Progestogens in Obstetrics and Gynecology [2 ed.] 9783030525088, 3030525082

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Howard J.A. Carp  Editor

Progestogens in Obstetrics and Gynecology Second Edition

Progestogens in Obstetrics and Gynecology

Howard J. A. Carp Editor

Progestogens in Obstetrics and Gynecology Second Edition

Editor Howard J. A. Carp Obstetrics and Gynecology Sheba Medical Center Tel Hashomer, Ramat Gan, Israel Sackler School of Medicine Tel Aviv University, Tel Aviv, Israel

ISBN 978-3-030-52507-1    ISBN 978-3-030-52508-8 (eBook) https://doi.org/10.1007/978-3-030-52508-8 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Foreword

In 1930, WM Allen and GW Corner used the name progestin (later renamed progesterone in 1935) to describe a hormone which was responsible for implantation, end embryo survival. They could not have imagined the profound relevance of the hormone and implications for the development of a class of drugs, which are in widespread use and affect our daily lives. For many years, progesterone was thought of as a hormone only affecting pregnancy, and the wider implications of triggering the progesterone receptor were relatively ignored. In the 1960s, the contraceptive pill became available and caused a revolution in the way that women could plan their pregnancies. Progestogens were introduced to modulate the estrogen used to inhibit ovulation in the contraceptive pill. Since then a whole host of synthetic drugs known as progestogens have come into clinical use. The main use of progestogens is in pregnancy. Progestogens are used in luteal support, to prevent miscarriage, and to prevent preterm labor. Progestogens are used outside of pregnancy, for abnormal uterine bleeding, cycle control, hormone replacement therapy, and even in the prevention and treatment of endometrial cancer. Today, we know that progesterone is found in nonmammalian vertebrates. Progesterone had a physiological role as an anti-inflammatory agent and neurosteroid long before mammalian pregnancy had evolved. Therefore, it is hardly surprising that progestogens are being used as possible anti-inflammatory agents in endometriosis, and even in male in traumatic brain injury, and in multiple sclerosis. Just as the early investigators in the 1930s could not realize the implications of their discovery, it is difficult to prophesy the future. A new field of development is receptor modulators. Mifepristone is a progesterone receptor modulator. It was introduced as an abortifacient. However, today new uses are being developed for receptor modulators. Experimental work with uterine fibroids may entirely change the management of fibroids and affect the whole approach to surgery for gynecological conditions. This book brings together all the aspects of progestogens in gynecological (and non-gynecological) practice. There are chapters governing basic scientific topics such as physiology and pharmacology. The major applications of progestogen v

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Foreword

t­herapy in luteal support, miscarriage, preterm labor, contraception, abnormal uterine bleeding, etc. have been described in depth. However, in clinical practice, there are always controversies, leaving the clinician puzzled as to how to help the patient. The different progestogens with their overlapping effects on estrogen, androgen, glucocorticoid, and mineralocorticoid receptors are described in order to allow the clinician to make the most appropriate choice of progestogen. It is hoped that this book will be read by gynecologists, endocrinologists, general practitioners, and associated disciplines, who wish to keep up to date and gain a comprehensive view of developments. Gynecology and Obstetrics  Andrea R. Genazzani University of Pisa, Pisa, Italy International Society of Gynecological Endocrinology (ISGE) European Society of Gynecology (ESG) International Academy of Human Reproduction (IAHR)

Preface to the Second Edition

Since the first edition of this book, much new knowledge has accumulated regarding the progestogens. In the field of infertility, the Lotus trials have added new opportunities for supporting the luteal phase. Similarly, in miscarriage, new research has clarified the role of progestogens, but alas, has brought up as many questions and controversies as have been clarified. Hence, Chaps. 4 and 5 have been updated considerably to show the current trends and new controversies. Chapter 14 on “Progestogens in Non-gynecological Indications” was a novel concept in the first edition. The subject has been broadened. Today progestogens are used in a wide variety of neurological conditions, which has necessitated rewriting the entire chapter. In addition, the use of progestogens has become modified in both endometrial and breast tumors requiring updates of these two important subjects. With all the changes mentioned above, progestogens are still probably the most widely used class of drugs in medical practice. Millions of women use progestogens in the contraceptive pill daily for many years. Progestogens are widely used to protect the endometrium in postmenopausal replacement therapy, cycle regulation, abnormal uterine bleeding, and endometriosis. However, the clinician is often in a quandary, as to which progestogen is most appropriate in any clinical situation. The vii

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actions of progestogens overlap with other steroids. Progestogens have estrogenic or antiestrogenic actions, androgenic or antiandrogenic actions, and glucocorticoid or mineralocorticoid actions. Each may have advantages or disadvantages depending on the clinical situation. Additionally, much evidence has accumulated regarding the pro-thrombotic effects of certain progestogens. Hence, definite choices are necessary for prescribing endocrine contraception, where thrombosis may be a risk in healthy women. Progestogens also have other side effects including stimulatory effects on the breast, possibly predisposing to breast carcinoma, breakthrough bleeding, acne mood changes, loss of libido, and dryness of the vagina. All of the above actions of progestogens have been incorporated into this book, which discusses the actions and uses of progestogens in depth. The book is planned for general gynecologists and specialists working in the field. Each contributing author is an authority on a specific area of progestogen use. I would like to thank each author for the time and effort taken in preparing the manuscript to make the publication of this second edition possible. Tel Aviv, Israel  Howard J. A. Carp

Contents

  1 Physiology of Progesterone���������������������������������������������������������������������    1 Edi Vaisbuch, Offer Erez, and Roberto Romero   2 Pharmacology of Progestogens ��������������������������������������������������������������   31 Adolf E. Schindler   3 Progestogens in Infertility Practice��������������������������������������������������������   39 Ameet S. Patki and Mrinmayi Dharmadhikari   4 Progestogens in Threatened Miscarriage����������������������������������������������   55 Howard J. A. Carp   5 Progestogens and Recurrent Miscarriage����������������������������������������������   69 Narmada Katakam and Luciano G. Nardo   6 Progestogens in Preterm Labour Prevention: An Update��������������������   83 Di Renzo Gian Carlo, Tosto Valentina, Neykova Konstantsa, and Giardina Irene   7 Abnormal Uterine Bleeding��������������������������������������������������������������������   97 Eran Zilberberg and Howard J. A. Carp   8 Progestogens in Contraception ��������������������������������������������������������������  117 Johannes Bitzer   9 Progestogens and Endometriosis������������������������������������������������������������  137 Matityahu Zolti and Howard J. A. Carp 10 Progestogens and Breast Cancer������������������������������������������������������������  157 Eitan Pe’er 11 Progestogens in Endometrial Cancer����������������������������������������������������  169 Oded Raban and Walter Gotlieb 12 Progestogens and the Menopause����������������������������������������������������������  193 Eitan Pe’er ix

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13 Progestogens and Autoimmunity������������������������������������������������������������  203 Abraham Tsur, Grant C. Hughes, and Yehuda Shoenfeld 14 Progestogens in Non Gynecological Indications������������������������������������  213 Howard J. A. Carp, Matityahu Zolti, and Christa Nadjafi-Triebsch

Chapter 1

Physiology of Progesterone Edi Vaisbuch, Offer Erez, and Roberto Romero

1  Introduction The corpus luteum was first discovered in 1672 by Reinier de Graaf and named in 1689 by Marcelo Malpighi. Malpighi proposed that the corpus luteum produces the ovarian follicles and that the yellow substance, like egg yolk, serves to nourish the ovum. In 1903, Fraenkel demonstrated that excission of the corpora lutea of rabbits, before implantation, prevented implantation. Moreover, lutectomy in early pregnancy (