of Natural Medicines 12, no. 1 (2014): 1–7. Patel, D. K., S. Kumar Prasad, R. Kumar, and S. Hemalatha. “An overview on antidiabetic medicinal plants having insulin mimetic property.” Asian Pacific Journal of Tropical Biomedicine 2, no. 4 (2012): 320–330. Patel, Shraddha V., Harsh Maru, Vishal K. Chavda, Jigar N. Shah, and Snehal S. Patel. “Ethanolic extract of Azadirachta indica ameliorates ovarian defects through phosphoinositide-3 kinase inhibition in a rat model of polycystic ovary syndrome.” Asian Pacific Journal of Reproduction 10, no. 1 (2021): 21. Rahmani, Arshad, Ahmad Almatroudi, Faris Alrumaihi, and Amjad Khan. “Pharmacological and therapeutic potential of neem (Azadirachta indica).” Pharmacognosy Reviews 12, no. 24 (2018): 250–255. Rahmatullah, Mohammed, Dilara Ferdausi, A. Mollik, Rownak Jahan, Majeedul H. Chowdhury, and Wahid Mozammel Haque. “A survey of medicinal plants used by Kavirajes of Chalna area, Khulna district, Bangladesh.” African Journal of Traditional, Complementary and Alternative Medicines 7, no. 2 (2010): 91–97. Rai, S., Basheer, M., Ghosh, H., Acharya, D., and Hajam, Y. A. “Melatonin attenuates free radical load and reverses histologic architect and hormone profile alteration in female rat: an in vivo study of pathogenesis of letrozole induced poly cystic ovary.” Clinical & Cellular Immunology 6 (2015): 1–8.

Anti-PCOS Plants in the Unani System of Medicines

129

Rani, R., Hajam, Y. A., Kumar, R., Bhat, R. A., Rai, S., and Rather, M. A. “A landscape analysis of the potential role of polyphenols for the treatment of polycystic ovarian syndrome (PCOS).” Phytomedicine Plus 2, no. 1 (2022): 100161. Raskin, Ilya, David M. Ribnicky, Slavko Komarnytsky, Nebojsa Ilic, Alexander Poulev, Nikolai Borisjuk, Anita Brinker, Diego A. Moreno, Christophe Ripoll, Nir Yakoby, Joseph M. O’Neal, Teresa Cornwell, Ira Pastor, Bertold Fridlender. “Plants and human health in the twenty-first century.” TRENDS in Biotechnology 20, no. 12 (2002): 522–531. Reddy, I. V., and P. Neelima. “Neem (Azadirachta indica): a review on medicinal Kalpavriksha.” International Journal of Economic Plants 9, no. 1 (2022): 59–63. Sabitha, M., K. Krishnaveni, M. Murugan, A. N. Basha, Gilse A. Pallan, C. Kandeepan, S. Ramya, and R. Jayakumararaj. “In-silico ADMET predicated pharmacoinformatics of quercetin-3-galactoside, polyphenolic compound from Azadirachta indica, a sacred tree from Hill Temple in Alagarkovil Reserve Forest, Eastern Ghats, India.” Journal of Drug Delivery and Therapeutics 11, no. 5–S (2021): 77–84. Saha, Jayita, Taniya Mitra, Kamala Gupta, and Sumona Mukherjee. “Phytoconstituents and HPTLC analysis in Saracaasoca (Roxb.) Wilde.” International Journal of Pharmacy and Pharmaceutical Sciences 4, no. 1 (2012): 96–99. Saiyed, Amrin, Nasreen Jahan, Sana Fatima Majeedi, and Mariyam Roqaiya. “Medicinal properties, phytochemistry and pharmacology of Withaniasomnifera: an important drug of Unani medicine.” Journal of Scientific & Innovative Research 5, no. 4 (2016): 156–160. Salim, Sajad, Mohd Afsahul Kalam, Aamir Yusuf, Suheena Khanday, Saba Shafi, and Iqbal Mohammad. “Asl-us-Sus (Glycyrrhiza glabra L.), a great munzij-i-balgham (concotive of phlegm) drug of Unani system of medicine: a review.” International Journal of Unani and Integrative Medicine 2, no. 3 (2018): 16–19. Saman, Anees, Mustafa Suboohi, S. Aamena Naaz, and Qamar Akhtar Kazmi. “Clinical evaluation of mizaj (temperament) in the patients of polycystic ovarian disease.” International Ayurvedic Medical Journal (IAMJ) 3, no. 11 (2015): 2173–2176. Sangeeta, Shah. “Metformin and pioglitazone in polycystic ovarian syndrome: a comparative study.” The Journal of Obstetrics and Gynecology of India 62, no. 5 (2012): 551–556. Shaikh, Rahman, Rubeena Lukhman Saudagar, Pathan Imran Khan, Firoz Shaikh Ayyub, Malik Tauheed Ahmad. “The concept and preventive aspect of ovarian diseasees in Unani system of medicine-a review.” Journal of Emerging Technologies and Innovative Research, 8, no. 11 (2021): b107–b121. Shakeri, Abolfazl, Amirhossein Sahebkar, and Behjat Javadi. “Melissa officinalis L.–a review of its traditional uses, phytochemistry and pharmacology.” Journal of Ethnopharmacology 188 (2016): 204–228. Sharangi, A. B. “Medicinal and therapeutic potentialities of tea (Camellia sinensis L.)–a review.” Food Research International 42, no. 5–6 (2009): 529–535. Sharma, Sachin. “Oxidative stress, chronic diseases and antioxidant potential of some religious grasses of poaceae family: an overview.” Atherosclerosis 43 (2013): 46. Sharma, P., Hajam, Y. A., Kumar, R., and Rai, S. “Complementary and alternative medicine for the treatment of diabetes and associated complications: a review on therapeutic role of polyphenols.” Phytomedicine Plus 2, no. 1 (2022): 100188. Sina, Ibne. “Al-Qanoon fit Tib (urdu translation by GH Kantoori).” Re-print by Idara Kitab-usShifa, New Delhi (2010): 1163–1164. Singh, Inder Pal, Furkan Ahmad, Debanjan Chatterjee, Ruchi Bajpai, and Neha Sengar. “Natural products: drug discovery and development.” In R. Poduri (ed.) Drug Discovery and Development. Singapore: Springer (2021): 11–65. https://doi.org/10.1007/978-98115-5534-3_2

130

Herbal Medicine Applications for Polycystic Ovarian Syndrome

Singh, Vinay Kumar, Shahid Umar, Shamim Akhtar Ansari, and Muhammad Iqbal. “Gymnemasylvestre for diabetics.” Journal of Herbs, Spices & Medicinal Plants 14, no. 1–2 (2008): 88–106. Sofowora, Abayomi. “Research on medicinal plants and traditional medicine in Africa.” The Journal of Alternative and Complementary Medicine 2, no. 3 (1996): 365–372. Tang, Thomas, Julie Glanville, Nic Orsi, Julian H. Barth, and Adam H. Balen. “The use of metformin for women with PCOS undergoing IVF treatment.” Human Reproduction 21, no. 6 (2006): 1416–1425. Teede, Helena J., Anju E. Joham, Eldho Paul, Lisa J. Moran, Deborah Loxton, Damien Jolley, and Catherine Lombard. “Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women.” Obesity 21, no. 8 (2013): 1526–1532. Teede, Helena, Amanda Deeks, and Lisa Moran. “Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan.” BMC Medicine 8, no. 1 (2010): 1–10. Uddin, Qamar, L. Samiulla, V. K. Singh, and S. S. Jamil. “Phytochemical and pharmacological profile of Withania somnifera Dunal: a review.” Journal of Applied Pharmaceutical Science Issue 2, no. 1 (2012): 170–175. Umer, Khan Heena, Fahmeeda Zeenat, Wasim Ahmad, Intezar Ahmad, and Abdul Vakil Khan. “Therapeutics, phytochemistry and pharmacology of Alsi (Linumusitatissimum Linn): an important Unani drug.” Journal of Pharmacognosy and Phytochemistry 6, no. 5 (2017): 377–383. Uwineza, Pascaline Aimee, Monika Urbaniak, Marcin Bryła, ŁukaszStepien, Marta Modrzewska, and Agnieszka Waśkiewicz. “In vitro effects of lemon balm extracts in reducing the growth and mycotoxins biosynthesis of Fusarium culmorum and F. proliferatum.” Toxins 14, no. 5 (2022): 355. Vadivel, Vellingiri, and Hans K. Biesalski. “Contribution of phenolic compounds to the antioxidant potential and type II diabetes related enzyme inhibition properties of Pongamia pinnata L. Pierre seeds.” Process Biochemistry 46, no. 10 (2011): 1973–1980. Viquar, Uzma, Raise Fatima, and Munawwar Hussain Kazmi. “Sailan-Ur-Rahem (Leucorrhoea): a most common gynecological problem and its management in Unani system of medicine.” European Journal of Biomedical 8, no. 4 (2021): 241–248. Wekker, Vincent, L. Van Dammen, Anton Koning, K. Y. Heida, R. C. Painter, Jacqueline Limpens, J. S. E. Laven, J. E. Roeters van Lennep, T. J. Roseboom, and A. Hoek. “Longterm cardiometabolic disease risk in women with PCOS: a systematic review and metaanalysis.” Human Reproduction Updates 26, no. 6 (2020): 942–960. Wołczyński, S., and W. Zgliczyński (Eds.). “Abnormalities of the menstrual cycle.” In Large Interna–Endocrinology. 2nd edition. Warsaw: Medical Tribune Poland (2012): 561–567. Yin, Jianli, Linfeng Yang, Lisha Mou, Kaili Dong, Jian Jiang, Shuai Xue, Ying Xu, Xinyi Wang, Ying Lu, and Haifeng Ye. “A green tea–triggered genetic control system for treating diabetes in mice and monkeys.” Science Translational Medicine 11, no. 515 (2019): eaav8826. Zaidi, I., and A. Hasan. “Textbook on Kulliyat e Umoor e tabi’yah.” Aligarh. p-1 15 (2011): 81–96. Zaki, Sana, Nasreen Jahan, MohdKalim, and Ghausia Islam. “In vitro antilithiatic activity of the hydro-alcoholic extracts of Cinnamomum zeylanicum Blume bark on calcium oxalate crystallization.” Journal of Integrative Medicine 17, no. 4 (2019): 273–281. Zameer, Saima, Abul Kalam Najmi, Divya Vohora, and Mohd Akhtar. “A review on therapeutic potentials of Trigonella foenum graecum (fenugreek) and its chemical constituents in neurological disorders: complementary roles to its hypolipidemic, hypoglycemic, and antioxidant potential.” Nutritional Neuroscience 21, no. 8 (2018): 539–545.

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Therapeutic and Pharmacological Perspectives of Some Herbal Resources for the Treatment of Polycystic Ovarian Syndrome A Fast-Spreading Endocrine Disorder Suresh Kumar Himachal Pradesh University

N. Mahakud, Adyasha Purohit, Sunita Patel, Kshipra Xaxa, and Gunja Roy Guru Ghasidas Vishwavidayalaya

Younis Ahmad Hajam Sant Baba Bhag Singh University

Seema Rai Guru Ghasidas Vishwavidayalaya

CONTENTS 6.1 Introduction................................................................................................... 132 6.2 Causes of Polycystic Ovarian Syndrome (PCOS)......................................... 134 6.2.1 Obesity............................................................................................... 134 6.2.2 Insulin Resistance.............................................................................. 134

DOI: 10.1201/9781003344728-6

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6.2.3 Hyperandrogenism............................................................................. 134 6.2.4 Hormonal Alteration.......................................................................... 135 6.2.5 Genetic Factors.................................................................................. 135 6.3 Prescribed Treatment for PCOS.................................................................... 136 6.4 Therapeutic Effects of Some Herbal Resources on PCOS............................ 137 6.4.1 Aloe Vera........................................................................................... 137 6.4.1.1 Major Bioactive Constituents of Aloe Vera........................ 137 6.4.1.2 Pharmacological Effects..................................................... 138 6.4.2 Cinnamon.......................................................................................... 139 6.4.2.1 Major Bioactive Constituents of Cinnamon........................ 140 6.4.2.2 Pharmacological Effects..................................................... 141 6.4.3 Fennel................................................................................................ 143 6.4.3.1 Major Bioactive Constituents of Fennel.............................. 143 6.4.4 Liquorice............................................................................................ 146 6.4.4.1 Major Bioactive Constituents of Liquorice......................... 146 6.4.4.2 Pharmacological Effects..................................................... 147 6.4.5 Pomegranate...................................................................................... 150 6.4.5.1 Major Bioactive Constituents of Pomegranate.................... 150 6.4.5.2 Pharmacological Effects..................................................... 151 6.4.6 Soybean.............................................................................................. 153 6.4.6.1 Major Bioactive Constituents of Soybean........................... 153 6.4.6.2 Pharmacological Effects..................................................... 153 6.4.7 Spearmint.......................................................................................... 154 6.4.7.1 Major Bioactive Constituents of Spearmint........................ 155 6.4.7.2 Pharmacological Effects..................................................... 155 6.5 Conclusion..................................................................................................... 158 Bibliography........................................................................................................... 158

6.1 INTRODUCTION Polycystic ovarian syndrome (PCOS), also known as Stein–Leventhal syndrome, was first reported in 1935 by Stein and Leventhal. However, Vallisneri, in 1721, an Italian scientist, described a married, infertile woman having shiny ovaries with a white surface, and the size of ovaries was similar to pigeon eggs (Leventhal, 1958; Insler and Lunenfeld, 1990; Knochenhauer et al., 1998). Polycystic ovary syndrome is a fastspreading endocrine and metabolic abnormality among women of reproductive age, characterized by hyperandrogenism, insulin resistance, obesity, infertility, chronic anovulation, menstrual irregularities, and hirsutism (Allahbadia and Merchant, 2011; Rai et al., 2015; Rani et al., 2022). Women with PCOS have many small cysts of size exceeding 0.5 cm in ovaries and its symptoms varies from women to women (Akkasheh et al., 2016). PCOS is negatively affected by certain factors which are diet, lifestyle, and exposure to environmental toxins. The features of PCOS are evident from prepubertal age until the postmenopausal years, and they can change over the lifespan or overlap each other (Papadakis et al., 2021). According to US National Institutes of Health (NIH) diagnostic criteria (1990), the average rate of PCOS in women of reproductive age from United States, Europe, Asia, and Australia ranges between 5% and 9% (Azziz et al.,

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2016). The prevalence rate of PCOS has been reported to be high among Indian women. The pooled prevalence of this disease was found to be about 10% using Rotterdam’s criteria and AES (Androgen Excess Society) criteria. However, it was found to be 5.8% using NIH (National Institutes of Health) criteria (Bharali et al., 2022). There have been several attempts to categorize polycystic ovarian syndrome. According to the National Institutes of Health (NIH) criteria, women having hyperandrogenism and oligo-anovulation were classified to have polycystic ovarian syndrome excluding other endocrine dysfunctions. Later, Rotterdam’s expert committee considered the presence of two out of three parameters: oligo-anovulation, clinical hyperandrogenism, and polycystic ovaries in ultrasound. Thus, according to Rotterdam criteria, presence of two out of three following conditions (Szydlarska et al., 2017) are necessary to make PCOS diagnosis: 1. Lack of ovulation or rare ovulation 2. Excessive activity of androgens diagnosed by clinical examination 3. Appearance of polycystic ovaries in the ultrasound after the exclusion of other pathologies characterized by hyperandrogenism.

A HA+OD+PCO (67.7%)

B HA+OD (11%)

C HA+PCO (17.7%)

D OD+PCO (3.6%)

PHENOTYPE A

HYPERANDROGENISM, OVULATORY DYSFUNCTION AND POLYCYSTIC OVARIES

PHENOTYPE B

HYPERANDROGENISM AND OVULATORY DYSFUNCTION

PHENOTYPE C

HYPERANDROGENISM AND OVULATORY OVARIES

PHENOTYPE D

OVULATORY DYSFUNCTION AND POLYCYSTIC OVARIES

FIGURE 6.1  Phenotypic classification of PCOS recommended by NIH consensus panel (2012).

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In 2006, AE-PCOS (Androgen Excess and PCOS Society) defined the diagnosis of PCOS to be based on clinical hyperandrogenism along with oligo-anovulation or polycystic ovaries. Thus, hyperandrogenism remained the main determinant for the diagnosis of PCOS. Finally, NIH consensus panel proposed the following phenotypic approach (Figure 6.1) to categorize PCOS (Sachdeva et al., 2019).

6.2  CAUSES OF POLYCYSTIC OVARIAN SYNDROME (PCOS) 6.2.1 Obesity Body fat is excessive in PCOS condition. This is because insulin in excess stimulates adipogenesis and abdominal lipogenesis and inhibits lipolysis, leading to adipocyte hypertrophy (Rosenfield, 2020). Obesity is not really a cause of PCOS but it can definitely modify the phenotype of PCOS, specifically visceral adiposity worsens all metabolic and reproductive functions in obese and nonobese women with PCOS (Glueck and Goldenberg, 2019). It has been observed that the body mass index (BMI) and weight gain is higher in women with PCOS as compared with the women who don’t have PCOS (Joham et al., 2016; Sharma et al., 2022). Abnormal function of hypothalamic-pituitary-ovarian (HPO) axis which can develop PCOS condition has also been linked to obesity (Legro, 2012). Due to excess adiposity, obese women with PCOS possess additional trouble of insulin resistance, resulting in hyperinsulinemia (Matalliotakis et al., 2006; Louwers and Laven, 2020).

6.2.2 Insulin Resistance Insulin resistance refers to the reduced response of glucose to a given amount of insulin. It can occur through peripheral target tissue resistance, decreased hepatic clearance, and/or increased pancreatic sensitivity (Balen, 2004). A variety of reproductive abnormalities in women with PCOS are associated with insulin resistance. In normal individuals, the circulating level of insulin is 6–15 μIU/m but in women with PCOS it goes up to 22 μIU/ml, which leads to hyperinsulinemia. This is also responsible for increased level of androgens, ultimately causing insulin resistance and diabetes mellitus along with the development of PCOS (Krishnan and Muthusami, 2017). Insulin directly causes specialized cells in the ovary called thecal cells to produce androgen by the activation of P450c17α (Jeanes and Reeves, 2017). Hyperinsulinemia further exacerbates the pathogenesis of PCOS by inhibiting the production of insulin-like growth factor-1 (IGF-1) binding protein in the liver, leading to elevated circulating levels of IGF-1, which in turn stimulates ovarian thecal cell androgen production (Rosenfield and Ehrmann, 2016).

6.2.3 Hyperandrogenism The main cause of the elevated ovarian androgen production in PCOS is the follicular theca cells’ accelerated androgen synthesis which is caused by the increased expression of many genes encoding steroidogenic enzymes (Basheer et al., 2018). According to estimates, more than 80% of women exhibit hyperandrogenism’s signs

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and symptoms which include hirsutism, acne, alopecia, and PCOS (Sirmans and Pate, 2013). Research has shown that the main cause of hyperandrogenism in PCOS women is androgen production (Baptiste et al., 2010) from both the ovary (60%) and adrenal (40%). Hyperandrogenism in PCOS may be brought about by impaired intrinsic steroidogenesis in ovarian theca cells or increased LH levels as a result of abnormal hypothalamic-pituitary axis control impacted by insulin (Armanini et al., 2022).

6.2.4 Hormonal Alteration Neuroendocrine abnormalities appear to play an important role in PCOS pathophysiology with an increase in frequency of GnRH pulses. PCOS patients are known to present a GnRH-generating pulse resistance to negative feedback by progesterone resulting in a higher LH pulses frequency and amplitude (Crespo et al., 2018). Increase GnRH pulse frequency and amplitude can promote LH synthesis over FSH synthesis, leading to a high LH/FSH ratio in women with PCOS. Elevating LH levels plays a vital role in the development of reproductive and metabolic disorders. First, LH promotes the synthesis of androgen in ovarian theca cells, which leads to hyperandrogenism and arrested follicle development. Second, increased LH pulse frequency impairs estrogen and FSH synthesis, thus inhibiting follicle growth and ovulation. Third, LH promotes ovarian secretion of IGF-1, which can further promote LH binding and androgen synthesis in theca cell, and finally it contributes to the formation of polycystic ovaries in PCOS patients (Glueck and Goldenberg, 2019; Liao et al., 2021). Clinically, an altered or abnormal LH/FSH ratio can be utilized as a diagnostic tool to identify early-stage PCOS (Malini and Roy George, 2018). Gonadotropin-releasing hormone (GnRH) pulsatility is disturbed as a result of excessive LH production due to hypothalamic-pituitary-ovarian or adrenal axis dysfunction which also affects the LH/FSH ratio (Figure 6.2). Hypothyroidism (lack of thyroid hormone production by the thyroid gland) is linked to delayed puberty onset, anovulation, amenorrhea, irregular menstrual cycles, infertility, the hyperandrogenism sign, weight gain, and a slight increase in total testosterone levels (de Medeiros et al., 2018; Nath et al., 2019).

6.2.5 Genetic Factors The genetic basis of polycystic ovarian syndrome (PCOS) was first reported in 1968 by Cooper and colleagues (Khan et al., 2019). Studies of Kahsar-Miller and Cols have suggested an important genetic basis contributing symptoms of PCOS. According to them, first-degree relatives of 93 PCOS patients had a higher risk of being affected in which 35% are nonmenopausal mothers and 40% are sisters. Examining a large twin cohort of monozygotic and dizygotic twin sisters, it has been concluded that genetic components contribute over 70% of PCOS pathogenesis. Hence, it is a complex genetic disease with high inheritance rates (Crespo et al., 2018). A number of genes seem to be involved in PCOS symptoms. Some studies hypothesized that the alteration of expression of specific genes associated with adrenal and ovarian steroidogenesis contribute to hyperandrogenism, e.g., CYP11A1 (coding for P450 cholesterol side-chain cleavage, P450scc), CYP17A1 (coding for 17 alpha hydroxylase and 17,20-lyase), and

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Hypothalamus

Abnormal GnRH (LH, FSH) pulsatility

INSULIN RESISTANCE • Insulin resistance of muscle and liver • Adipocyte dysfunction

Pituitary gland

Abnormal gonadotropin ratio LH/FSH

Hyperinsulinemia Ovary

Ovulatory dysfunction Pancreas Hyperandrogenism Adrenal androgens

Follicular arrest

PCOS

FIGURE 6.2  Pathophysiology of polycystic ovary syndrome (PCOS).

CYP21 (coding for 21-hydroxylase). Some studies suggest DENND1A gene is found in cells of ovarian theca and adrenal glands and its variant is upregulated in theca cells of women with PCOS, favoring androgen excess (Bruni et al., 2022).

6.3  PRESCRIBED TREATMENT FOR PCOS PCOS condition exhibits disruption in reproductive cycle (primates-menstrual cycle and nonprimates-estrus cycle). Primary treatment in PCOS is lifestyle management, including exercise and balanced diet (Cooney and Dokras, 2017). The type of procedure used in PCOS treatment mainly depends on clinical effects such as infertility treatment, regulation of menstrual disturbances, alleviation of symptoms of hyperandrogenism, or obesity treatment. Women with infertility issues are prescribed to take clomiphene, an estrogen receptor modulator that directly affects the hypothalamicpituitary axis (Bednarska and Siejka, 2017). A recent metanalysis suggested that letrozole is recommended as the first line treatment for PCOS and infertility (Hoeger et al., 2021). Metformin, an insulin sensitizer, lowers theca cell androgen synthesis invitro and has a positive effect on metabolic disturbances and bleeding disorders in women with PCOS. Myoinositol promotes glucose uptake and FSH activity while D-chiro-inositol has a role in androgen synthesis in ovary. Both positively affect the ovarian function in PCOS (Tanbo et al., 2018). Oral contraceptives are the most common options for the treatment of PCOS nowadays (Moini Jazani et al., 2019). Apart from this, herbal medicines and plant extracts are effective to the condition of PCOS. Presently, conventional therapies are not effective and may have some side effects. Therefore, plant-based drugs especially phytoestrogens are considered

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to be comparatively more effective to the condition of PCOS. Traditional practitioners have developed plant-based remedies which are effective on patients with PCOS or amenorrhea and also on underlying metabolic dysfunctions (Hosseinkhani et al., 2017). Traditional medicinal systems describe certain herbal formulations that have been used for centuries and can be good source for finding possible new drugs for the treatment of PCOS.

6.4 THERAPEUTIC EFFECTS OF SOME HERBAL RESOURCES ON PCOS 6.4.1 Aloe Vera Kingdom: Plantae Division: Tracheophyta Class: Magnoliopsida Order: Asparagales Family: Asphodelaceae Botanical name: Aloe vera (L.) Burm. f. Aloe vera, commonly called as ‘Ghrit Kumari’ or ‘Gwar Patha,’ is a succulent plant belonging to family Asphodelaceae. It grows mainly in the dry regions of Africa, Asia, and many islands of Western Indian Ocean (Cousins and Witkowski, 2012). It is a perennial herb with thick, fleshy, green leaves with serrated margins. Yellow, tubular, drooping flowers arise in long racemes (Figure 6.3). 6.4.1.1  Major Bioactive Constituents of Aloe Vera Aloe vera has been reported to yield about 75 different chemical compounds including sugars such as mannose-6-phosphate (monosaccharides), glucomannans, and acemannans (polysaccharides); anthraquinones (aloin, emodin and barbaloin); minerals (copper, zinc, calcium and selenium); vitamins (vitamin A, C, E and B12); enzymes (amylase and catalase); fatty acids (lupeol and campesterol); hormones

FIGURE 6.3  Aloe vera.

138

Herbal Medicine Applications for Polycystic Ovarian Syndrome HO OH

O

OH HO

OH H

H

O

OH

OH

HO

OH

O O

OH

HO

OH

OH

OH 2

1 O OH

OH

O

OH

3

FIGURE 6.4  (1) Alonin, (2) aloe emodin, and (3) barbaloin.

(auxins and gibberellins); lignin, salicylic acid, and saponins (Surjushe et al., 2008; Sanchez et  al., 2020). The major bioactive constituents of aloe vera are shown in Figure 6.4. 6.4.1.2  Pharmacological Effects Aloe vera (L.) Burm. f. has been popularly known for its medicinal effect such as hypoglycemic, lipid lowering, anti-inflammatory, and antioxidant properties (Desai et al., 2012). Its potentially active constituents such as vitamins, enzymes, minerals, sugars, lignin, saponins, salicylic acids, and amino acids possess purgative, antimicrobial, immunostimulatory, wound healing, antitumor, and antidiabetic activities (Hussain et al., 2015). Clinical trial has shown that aloe vera gel dose can improve glucose tolerance in dose-dependent manner, and may cause change in the structure of ovary, and high-dose treatment decreases atretic follicles and 3-beta hydroxy steroid dehydrogenase (3βHSD) and 17βHSD activates. This herb has a hypoglycemic impact and is high in fiber, which has the function of accelerating gastrointestinal transit, absorption, and homeostasis modulation. Aloe vera phytosterols have the ability to modify the steroidogenic response, express estrogen receptor protein, decrease androgen levels, raise estrogen levels, and eventually ameliorate PCOS symptoms. According to certain research, aloe vera can enhance glucose intolerance and lipid metabolizing enzyme activities, lower levels of triglycerides (TG) and low-density lipoprotein, reduce atretic follicles, and diminish atretic follicles (Ashkar et al., 2020). Various clinical/laboratory studies on effect of aloe vera for the treatment of PCOS have been depicted in Table 6.1.

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TABLE 6.1 Impact of Aloe vera (Aloe vera (L.) Burm. f.) during PCOS-Associated Reproductive Impairments References

Model

Intervention (Daily Dose)

Duration

Outcome

Maharjan et al. (2010)

5-monthold Charles Foster female rats.

Rats were orally fed with letrozole which urged PCOS in them, then administered orally 1 mL daily dose of aloe vera gel.

45 days

Desai et al. (2012)

Charles Foster female rats.

30 days

Radha et al. (2014)

Charles Foster adult female rats.

PCOS was induced in rats through oral administration of letrozole at a dose of 0.5 mg/kg body weight. The PCOS positive rats were divided into four groups: 1. PCOS control group 2. Aloe vera gel treated PCOS rats – 1 ml (10 mg)/ day for 30 days) 3. PCOS rats treated with metformin 4. positive control group treated with atorvastatin. Aloe vera gel fed orally at dose of 5, 10, and 15 mg/kg.

Treatment with aloe vera gel restored estrus cyclicity, maintained normal blood glucose level and reduced androgen level. Aloe vera gel, having phytochemicals such as flavonoids, polyphenols, sterols, has efficacy to prevent the expression of phenotype of PCOS. PCOS rats treated with aloe vera gel showed significant reduction in LDL cholesterol levels and plasma triglyceride, and increase in HDL cholesterol. Aloe vera gel also caused reversion of abnormal estrous cyclicity, glucose intolerance and lipid metabolizing enzyme activities, bringing them to normal.

60 days

6.4.2  Cinnamon Kingdom: Plantae Division: Tracheophyta Class: Magnoliopsida Order: Laurales Family: Lauraceae Botanical name: Cinnamomum verum J. Presl

Treatment with aloe vera gel caused changes to ovarian structure, restored the ovarian steroid status, decreased the insulin resistance, and lowered the testosterone level.

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Cinnamomum verum J. Presl, also known as true cinnamon, belongs to ­family Lauraceae. It is a small evergreen tree having simple ovate-oblong leaves with smooth margins. Flowers are borne in panicles. Fruit is a drupe having single seed (Figure 6.5). 6.4.2.1  Major Bioactive Constituents of Cinnamon Leaves – Cinnamaldehyde: 1%–5% Eugenol: 70%–95% Bark – Cinnamaldehyde: 65%–80% Eugenol: 5%–10% Root – Camphor: 60%

FIGURE 6.5  Cinnamomum verum.

O HO

H

H3C 1

O 2

O CH3 H3C

H3C 3

FIGURE 6.6  (1) Cinnamaldehyde, (2) eugenol, and (3) camphor.

Therapeutic Perspectives of Herbal Resources for Treatment of PCOS

141

Cinnamaldehyde has been shown to increase progesterone and lower androgens such as testosterone and DHEA, thus maintaining the menstrual cycle. Eugenol extracts from essential oil of cinnamon contain antioxidant, anti-inflammatory, antidiabetic, and antiandrogenic properties (Vangalapati et al., 2012). The major bioactive constituents of cinnamon are shown in Figure 6.6. 6.4.2.2  Pharmacological Effects Cinnamomum verum is an attractive spice because of its aroma and taste and also has several health-promoting effects (Kort and Lobo, 2014). According to a report, taking cinnamon supplements may reduce insulin resistance and enhance the health of PCOS patients (Table 6.2). By acting as a potential therapeutic agent, cinnamon decreases insulin and testosterone levels, lowers insulin-like growth factor-1, and raises insulin-like growth factor-1 (IGF-1) binding protein levels in plasma and the ovary in PCOS (Ashkar et al., 2020). Extracts of cinnamon promote insulin receptor adhesion. It has been discovered to improve the insulin signaling pathway, reduce insulin resistance brought on by high fructose diets, and improve glucose utilization. Additionally, it includes polyphenolic compounds with insulin-like properties such as rutin, catechin, quercetin, and kaempferol (Dou et al., 2018).

TABLE 6.2 Impact of Cinnamon (Cinnamomum verum J. Presl) during PCOS-Associated Reproductive Impairments References

Model

Wang et al. (2007)

15 women with PCOS (with mean BMI 28.8 ± 1.3 kg/m2 and mean age 31.1 ± 2.0 years.

Borzoei et al. 84 overweight or (2017) obese PCOS patients in the age group of 20–38 years.

Intervention (Daily Dose) Daily 1 g cinnamon extract was given orally to the patients (1 capsule containing 333 mg of cinnamon extract given 3 times per day). Patients in cinnamon group (n = 42) and placebo group (n = 42) were administered with 3 cinnamon capsules (each one containing 500 mg).

Duration

Outcome

8 weeks

In the cinnamon group, fasting glucose level decreased, HOMA-IR decreased and improved insulin sensitivity.

8 weeks

Treatment with cinnamon improved antioxidant status and serum lipid profile in PCOS patients, increased HDL-C levels and decreased serum level of total cholesterol and LDL-C. (Continued)

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TABLE 6.2 (Continued) Impact of Cinnamon (Cinnamomum verum J. Presl) during PCOS-Associated Reproductive Impairments References

Model

Intervention (Daily Dose)

Duration

Outcome

Borzoei et al. 84 overweight or (2018) obese PCOS patients in the age group of 20–38 years.

Patients were administered with cinnamon powder 1.5 g/ day (3 cinnamon capsules; each one contained 500 mg).

8 weeks

Dou et al. (2018)

The mice were randomly divided into three groups (control group, DHEA group and DHEA + cinnamon group). In DHEA + cinnamon group (n = 25), the mice were administered with DHEA (6 mg/100 g body weight and cinnamon powder (10 mg/100 g body weight mixed in 100 μL 0.5% methyl cellulose). Rats were divided into four groups: G1: control group G2: PCOS group without any therapy G3:rats with PCOS that received a daily oral dose of hydroalcoholic extract of cinnamon (200 mg/kg) for 2 weeks G4: the group with no PCOS but receiving a daily dose of the cinnamon extract (200 mg/kg) for 2 weeks. PCOS was induced by injecting a single dose of estradiol valerate.

20 days

Administration of cinnamon decreased serum fasting blood glucose, insulin, HOMA-IR (homeostatic model assessment for insulin resistance), total cholesterol, LDL-C and weight, and increased HDL-C. Treatment with cinnamon restores the estrous cyclicity and ovary morphology. It improves insulin sensitivity and reduces insulin resistance, mitigates impaired glucose tolerance, and downregulate/reduce testosterone as well as LH levels.

60 Prepubertal C57BL/6 mice (age 25 days)

Khodaeifar 32 female Wistar et al. (2019) rats weighing 200 ± 20 g.

14 days

Hydroalcoholic extract of cinnamon can regulate the level of gonadotropin and steroid hormones, decrease the oxidative stress, prevent cystic follicle production, and increase the number of normal follicles.

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6.4.3  Fennel Kingdom: Plantae Division: Tracheophyta Class: Magnoliopsida Order: Apiales Family: Apiaceae Botanical name: Foeniculum vulgare Mill. Foeniculum vulgare Mill., commonly called fennel, is an important medicinal and aromatic plant belonging to family Apiaceae. It is indigenous to the shores of Mediterranean sea but widely naturalized in several parts of the world. It is generally cultivated as home yard crop throughout India up to an altitude of 2,000 m (Sood et al., 2012). It is an erect perennial herb with hollow stem and finely dissected feathery leaves. The yellow flowers are borne in terminal compound umbels. Fruit is a dry schizocarp (Figure 6.7). 6.4.3.1  Major Bioactive Constituents of Fennel Phenols, phenolic glycosides, and volatile aroma compounds such as transanethole, estragole, and fenchone and α-phellandrene have been reported as the major phytoconstituents of this species (Figure 6.8). Phenolic compounds isolated from F.  vulgare are considered to be responsible for its antioxidant activity while the volatile aroma compounds make it an excellent flavoring agent. Phenolic acids such as 3-O-Caffeoylquinic acid, 4-O-caffeoylquinic acid, 5-O-caffeoylquinic acid, 1,3-O-di-caffeoylquinic acid, 1,4-O-di-caffeoylquinic acid, 1,5-O-dicaffeoylquinic acid, and flavonoids such as quercetin-3-rutinoside, eriodictyol7-rutinoside, and rosmarinic acid have been reported to be isolated from F. vulgare (Rather et al., 2012).

FIGURE 6.7  Foeniculum vulgare.

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O H3CO

1

2

OH OH OH O

HO

O HO O

H3CO

OH 3

OH OH

OCH3 HO

O

O

O 4

OH HO

OH OH

O

O

OH OH

O 5

O

OH 6

FIGURE 6.8  (1) Trans-anethole, (2) fenchone, (3) estragol, (4) quercetin-3-rutinoside, (5) kaempferol, and (6) acacetin.

Fennel has been reported to exhibit antibacterial, antifungal, hepatoprotective, antiviral, gastroprotective, anthelmintic, antidiabetic, anticancer, memory-protective, estrogenic, antioxidant, antianxiety, and anti-inflammatory properties (Singh, 2019). Extracts of fennel seeds have been shown in animal studies to have a potential use in the treatment of glaucoma, as a diuretic and a potential drug for the treatment of hypertension. Extract of the seeds is used as a galactagogue improving the milk supply of a breast feeding mother (Rather et al., 2012). Different parts of the plant including fruit are used to cure various ailments like mouth ulcer, gum disorders, constipation, conjunctivitis, cold, cough, insomnia, arthritis, diarrhea, fever, liver pain, leucorrhea, and digestive disorders (Badgujar et al., 2014). Anethole, the main constituent of essential oil,, has been reported to be the active estrogenic agent. Aqueous extract of seeds especially at the dose of 150 mg/kg b.w. possessed beneficial effect on renal function in PCOS rats. Phytoestrogen content in fennel is responsible for bringing down insulin resistance and reducing inflammation in PCOS. It has also been reported to reduce the cellular imbalance which leads to metabolic disturbances in PCOS (Sadrefozalayi and Farokhi, 2014; Meena et al., 2019). Various clinical/laboratory studies on effect of fennel for the treatment of PCOS have been depicted in Table 6.3.

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TABLE 6.3 Impact of Fennel (Foeniculum vulgare Mill.) during PCOS-Associated Reproductive Impairments References Karampoor et al. (2014)

Sadrefozalayi and Farokhi (2014)

Aliakbari et al. (2022)

Model

Intervention

Duration

30 rats with Rats were injected 60-days induced PCOS administration with 2 mL of and 6 normal rats estradiol valerate. with estradiol After 60 days, the valerate and as control. rats in experiment 10-day group were treatment with treated with 250, the extract. 500, and 1,000 mg/kg of the extract. Dosage: 100, 150 For 4 weeks. 40 adult female mg/kg/day. Wistar rats (200 ± 20 g).

The intervention 4 months. 70 women with PCOS having age group received B. persicum range of 16–40 years. capsule (60 mg) + F. vulgare capsule (25 mg) twice daily.

Outcome Fennel extract increased the serum concentration of FSH and decreased LH and Testosterone in treatment groups.

1. Serum urea levels were decreased (only at a dose of 150 mg/kg/day). 2. Histopathology: normal glomerulus, normal basement membrane, and capillaries; Bowman’s space (urinary space) and acute tubular necrosis were improved toward normal. The treatment of women with PCOS by the combination of fennel and cumin decreased LH and DHEAS levels, hirsutism score and increased menstrual duration.

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6.4.4 Liquorice Kingdom: Plantae Division: Tracheophyta Class: Magnoliopsida Order: Fabales Family: Fabaceae Botanical name: Glycyrrhiza glabra L. Glycyrrhiza glabra L., commonly known as ‘liquorice’ belongs to family Fabaceae. It is native to the Mediterranean and certain areas of Asia. It is grown in India, Spain, Iran, Russia, China, and Italy. It is herbaceous perennial plant, with pinnate leaves. The flowers are purple to pale whitish blue in color, produced in a loose ­inflorescence. The fruit is an oblong pod containing many seeds (Figure 6.9). 6.4.4.1  Major Bioactive Constituents of Liquorice Liquorice root yields a large number of components including a water soluble complex containing starch, pectins, polysaccharides, simple sugars, amino acids, ­triterpene, saponin, flavonoids, asparagines, female hormone estrogen, mineral salts, gums, essential oil, fat, resins, tannins, glycosides, protein, sterols, volatile oils, etc. The major bioactive constituents of liquorice are shown in Figure 6.10. Glycyrrhizin, a ­triterpenoid compound, represents a mixture of potassium–calcium–­magnesium salts of glycyrrhizic acid that constitutes 10%–25% of liquorice root extract. Flavonoidrich fractions include liquirtin, isoliquertin, liquiritigenin, and rhamnoliquirilin. The isoflavones glabridin and hispaglabridins A and B have been reported to possess considerable antioxidant activity (Sharma et al., 2018).

FIGURE 6.9  Glycyrrhiza glabra.

147

Therapeutic Perspectives of Herbal Resources for Treatment of PCOS O HO O

O

O H HO

OH

H HO

H

1

2 COOH

HOOC HO HO HOOC HO HO

H

O O H O O

O

H

OH 3 HO

HO

O O O

HO

OH

HO

OH 4 OH HO

O HO

O

O

OH OH

O 5

FIGURE 6.10  (1) Glabridin, (2) glycyrrhetic acid, (3) glycyrrhizin, (4) isoliquiritin, and (5) liquiritin.

6.4.4.2  Pharmacological Effects Liquorice root exhibits multifaceted therapeutic properties such as antimicrobial, antitussive, expectorant, anticoagulant, antiviral, antihyperglycemic/antidiabetic activity, anticarcinogenic, antimutagenic, hepatoprotective, immunomodulator,

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Herbal Medicine Applications for Polycystic Ovarian Syndrome

antihyperlipidemic, antioxidant, anti-inflammatory, antiulcer activity, and also used to cure throat infection, tuberculosis, respiratory disorders, and liver diseases (Sharma et  al., 2018; Wahab et al., 2021). Glycyrrhiza roots are useful for treating cough because of its demulcent and expectorant property. It is also used for the treatment of sore throat, anemia, tonsillitis, fever, flatulence, sexual debility, hyperdipsia, skin diseases, swellings, acidity, leucorrhea, bleeding, jaundice, epilepsy, hoarseness, bronchitis, diarrhea, gout, rheumatism, hemorrhagic diseases, and paralysis (Damle, 2014). Administration of liquorice extract leads to the successful elimination of PCOS-associated symptoms, including thinning of the granulosa layer of antral follicles, thickening of the theca layer, reduction in the number of antral follicles, and induction of number of follicular cysts (Kamble et al., 2020). Different clinical/laboratory studies on the effect of liquorice for the treatment of PCOS have been shown in Table 6.4.

TABLE 6.4 Impact of Liquorice (Glycyrrhiza glabra L.) during PCOS-Associated Reproductive Impairments References

Duration

Outcome

Armanini Nine healthy 3.5 g of a commercial et al. (2004) women preparation of liquorice aged (containing 7.6% w.w. of 22–26 years. glycyrrhizic acid) given daily for two cycles.

2 months (two menstrual cycles).

Armanini The effect of Women with PCOS were et al. (2007) Glycyrrhiza divided into two groups: glabra was 16 received 100 mg studied in spironolactone and 16 32 women spironolactone plus 3.5 g with PCOS. of liquorice a day.

2 months (two menstrual cycles).

After treatment with Glycyrrhiza glabra, total serum testosterone decreased from a mean of 27.8 ± 8.2 ng/dL to 19.0 ± 9.4 ng/dL after one cycle (p