Ovarian Reserve: Current Trends and Applications 9781536189698, 2020052643, 2020052644, 9781536189810

Table of contents :
Contents
Preface
Chapter 1
Introduction – The Concept of Ovarian Reserve
Definitions and Physiology
Ovarian Reserve Abnormalities
Ovarian Reserve Utility
References
Chapter 2
Natural History of the Primordial Follicles
Prenatal Folliculogenesis
Prepubertal Folliculogenesis
Folliculogenesis Beyond Puberty
Perimenopausal Ovarian Function
References
Chapter 3
Ovarian Reserve Testing
Historical Perspective and Definition
Limitations of Ovarian Reserve Testing
The Choice of an Ovarian Reserve Test
Ovarian Reserve Tests in Current Use
Anti-Müllerian Hormone (AMH)
Antral Follicle Count (AFC)
Follicle Stimulating Hormone (FSH)
Less Commonly Used Ovarian Reserve Tests
Early Follicular Serum Oestradiol (E2)
Inhibin B
Ovarian Volume
Ovarian Stromal Blood Flow
Abandoned - Dynamic Ovarian Reserve Tests
Clomiphene Citrate Challenge Test (CCCT)
GnRH Agonist Stimulation Test (GAST)
Exogenous FSH Ovarian Reserve Test (EFORT)
Combined Ovarian Reserve Tests
Clinical Applications of Ovarian Reserve Testing
Conclusion
References
Chapter 4
Anti-Müllerian Hormone
Definition, Historical Perspective, and Function
AMH and the Menstrual Cycle
Evolution of the AMH Assay
Age-Related AMH Changes
Variability of Serum AMH
The Role and Clinical Utility of AMH
References
Chapter 5
Anti-Müllerian Hormone and Polycystic Ovarian Syndrome
The Mechanism of Increased AMH Concentration in PCOS
Role of AMH in the Pathophysiology of PCOS
Diagnostic Application
Follicle Count for the Diagnosis of PCOS
Prognostic Value of AMH in Women Receiving Fertility Treatment
Ovarian Reserve and Age of Menopause in Women with PCOS
Conclusion
References
Chapter 6
Diminished Ovarian Reserve
Introduction
Idiopathic DOR (Early Ovarian Aging)
Concept, Physiology and Epidemiology
Consequences of Early Ovarian Aging (EOA)
Screening and Diagnosis
Management
Pathological DOR
Endometriomas and Ovarian Reserve
Follicular Density and Other Histological Effects of Endometriomas
Antral Follicle Count (AFC)
Anti-Müllerian Hormone (AMH)
Ovulation and Fecundability
Response to Controlled Ovarian Hyperstimulation
Possible Mechanisms of Detrimental Effect of Endometrioma on Ovarian Reserve
Non-Endometriotic Ovarian Cysts
Antral Follicle Count
Anti-Mullerian Hormone
Endometriosis
Chronic Pelvic Inflammatory Disease
Iatrogenic DOR - Reproductive Surgery
Surgery for Ovarian Cysts
Anti Müllerian Hormone
Short- to Medium- Term Effects on AMH
Long-Term Effect
Impact of Surgery on AFC
Impact of Surgery on Ovarian Response to Controlled Ovarian Hyperstimulation (COH)
ART Outcome
Premature Ovarian Insufficiency
Surgery for Endometriomas and the Onset of Menopause
Mechanism of Surgical Damage to Ovarian Reserve
Surgery for Endometriomas and Reproductive Function
Short Term Effects
Spontaneous Ovulation
Spontaneous Pregnancy
Long-Term Effects
Unilateral Oophorectomy
Laparoscopic Ovarian Drilling
Salpingectomy
Hysterectomy
Uterine Artery Embolisation
Concluding Remarks on Pelvic Surgery and the Risk of DOR
Iatrogenic DOR - Chemotherapy
Factors Affecting the Severity of Gonadotoxicity Related to Chemotherapy
Mechanisms of DOR in Women Receiving Chemotherapy
Chemotherapy and Fertility
Concluding Remarks
Iatrogenic DOR - Radiotherapy
Conclusion
References
Chapter 7
Ovarian Reserve and IVF – The Problem of Poor Ovarian Response
Prediction of Ovarian Response to Controlled Ovarian Stimulation
Individualisation of Controlled Ovarian Stimulation (COS) Based on OR Testing
High Responders
Normal Responders
Poor Ovarian Responders
Definitions and Classifications
Management
Higher FSH Doses
GnRH Agonist and Antagonist Protocols
Letrozole Co-Treatment
Clomiphene Citrate Co-Treatment
The Use of Adjuvants
Androgens
Growth Hormone (GH)
Estradiol Priming in Luteal Phase
Recombinant LH
Aspirin
Other Adjuvants
Modified Natural Cycle
Luteal Phase Start Ovaria Stimulation
Double Stimulation
Oocyte Accumulation
Conclusion
References
Chapter 8
Premature Ovarian Insufficiency
Definition and Epidemiology
Mechanisms and Causes
Consequences of POI
Clinical Presentation of POI
Clinical Evaluation and Diagnosis of POI
Management
Conclusion
References
About the Author
Index
Blank Page

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OBSTETRICS AND GYNECOLOGY ADVANCES

OVARIAN RESERVE CURRENT TRENDS AND APPLICATIONS

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OBSTETRICS AND GYNECOLOGY ADVANCES Additional books and e-books in this series can be found on Nova’s website under the Series tab.

OBSTETRICS AND GYNECOLOGY ADVANCES

OVARIAN RESERVE CURRENT TRENDS AND APPLICATIONS

SAAD ALI KAMEL S. AMER

Copyright © 2020 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470

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NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the Publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data ISBN: 978-1-53618-969-8 Names: Amer, Saad, author. Title: Ovarian reserve: : current trends and applications / Saad Amer. Description: New York : Nova Science Publishers, [2021] | Series: Obstetrics and gynecology advances | Includes bibliographical references and index. | Identifiers: LCCN 2020052643 (print) | LCCN 2020052644 (ebook) | ISBN 9781536189698 (hardcover) | ISBN 9781536189810 (adobe pdf) Subjects: LCSH: Reproductive health. | Ovaries--Physiology. | Polycystic ovary syndrome. Classification: LCC RG133 .A52 2021 (print) | LCC RG133 (ebook) | DDC 618.1/1--dc23 LC record available at https://lccn.loc.gov/2020052643 LC ebook record available at https://lccn.loc.gov/2020052644

Published by Nova Science Publishers, Inc. † New York

CONTENTS Preface

vii

Chapter 1

Introduction – The Concept of Ovarian Reserve

1

Chapter 2

Natural History of the Primordial Follicles

9

Chapter 3

Ovarian Reserve Testing

19

Chapter 4

Anti-Müllerian Hormone

51

Chapter 5

Anti-Müllerian Hormone and Polycystic Ovarian Syndrome

69

Chapter 6

Diminished Ovarian Reserve

87

Chapter 7

Ovarian Reserve and IVF – The Problem of Poor Ovarian Response

147

Premature Ovarian Insufficiency

179

Chapter 8

About the Author

191

Index

193

PREFACE This is the first book that provides a comprehensive and in-depth account of the current state of knowledge of ovarian reserve and its clinical applications in Gynaecology and Reproductive Medicine. Ovarian reserve is a term commonly used to reflect the total number of the remaining primordial follicles, which determines woman’s fertility potential. Since its emergence in the late 1980s during the early days of Assisted Reproduction Technology, the concept of ovarian reserve has continued to gain more importance in clinical practice as well as research as reflected by the exponentially growing number of publications on the topic. A wide range of ovarian reserve markers have been introduced over the years starting with serum follicle stimulating hormone level in 1988 with the latest being antiMüllerian hormone (AMH) in 2002. This book starts with a detailed background on the physiology of ovarian reserve including early ovarian development, follicular dynamics, and the natural history of primordial follicles. This is followed by a comprehensive account on various biochemical, sonographic, and dynamic markers and their current applications. A special chapter will be devoted to AMH, which is the most extensively researched and most widely used ovarian reserve marker. The role of AMH and its clinical utility in polycystic ovarian syndrome is presented in a separate chapter. The book then explores the clinical applications of ovarian reserve testing in various reproductive disorders

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including early ovarian aging, diminished ovarian reserve (pathological and iatrogenic), poor ovarian response during assisted reproduction technology, and premature ovarian insufficiency.

Chapter 1

INTRODUCTION – THE CONCEPT OF OVARIAN RESERVE DEFINITIONS AND PHYSIOLOGY Ovarian reserve (OR) is a widely used term with no clear or universally agreed definition. It is generally used to describe a woman’s reproductive potential as determined by the total ovarian follicle pool including both primordial and growing follicles (Practice Committee of the American Society for Reproductive Medicine (ASRM), 2015). These follicles contain oocytes arrested in meiotic prophase I. During in-utero development, a small number (30-40) of primordial germ cells (PGCs) migrate from the yolk sac along the dorsal mesentery of the hind gut to eventually enter genital ridges. Once in the genital ridges, PGCs are referred to as oogonia. These proliferate by mitosis until 10 weeks gestation then by a combination of mitosis and meiosis (arrested at prophase I). Meiosis transforms oogonia to primary oocytes and at 20 weeks of gestation, the ovarian germ cell number reaches its peak totaling approximately 7 million cells, of which one third are oogonia and two thirds are primary oocytes. The PGCs then become integrated into primordial follicles. From that point onwards, the total cohort of primordial follicles continues to decline rapidly from 7 million to

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approximately 2 million at birth. This depletion continues at a slower rate during childhood to ~400,000 at puberty. The depletion slows further during reproductive live to reach 25,000 at age ~38 when the pace accelerates again to reach ~1,000 follicles at menopause (age 50-51). Aging is not only associated with a decline in the number but also a deterioration in the quality of the oocytes especially beyond the age of 40. The prenatal meiotic arrest of the primary oocytes is believed to set the limit of the ovarian reserve with no further oogenesis after birth. In other words, every woman is born with a genetically determined number of oocytes. This dogma stems from Waldeyer's initial proposal in 1870 that female mammals cease production of oocytes at or shortly after birth (Tilly et al., 2009; Zuckerman, 1951). This widely adopted concept is largely based on the absence of experimental evidence of postnatal neo-oogenesis. In recent years however, this concept has been challenged by emerging evidence supporting possible replenishment of follicle numbers by post-natal oogenesis from germline stem cells in the ovary or bone marrow (Johnson et al., 2004; Zou e t a l . , 2009; Zhang et al., 2008; Virant-Klun et al., 2008; Virant-Klun et al., 2009). Mechanisms regulating and influencing the dynamics of ovarian reserve and ovarian aging remain to be fully understood. In addition to the main genetic and age determinants, several developmental and environmental factors have been found to impact on ovarian reserve and long-term reproductive potential. For instance, elevated prenatal androgens and maternal nutrient restriction may have an adverse effect on the early establishment of ovarian reserve (Richardson et al., 2014). Exposure to certain environmental compounds such as Polycyclic Aromatic Hydrocarbons in cigarette smoke may accelerate loss of ovarian reserve leading to earlier age at last child and earlier menopause (Jurisicova et al., 2007; Richardson et al., 2014). Understanding such mechanisms may pave the way to potential therapeutic interventions, which could modulate the rate of ovarian aging.

Introduction – The Concept of Ovarian Reserve

3

OVARIAN RESERVE ABNORMALITIES Diminished ovarian reserve (DOR) represents a real clinical challenge especially in young women wishing to have children. Whilst the prevalence of DOR in the general population is unknown, it has been reported in approximately 10% of subfertile women (Levi et al., 2001; Pastore et al., 2012; May-Panloup et al., 2012; Gleicher et al., 2009). In practice, DOR is often used to describe women of reproductive age with regular cycles mostly ovulatory and with abnormal ovarian reserve test indicative of reduced follicle pool. It is often associated with reduced fecundity and long-term health risks due to early age at menopause. Although several aetiologies of DOR have been recognised including genetic, autoimmune, pathological (e.g., endometriomas) and iatrogenic, most cases are idiopathic. Iatrogenic causes include extensive ovarian surgery, chemotherapy, and radiation, which all cause ovarian tissue damage with loss of follicles. DOR should be distinguished from premature ovarian insufficiency (POI), which is defined as loss of ovarian activity before the age of 40 and is characterised by infrequent periods with absent or infrequent ovulation with raised circulating gonadotrophins and symptoms of oestrogen deficiency. DOR should also not be confused with poor ovarian response (POR), which implies a reduced response to controlled ovarian hyperstimulation during IVF treatment resulting in reduced number of retrieved oocytes (Yun et al., 2017). According to the European Society of Human Reproduction (ESHRE) Bologna consensus, DOR can be diagnosed in the presence of at least two of three criteria including 1) Advanced maternal age > 40 yrs. or any other risk factors for poor ovarian response, 2) Previous POR (≤ 3 oocytes with conventional stimulation of >149 IU FSH daily), and 3) and abnormal ovarian reserve test (antral follicle count (AFC) < 5–7, or anti-Müllerian hormone (AMH) < 0.5–1.1 ng/ml) (Ferraretti et al., 2011).

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OVARIAN RESERVE UTILITY In clinical practice, testing for ovarian reserve is used to assess fertility potential and to predict ovarian response to various fertility treatments especially in-vitro fertilisation (IVF). Testing for reproductive potential is usually considered in women presenting with subfertility, women with suspected ovarian damage and those wishing to delay their fertility. Currently, an increasing number of women particularly in the developed world opt to defer childbearing until later in life for various reasons such as education, career establishments, partnership changes, and economic uncertainty (Mills et al., 2011). Most of these women would wish to establish their fertility status and to assess their reproductive life span to help them plan their future (Tremellen et al., 2014; Hvidman et al., 2014). In women undergoing IVF, assessment of ovarian reserve helps to predict success, counsel patients, and modify treatment regimen to maximise success. Currently there is no method that can directly measure the true ovarian reserve i.e., the total follicle pool. Several surrogate markers have been developed over the last 2-3 decades to serve as a proxy for oocyte quantity but are considered poor predictors of oocyte quality. Commonly used tests include biochemical markers, such as circulating follicle stimulating hormone (FSH), inhibin B, estradiol (E), and anti-Müllerian hormone (AMH); ultrasound markers, including antral follicle count (AFC) and ovarian volume (OV); and dynamic tests including clomiphene citrate challenge test (CCCT), gonadotrophin-releasing hormone agonist stimulation test (GAST) and exogenous FSH ovarian reserve test (EFORT). Circulating AMH and AFC are widely accepted as the most reliable ovarian reserve marker (Jayaprakasan et al., 2010; Boer et al., 2009). Although both these tests only reflect the number of small antral follicles, it is believed that this number correlates with the total follicle pool. However, this correlation remains largely uncertain and whether it changes with the advancing age remains to be investigated. AMH, and AFC should therefore be considered as surrogate markers that can only give a rough estimate of the true ovarian reserve.

Introduction – The Concept of Ovarian Reserve

5

This book presents a detailed background on the physiology of ovarian reserve including early ovarian development, follicular dynamics, and the natural history of primordial follicles. This will be followed by a detailed and comprehensive account on various biochemical, sonographic, and dynamic markers and their current applications. A special chapter will be devoted to anti-Müllerian hormone (AMH), which is the most extensively researched and most widely used ovarian reserve marker. The book will also discuss the role of AMH and its clinical utility in polycystic ovarian syndrome (PCOS). The book will then explore the clinical applications of ovarian reserve testing in health and in various reproductive disorders including early ovarian aging, diminished ovarian reserve (DOR), poor ovarian response (POR) during assisted reproduction technology (ART), and premature ovarian insufficiency (POI).

REFERENCES Broer SL, Mol BW, Hendriks D, Broekmans FJ. The role of anti-Müllerian hormone in prediction of outcome after IVF: comparison with the antral follicle count. Fertil Steril. 2009; 91:705–714. Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna Criteria. Hum Reprod. 2011; 26:1616– 1624. doi: 10.1093/humrep/der092. Gleicher N, Weghofer A, Oktay K, Barad DH. Is the immunological noise of abnormal autoimmunity an independent risk factor for premature ovarian aging? Menopause. 2009; 16:760–764. doi: 10.1097/gme.0b013 e318193c48b. Hvidman HW, Petersen KB, Larsen EC, Macklon KT, Pinborg A, Nyboe Andersen A. Individual fertility assessment and pro-fertility counselling; should this be offered to women and men of reproductive age? Hum Reprod. 2014; 30:9–15.

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Jayaprakasan K, Campbell B, Hopkisson J, Johnson I, Raine-Fenning N. A prospective, comparative analysis of anti-Müllerian hormone, inhibinB, and three-dimensional ultrasound determinants of ovarian reserve in the prediction of poor response to controlled ovarian stimulation. Fertil Steril. 2010; 93:855-864. doi: 10.1016/j.fertnstert.2008.10.042. Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004; 428(6979):145-150. Jurisicova A, Taniuchi A, Li H, Shang Y, Antenos M, Detmar J, Xu J, Matikainen T, Benito Hernández A, Nunez G, Casper RF. Maternal exposure to polycyclic aromatic hydrocarbons diminishes murine ovarian reserve via induction of Harakiri. J Clin Invest. 2007; 117:3971– 3978. doi: 10.1172/JCI28493. Levi AJ, Raynault MF, Bergh PA, Drews MR, Miller BT, Scott RT, Jr. Reproductive outcome in patients with diminished ovarian reserve. Fertil Steril. 2001; 76:666–669. doi: 10.1016/S0015-0282(01)02017-9. May-Panloup P, Ferré-L'Hôtellier V, Morinière C, Marcaillou C, Lemerle S, Malinge MC, Coutolleau A, Lucas N, Reynier P, Descamps P, Guardiola P. Molecular characterization of corona radiata cells from patients with diminished ovarian reserve using microarray and microfluidic-based gene expression profiling. Hum Reprod. 2012; 27:829–43. doi: 10.1093/humrep/der431. Mills M, Rindfuss RR, McDonald P, Te Velde E. Why do people postpone parenthood? Reasons and social policy incentives. Hum Reprod Update. 2011; 17:848–860. Pastore LM, Young SL, Baker VL, Karns LB, Williams CD, Silverman LM. Elevated prevalence of 35–44 FMR1 trinucleotide repeats in women with diminished ovarian reserve. Reprod Sci. 2012; 19:1226–1231. doi: 10.1177/1933719112446074. Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril 2015; 103:e9–e17. doi: 10.1016/j.fertnstert.2014. 12.093.

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Richardson MC, Guo M, Fauser BCJM, Macklon NS. Environmental and developmental origins of ovarian reserve. Human Reproduction Update. 2014; 20:353-369 https://doi.org/10.1093/humupd/dmt057. Tilly JL, Niikura Y, Rueda BR. The current status of evidence for and against postnatal oogenesis in mammals: a case of ovarian optimism versus pessimism?. Biol Reprod. 2009; 80:2–12. doi: 10.1095/ boilreprod.108.069088. Tremellen K, Savulescu J. Ovarian reserve screening: A scientific and ethical analysis. Hum Reprod. 2014; 29:2606–2614. Virant-Klun I, Zech N, Rozman P, Vogler A, Cvjeticanin B, Klemenc P, Malicev E, Meden-Vrtovec H. Putative stem cells with an embryonic character isolated from the ovarian surface epithelium of women with no naturally present follicles and oocytes. Differentiation. 2008; 76:843856. Virant-Klun I, Rozman P, Cvjeticanin B, Vrtacnik-Bokal E, Novakovic S, Rülicke T, Dovc P, Meden-Vrtovec H. Parthenogenetic embryo-like structures in the human ovarian surface epithelium cell culture in postmenopausal women with no naturally present follicles and oocytes. Stem Cells Dev. 2009; 18:137-149. Yun BH, Kim G, Park SH, Noe EB, Seo SK, Cho S, Choi YS, Lee BS. In vitro fertilization outcome in women with diminished ovarian reserve. Obstet Gynecol Sci. 2017; 60:46–52. doi: 10.5468/ogs.2017.60.1.46. Zhang D, Fouad H, Zoma WD, Salama SA, Wentz MJ, Al-Hendy A. Expression of stem and germ cell markers within nonfollicle structures in adult mouse ovary. Reprod Sci. 2008; 15:139-146. Zou K, Yuan Z, Yang Z, Luo H, Sun K, Zhou L, Xiang J, Shi L, Yu Q, Zhang Y, Hou R, Wu J. Production of offspring from a germline stem cell line derived from neonatal ovaries, Nat Cell Biol. 2009; 11:631–636. Zuckerman S. The number of oocytes in the mature ovary. Rec Prog Horm Res. 1951; 6:63–108.

Chapter 2

NATURAL HISTORY OF THE PRIMORDIAL FOLLICLES Primordial follicles are the initial phase of the ovarian follicles that comprise the total pool of resting (nongrowing) follicles, which are formed during the second half of the fetal life and from which all growing follicles are derived. Each primordial follicle consists of a small primary oocyte surrounded by a single layer of squamous granulosa cells enclosed in a thin basal lamina. Each follicle either remains dormant, dies by attrition, or enters the growing phase. A small number of primordial follicles are continuously activated to exit the ovarian reserve and begin the process of folliculogenesis, which is initiated during fetal life and continues until the end of reproductive phase of the woman’s life (Edson et al., 2009). The majour stages of folliculogenesis include formation of primordial follicles, recruitment into the growing phase to form primary, secondary, and tertiary follicles; and subsequent ovulation with formation of a corpus luteum. Preantral and antral follicles appear in fetal ovary from 26 weeks onwards (Kurilo et al., 1981; Reynaud et al., 2004; Baker, 1963).

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PRENATAL FOLLICULOGENESIS During early embryonic development, precursors of the primordial germ cells (PGCs) originate as early as post-fertilisation day 6 in the proximal region of the epiblast, close to the extraembryonic endoderm. Around postfertilisation day 7 (i.e., end of 3rd week of gestation), these precursor cells produce 30-40 PGCs. Early in the process of gastrulation, the PGCs are the first cells in the epiblast to migrate through the primitive streak into the posterior endoderm that forms the hindgut (Fujimoto et al., 1977). PGCs first become recognizable at 24 days post-fertilization in the endoderm of the dorsal yolk sac wall mainly in the yolk stalk at the junction with the hindgut. PGCs are identifiable by their large size and clear cytoplasm containing fewer organelles, which distinguish them from the endodermal cells (Motta et al., 1997a; Motta et al., 1997b). Once specified, PGCs enter a period of migration and proliferation. They first change from a resting round or elliptic form, to an irregular shape with pseudopodia to allow for amoeboid movement (Fuyuta et al., 1974; Fujimoto et al., 1977). At the end of the fourth post-fertilisation week, the hindgut is formed by invagination of the yolk sac wall into the embryo proper. This invagination takes the PGCs into an intraembryonic position. They then separate from the yolk sac epithelium and migrate to the hindgut by approximately 4 weeks post-fertilization. From the hindgut epithelium, the PGCs migrate through the dorsal mesentery, finally reaching the genital ridge by approximately 6 weeks post-fertilization. PGCs that go astray during migration ending up in extra-gonadal locations usually undergo apoptosis, but if they survive, they may develop into teratomas. PGCs that arrive at the genital ridge are referred to as oogonia. They continue to proliferate by mitosis reaching approximately 600,000 cells by 10 weeks of gestation. Oogonial proliferation is characterized by incomplete cytoplasmic division (known as cytokinesis), resulting in clusters of cells known as “oocyte nests” that form a network as a result of cytoplasmic continuity via intracellular bridges (Gondos and Zamboni, 1969; Gondos et al., 1971; Pepling and Spradling, 1998; Gomperts et al., 1994). From 10 weeks onwards, oogonia take three different routes including mitosis,

Natural History of the Primordial Follicles

11

meiosis and atresia. Meiosis transforms oogonia to primary oocytes, which are temporarily protected from atresia. At 20 weeks of gestation, the ovarian germ cell number reaches its peak totaling approximately 7 million cells, of which two thirds are primary oocytes and one third are oogonia (Peters, 1976). The number of germ cells continues to decline until birth as explained below. At 20 weeks of gestation, the rate of oogonial atresia increases and mitosis declines resulting in a complete exhaustion of the oogonial component by 30 weeks of gestation. On the other hand, at 20 weeks of gestation the primary oocytes undergo oocyte nest breakdown as the intercellular bridges are lost and become surrounded by squamous pregranulosa cells forming primordial follicles. Each of these follicles measures 30 - 60 μm in diameter and contains a primary oocyte measuring 9-25 μm (Lintern et al., 1974). From 26 weeks onwards, resting primordial follicles either remain quiescent, die by attrition, or enter the growing phase with subsequent atresia at the primary, secondary, or antral phase. Follicular atresia continues at a rapid pace leaving approximately two million follicles at birth (Gougeon, 1996; Gougeon and Chainy 1987; Reynaud et al., 2004; Kurilo et al., 1981). A randomly selected small cohort of the resting primordial follicles are continuously activated by an unknown stimulus to enter the growing phase. The rate of primordial follicle activation seems to be tightly regulated through mechanisms yet to be fully determined to ensure continuous replenishment of a stable number of growing follicles. Whilst the preantral follicle development is independent of gonadotropin stimulation, antral follicle formation and further progression is dependent on gonadotropins, especially FSH. However, FSH seems to play a role in the early preantral follicle activation as evidenced by presence of FSH receptors in the granulosa cells of these follicles. The initiation of follicular growth is characterized by granulosa cell proliferation and change to a cuboidal shape followed by oocyte enlargement and zona pellucida formation. The follicles reaching diameter >60 μm with a single cuboidal granulosa cell layer are called primary follicles. Subsequent increases in oocyte diameter to 80 μm and granulosa

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cell layers (approximately 600 cells) leads to the formation of secondary follicles (diameter 110-120 μm). Both primary and secondary follicles appear in the ovary from 26 weeks onwards. The early theca interna is acquired at the end of the primary follicle stage. The theca externa forms as the follicle expands and compresses the surrounding stroma. As a secondary follicle is being formed, the granulosa cells develop FSH, estrogen, and androgen receptors and become coupled by gap junctions. The formation of the thecal layer is associated with the development of a follicular blood supply from arterioles that terminate in a wreath-like network of capillaries adjacent to the basement membrane. Concomitantly, the theca cells acquire LH receptors and the capacity to synthesize steroid hormones. Follicles in the fetal and infant ovary have no steroidogenic capacity, which only becomes evident at puberty, although they express cholesterol side-chain cleavage and 17α-hydroxylase/17, 20desmolase activities.

PREPUBERTAL FOLLICULOGENESIS The newborn ovary measures approximately 1.3 cm × 0.5 cm × 0.3 cm and weighs >0.3 g. After birth, the follicular number continues to decrease due to follicular atresia, but at a slower rate compared to prenatally. By the onset of puberty, approximately 400,000 follicles constitute the total ovarian reserve. Although there is an emerging body of evidence suggesting that neooogenesis may occur after birth from ovarian or extra-ovarian germline stem cells, this hypothesis remains controversial (Hübner et al., 2003; Telfer et al., 2012). It is unlikely, however, that this hypothesized post-natal oogenesis, could have a significant impact on the rate of depletion of the follicle pole because the rate of follicle loss far outweighs that of any oocyte renewal. Nevertheless, if validated, this concept could pave the way to important therapeutic developments through the use of germline cells to restore ovarian reserve in women with premature ovarian aging.

Natural History of the Primordial Follicles

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The steady decline in the population of primordial follicles results from either progression of follicles through the various stages of development or from loss by atresia (Block et al., 1952; Richardson et al., 1987; Forabosco et al., 1991; Gougeon et al., 1994). Follicular development occurs during childhood, but without ovulation, hence no corpora lutea or corpora albicans are observed in the prepubertal ovary. Follicular atresia occurs in the resting phase as well as throughout all stages of development, with the most obvious follicle loss affecting the antral stages.

FOLLICULOGENESIS BEYOND PUBERTY Adult ovaries are ovoid, measuring on average 4 cm × 2 cm × 1 cm, and weighing 7 g. After puberty, depletion of the primordial follicles by atresia in the resting or the growing phase continues, but at a slower rate reducing the total pool from 400,000 follicles to approximately 25,000 at age 37.5 years. Thereafter the follicle depletion speeds up taking the follicles down to approximately 1000 by the age of 50 (Faddy and Gosden, 1996; Faddy and Gosden, 1995). With the onset of puberty, and with the rise of circulating FSH a small cohort of antral follicles (2-5mm) start to escape from atresia to be recruited into monthly ovulatory cycles as explained below. Approximately 400 follicles ovulate during a woman’s reproductive life, with most of the follicles dying before maturation (Morita and Tilly, 1999). Morphometric and animal studies have demonstrated that follicle loss occurs at a relatively high speed during childhood, then slows down during the peak reproductive years and accelerates again in the premenopausal years (Richardson et al., 1987; Faddy et al., 1992). The slowing down of follicle loss during the respective years has been attributed to the maturing follicles during the ovulatory cycles, which exert an inhibitory effect on initial recruitment of primordial follicles. The accelerated follicle loss in the perimenopausal years may reflect diminished inhibitory influences amongst the remaining primordial follicles, which become increasingly less packed and fewer in numbers (McGee et al., 2000).

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Puberty is associated with maturation of the hypothalamic pituitary ovarian (HPO) axis resulting in an increase in circulating FSH. When this reaches a certain threshold, it rescues the available cohort of small antral follicles from atresia and recruit them into an ovulatory cycle. These follicles continue to grow further until the largest reaches 8 mm in diameter and gets selected, whilst the remaining smaller follicles will become atretic. The rising levels of oestrogen and inhibins secreted by the growing follicles inhibit FSH secretion via a negative feedback mechanism resulting in decrease of FSH below the threshold level thereby closing the FSH window. This results in atresia of the small unselected follicles, which are FSHdependant. This mechanism is essential to ensure mono ovulation. The selected follicle, which has by now acquired LH-receptors and changed from FSH- to LH-dependence, continues to grow to maturation and finally ovulation. The increasing oestrogen levels from the dominant follicle result in an increase in LH by means of positive feedback mechanism leading to an LH surge that is necessary for ovulation. Following ovulation, the follicle changes to the corpus luteum, which will continue to secrete sex hormones to support any potential conception by preparing the endometrium for embryonic implantation. If no conception occurs, the corpus luteum will start to degenerate after one week to become fibrotic resulting in the corpus albicans. The decline in circulating oestrogen and progesterone because of the CL degeneration, results in a feedback increase in FSH levels. When this reaches the threshold level, it will trigger a new ovulatory cycle. It has been estimated that progression from the primordial to primary follicles takes several months and from primary to antral follicles 120 days. Antral follicles measuring 2-5mm develop into the Graafian follicles in 14 days during the follicular phase of the menstrual cycle (Gougeon, 1986; Gougeon, 1996). Follicular development is associated with oocyte morphological and functional changes supported by transport of nutrients and other essential factors across the gap junctions that connect the surrounding granulosa cells to the oocyte (Albertini et al., 2001). Oocytes continue to grow until ovulation, but do not resume meiosis until fertilised (Johnson et al., 2007).

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Morphological oocyte changes include growth, complete elaboration of the zona pellucida and increase in cytoplasmic organelles, particularly the mitochondria, which become clustered around the germinal vesicle (Pozo et al., 1990). When the oocytes reach a critical size, they acquire “meiotic competence” i.e., ability to resume meiosis. In addition, oocytes also acquire “developmental competence,” i.e., the ability to support preimplantation embryo development (McLay et al., 2002; Carroll et al., 1994). At the completion of oocyte growth, mRNA transcription is actively silenced and protein translation slows substantially. After this transcriptional silencing, preovulatory oocytes rely on proteins and mRNA derived from cumulus granulosa cells through the gap junctional communication.

PERIMENOPAUSAL OVARIAN FUNCTION Beyond age 37, the rate of follicle loss is accelerated and by the age 50, only 1000 follicles remain (Faddy and Gosden, 1996; Faddy and Gosden, 1995). However, there is a wide variation amongst women in the rate of follicle loss, which is reflected in the wide range of onset of menopause between 45 and 51 years. Aging is also associated with a progressive deterioration in the quality of the oocytes especially beyond the age of 40. This is associated with a reduction in the competence of oocytes to be fertilized and to develop into healthy embryos resulting in progressively reduced fertility and increased aneuploidy and early pregnancy loss. Menopausal ovaries weigh half as much as the adult ovary and contain few if any primordial follicles and a wide variety of stromal-like cells (Battaglia et al., 2008; Selesniemi et al., 2011).

REFERENCES Albertini DF, Combelles CM, Benecchi E, Carabatsos MJ. Cellular basis for paracrine regulation of ovarian follicle development. Reproduction. 2001; 121:647-653. doi: 10.1530/rep.0.1210647.

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Battaglia DE, Goodwin P, Klein NA, Soules MR. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod. 1996; 11:2217-2222. doi: 10.1093/oxfordjournals. humrep.a019080. Block E. Quantitative morphological investigations of the follicular system in women; variations at different ages. Acta Anat (Basel). 1952;14(12):108-123. doi: 10.1159/000140595. Carroll J, Swann K, Whittingham D, Whitaker M. Spatiotemporal dynamics of intracellular [Ca2+]i oscillations during the growth and meiotic maturation of mouse oocytes. Development. 1994; 120(12):3507-3517. Edson MA, Nagaraja AK, Matzuk MM. The mammalian ovary from genesis to revelation. Endocr Rev. 2009; 30:624–712. Faddy MJ, Gosden RG. A mathematical model of follicle dynamics in the human ovary. Hum Reprod 1995; 10:770–775. Faddy MJ, Gosden RG. A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod 1996; 11:1484–1486. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992; 7:1342-1346. Forabosco A, Sforza C, De Pol A, Vizzotto L, Marzona L, Ferrario VF. Morphometric study of the human neonatal ovary. Anat Rec. 1991; 231:201-208. doi: 10.1002/ar.1092310208. Fujimoto T, Miyayama Y, Fuyuta M. The origin, migration and fine morphology of human primordial germ cells. Anat Rec. 1977; 188:315330. doi: 10.1002/ar.1091880305. Fuyuta M, Miyayama Y, Fujimoto T. Histochemical identification of primordial germ cells in human embryos by PAS reaction. Okajimas Folia Anat Jpn. 1974; 51:251-262. doi: 10.2535/ofaj1936.51.5_251. Gomperts M, Garcia Castro M, Wylie C, et al: Interactions between primordial germ cells play a role in their migration in mouse embryos. Development. 1994; 120:135–141. Gondos B, Zamboni L: Ovarian development: the functional importance of germ cell interconnections, Fertil Steril. 1969; 20:176–189.

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Gondos B, Bhiraleus P, Hobel CJ: Ultrastructural observations on germ cells in human fetal ovaries, Am J Obstet Gynecol. 1971;110:644–652. Gougeon A. Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod. 1986; 1:81-87. doi: 10.1093/oxford journals.humrep.a136365. Gougeon A, Chainy GB. Morphometric studies of small follicles in ovaries of women at different ages. J Reprod Fertil 1987; 81:433–442. Gougeon A, Ecochard R, Thalabard JC. Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol Reprod. 1994; 50:653-663. doi: 10.1095/biolreprod50.3.653. Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev 1996; 17:121–155. Hübner K, Fuhrmann G, Christenson LK, et al: Derivation of oocytes from mouse embryonic stem cells. Science 2003; 300:1251–1256. Hübner K, Fuhrmann G, Christenson LK, Kehler J, Reinbold R, De La Fuente R, Wood J, Strauss JF 3rd, Boiani M, Schöler HR. Derivation of oocytes from mouse embryonic stem cells. Science. 2003; 300(5623):1251-1256. doi: 10.1126/science.1083452. Johnson MT, Freeman EA, Gardner DK, Hunt PA. Oxidative metabolism of pyruvate is required for meiotic maturation of murine oocytes in vivo. Biol Reprod. 2007; 77:2-8. doi: 10.1095/biolreprod.106.059899. Kurilo LF. Oogenesis in antenatal development in man. Hum Genet 1981; 57:86–92. Lintern-Moore S, Peters H, Moore GP, Faber M. Follicular development in the infant human ovary. J Reprod Fertil. 1974; 39:53-64. doi: 10.1530/ jrf.0.0390053. McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev. 2000; 21(2):200-214. https://doi.org/10.1210/edrv.21.2. 0394. McLay DW, Carroll J, Clarke HJ. The ability to develop an activity that transfers histones onto sperm chromatin is acquired with meiotic competence during oocyte growth. Dev Biol. 2002; 241:195-206. doi: 10.1006/dbio.2001.0499.

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Morita Y, Tilly JL. Oocyte apoptosis: like sand through an hourglass. Dev Biol 1999; 213:1–17. Motta PM, Makabe S, Nottola SA. The ultrastructure of human reproduction. I. The natural history of the female germ cell: origin, migration and differentiation inside the developing ovary. Hum Reprod Update. 1997a; 3:281-295. doi: 10.1093/humupd/3.3.281. Motta PM, Nottola SA, Makabe S. Natural history of the female germ cell from its origin to full maturation through prenatal ovarian development. Eur J Obstet Gynecol Reprod Biol. 1997b; 75:5-10. doi: 10.1016/s03012115(97)00216-9. Pepling ME, Spradling AC. Female mouse germ cells form synchronously dividing cysts. Development. 1998; 125:3323-3328. Peters H: Intrauterine gonadal development. Fertil Steril. 1976; 27:493–500. https://doi.org/10.1016/S0015-0282(16)41829-7. Pozo J, Corral E, Pereda J. Subcellular structure of prenatal human ovary: mitochondrial distribution during meiotic prophase. J Submicrosc Cytol Pathol. 1990; 22(4):601-607. Reynaud K, Cortvrindt R, Verlinde F, De Schepper J, Bourgain C, Smitz J. Number of ovarian follicles in human fetuses with the 45,X karyotype. Fertil Steril. 2004; 81(4):1112-1119. doi: 10.1016/j.fertnstert.2003.12. 011. Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987; 65:1231-1237. Selesniemi K, Lee HJ, Muhlhauser A, Tilly JL. Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proc Natl Acad Sci U S A. 2011; 108:12319-24. doi: 10.1073/pnas.1018793108. Telfer EE, Albertini DF: The quest for human ovarian stem cells, Nat Med 2012; 18:353–354.

Chapter 3

OVARIAN RESERVE TESTING HISTORICAL PERSPECTIVE AND DEFINITION Historically, the term ovarian reserve was first used by Navot et al. (1987) who introduced the clomiphene citrate challenge test (CCCT) as a predictor of natural fertility in women of ≥35 years of age. An exaggerated FSH response to the CCCT was predictive of a low chance of spontaneous pregnancy and was considered an evidence of diminished ovarian reserve (DOR). The test was shown to be of value in unmasking DOR, which would not have been detected by basal FSH screening alone. Since then ovarian reserve testing gained an increasing importance as a means of predicting the outcome of assisted reproductive technology (ART). In that context, circulating early follicular FSH was the first test to be introduced in 1988 (Scott et al., 1989), followed by GnRH agonist stimulation test (GAST) in 1990 (Garcia et al., 1990; Padilla et al., 1990) then exogenous FSH ovarian reserve test (EFORT) in 1994 (Fanchin et al., 1994). In 1997, circulating inhibin B (Seifer et al., 1997), antral follicular count (AFC) and ovarian volume (Tomas et al., 1997) were introduced followed by circulating anti-Müllerian hormone (AMH) in 2002 (van Rooij et al., 2002). The provocative tests (CCCT, GAST and EFORT) have gradually been abandoned due to complexity, costs, and inconvenience.

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Currently, the most widely used OR tests in clinical practice are the early follicular serum FSH and AMH concentrations in addition to AFC. Although the term ovarian reserve (OR) has been widely used in clinical practice for decades, it still lacks a clear and a universally agreed definition. It is commonly used to describe a woman’s reproductive potential as determined by the number of the total ovarian follicle pool (Practice Committee of the American Society of Reproductive Medicine (ASRM), 2015). Several other definitions and terms have been proposed, such as “ovulatory potential” (Findlay et al., 2015) or “dynamic reserve” (Monniaux et al., 2014), indicating the growing follicle pool that can potentially progress to maturation and ovulation. The attainment of ovarian reserve and the rate of its decline with age are determined by genetic and environmental factors (Tal and Seifer, 2013). The decline in ovarian reserve with advancing age, which is irreversible, varies considerably in different women resulting in a wide variation in the onset of menopause (Dewailly et al., 2014a). Currently, there is no test that can directly measure the true ovarian reserve i.e., the total follicle pool. Instead ovarian reserve tests are considered surrogate markers, which serve as a proxy for the total oocyte number. While these markers may predict the oocyte quantity, they are poor predictors of the oocyte quality, for which age remains the best predictor (Gurtcheff and Klein, 2011; Tal and Seifer, 2017; Morin et al., 2018). Commonly used tests include biochemical markers, such as circulating FSH, inhibin B, oestradiol (E), and AMH; ultrasound markers including AFC and ovarian volume (OV); and dynamic tests such as CCCT, gonadotrophinreleasing hormone agonist stimulation test (GAST) and exogenous FSH ovarian reserve test (EFORT). Circulating AMH and AFC are widely accepted as the most reliable ovarian reserve markers (Jayaprakasan et al., 2010; Boer et al., 2009). Although both these tests only reflect the number of small antral follicles, it is believed that this number correlates with the total follicle pool. However, this correlation remains largely uncertain and whether it changes with the advancing age remains to be investigated. AMH, and AFC should therefore be considered a rough estimate of the true ovarian reserve.

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LIMITATIONS OF OVARIAN RESERVE TESTING It is important to recognise that all ovarian reserve tests have inherent limitations and should be interpreted with caution. Main reasons for these limitations include inter- and intra-cycle variability, assay variability (of biochemical markers) and inter- and intra-observer variability (in ultrasound markers). Caution should therefore be exercised when OR test results are used to assess fertility potential in young women or to determine suitability for various fertility treatments. For instance, evidence of moderately reduced OR does not necessarily mean inability to conceive, but a reduced chance of conception. Similarly, abnormal ovarian reserve tests should not be used to deny women access to ART treatment, but as a means to help counselling women allowing them to make informed decisions. Furthermore, OR test results should be used to better plan and choose an appropriate ART treatment regimen.

THE CHOICE OF AN OVARIAN RESERVE TEST Ovarian reserve testing could be considered as a screening test for the early detection of diminished ovarian reserve (DOR) in women who are otherwise asymptomatic. An ideal screening test should be inexpensive, non-invasive, acceptable to women, valid (i.e., sensitive and specific) and reproducible with minimal inter- and intra-cyclical variability (Wilson and Jungner, 1968; Andermann et al., 2008). A valid OR test should have acceptable sensitivity (with minimal false negative results) and specificity (i.e., with minimal false positive results) in detecting DOR early enough to allow timely interventions. Other important features for a good test is that the condition concerned should be an important health problem with an early asymptomatic phase, for which there should be an effective early intervention. Although there is currently no intervention that could correct DOR or prevent its progress to premature ovarian insufficiency (POI), women could be counselled appropriately with regards to their fertility potential and future risks associated with POI. Recognition of DOR in the

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context of ART could be crucial in determining the appropriate stimulation protocol to maximise success. As a perfect OR test is not yet available, the closest is the circulating AMH, which fulfils most of the above criteria.

OVARIAN RESERVE TESTS IN CURRENT USE Anti-Müllerian Hormone (AMH) Since the introduction of the commercially available assays in 2000, AMH has been the most extensively studied ovarian reserve marker in the last two decades with over 1200 publications on PubMed. Furthermore, there has been a growing interest in using AMH measurement outside ART such as screening for DOR, prediction of age of menopause, assessment of iatrogenic or pathological ovarian damage, diagnosis of PCOS and detection of POI. AMH is a much better screening tool for early detection of declining ovarian reserve as it starts to decrease years before the rise in FSH (Wiweko et al., 2013). Despite all the issues and limitations associated with the old and new AMH assays, there is now a plethora of evidence confirming that AMH is the most reliable ovarian reserve biomarker (Lukaszuk et al., 2014; Steiner et al., 2011; Depmann et al., 2016; Lukaszuk et al., 2014; Nelson et al., 2007). Given its relative stability with insignificant inter- and intracycle variability, AMH is superior to FSH with its marked inter-cycle fluctuations (Hadlow et al., 2013; Kissell et al., 2014). Furthermore, as AMH is secreted by follicles during early folliculogenesis, it correlates more closely to the primordial follicle pool compared to other follicular biomarkers including inhibin B and estradiol, which are produced during late folliculogenesis. AMH is also more reflective of the true follicle pool compared to AFC, which does not detect preantral follicles that are only reflected by AMH. This is supported by several recent multicentre trials in ART consistently reporting that AMH was a better predictor of ovarian response and the number of oocytes retrieved compared to AFC (Andersen et al., 2011; Arce et al., 2013; Polyzos et al., 2013; Nelson et al., 205).

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Like all other OR markers, AMH only reflects the quantity but not the quality of the follicle pool (Tal and Seife, 2017). AMH will be discussed in more details in chapter 4.

Antral Follicle Count (AFC) Antral follicle count (AFC) was first described in 1997 by Tomas et al. (1997) and has since been widely accepted as a useful and reliable ovarian reserve marker and predictor of IVF outcome. It is defined as the sum of small antral follicles in both ovaries identified in the early follicular phase (day 2-4) using transvaginal (TV) ultrasound scan with a minimum frequency of 7 MHz (Jayaprakasan et al., 2010). The most commonly used follicle diameter to define AFC is 2-10 mm (Hendriks et al., 2005; Practice Committee of the ASRM, 2015), although other diameters have been used as well e.g., 2-5, 2-6 and 2-8 mm (Chang et al., 1998; Sharara and McClamrock, 2000; Nahum et al., 2001; Bancsi et al., 2002; Haadsma et al., 2009). If a TV scan is not possible, e.g., in virgin women, a transrectal scan should be considered in preference to the transabdominal route, as it offers same image quality as TV scan (Lee et al., 2015; Sun et al., 2007; TimorTritsch et al., 2003). To obtain AFC, the ovary is centred on the screen and the image is adjusted along its largest axis to occupy at least 50% of the view. All follicles measuring 2–10 mm in diameter are counted while scanning the ovary from one margin to the other. For practicality, follicular diameter is only measured when in doubt if it is within the 2 to10 mm range (Coelho Neto et al., 2018). Gougeon et al. (1984) conducted a histological study of the ovaries, which demonstrated that the number of small antral follicles correlated well with the size of the primordial follicle pool. Pellicer et al. (1998) reported a high correlation between the sonographically and histologically counted small follicles (2-5mm in diameter). This led many investigators to consider the sonographically determined AFC as one of the best surrogate markers of the true ovarian reserve (Haadsma et al., 2009; Bancsi et al., 2002; Hendriks et al., 2005; Nelson et al., 2013). Furthermore, as the antral follicles are

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responsive to FSH, AFC may be considered a good predictor of ovarian responsiveness to gonadotropins (Nelson et al., 2013) and the chance of pregnancy during IVF (Jayaprakasan et al., 2012). AFC can predict both poor and exaggerated ovarian response (Farquhar et al., 2017; Ng et al., 2000) and can accurately predict the number of retrieved oocytes following ovarian stimulation during IVF (Practice Committee of the ASRM, 2105; Jayaprakasan et al., 2012, Hvidman et al., 2016; Nelson et al., 2103; Tremellen et al., 2014). Cut-off points ranging between four and ten follicles have been proposed in different studies to define the low AFC value that could accurately predict poor ovarian responsiveness, reduced number of retrieved oocytes and low pregnancy rate after IVF [Gabreel et al., 2009; Haadsma et al., 2007; Deb et al., 2010; Jayaprakasan et al., 2012). Some studies have reported an AFC  4 (13%) (Depmann et al., 2016; Wellons et al., 2013). AFC has several advantages as an ovarian reserve marker including its readily availability as a non-invasive, simple, technically easy, and quick test that provides an instant result in an outpatient setting. Additionally, it offers the added benefit of anatomical assessment of the reproductive system with assessment of ovarian position and accessibility for oocyte retrieval and detection of any tubo-ovarian or uterine pathology. There are, however, several limitations and downsides to the use of AFC as an ovarian reserve test. Firstly, the accuracy and reliability of AFC are operator and equipment dependent. The variations in the sonographers’ experience and in the ultrasound machine resolution inevitably result in high inter- and intra-observer variability of AFC. Another important limiting factor is the lack of standardisation of the techniques used to assess AFC, the follicle size to be included in the count and the cut-off thresholds used to predict IVF outcomes. Moreover, assessment of AFC may be technically

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challenging in some women due to poor visibility of the ovaries e.g., due to distended bowel, obesity, or higher position of the ovary. In addition, AFC cannot be reliably assessed in the presence of an ovarian cyst or in women receiving hormonal contraception. Finally, AFC could potentially include atretic follicles in the count, thereby overestimating the number of antral follicles.

FOLLICLE STIMULATING HORMONE (FSH) Early follicular serum FSH level has been in use for over 30 years as an indirect ovarian reserve marker, which has been widely utilised as a tool to predict ovarian response during IVF (Scott et al., 1989). FSH level does not directly reflect the total follicle pool but inversely correlates with follicle production of oestradiol (E2) and Inhibin B through the HPO negative feedback mechanism. When the ovarian reserve starts to decline, the number of growing follicles decreases resulting in reduced E2 and Inhibin B. This in turn will lead to an increase in circulating FSH levels. However, FSH levels may be falsely lowered in women with diminished ovarian reserve (DOR) due to high levels of E2 and inhibin B caused by the initial increase in early follicular FSH. It has therefore been recommended to measure E2 at the same time of FSH measurement to exclude high E2 levels. An ultrasound scan may also be needed to exclude any functional ovarian cyst that could be a source of the elevated E2 (Odell et al., 1986; Licciardi et al., 1995; Tal and Seifer, 2017). Given the cyclical changes in FSH levels during the menstrual cycles, it is recommended to measure FSH on cycle days 2–5, during which FSH remains relatively stable (Hansen et al., 1996). Most published nomograms used for the predictive role of FSH during IVF are based on cycle day 3 measurements. Early follicular FSH level is only clinically useful as a predictor of poor IVF outcome in women with high FSH levels but has very little or no predictive value when the levels are normal. Different studies reported different FSH cut-off values (between 10 and 25 IUL/L) to predict IVF

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outcome. Whilst the specificity of high FSH in predicting poor ovarian response and failure to conceive is high, its sensitivity is quite low (Esposito et al., 2002; Broekmans et al., 2006). As far as OHSS, FSH has no predictive value in identifying women at increased risk of this complication. Esposito et al. (2002) reported that using a cut-off FSH value of >11.4 IU/L, based on WHO 78/549 standard, high FSH was a good predictor of poor prognosis in IVF whilst moderately elevated FSH (10–11.4 IU/L) had limited predictive ability. In a large systematic review including 34 studies, Broekmans et al. (2006) concluded that the probability of poor response in women with elevated FSH increases substantially (≥3-fold) with the increase of the cutoff FSH level used in different studies. According to a 2016 guideline from the European Society of Human Reproduction and Embryology (ESHRE), a consistent FSH value > 25 IU/L on two measurements > 4 weeks apart in women under 40 years of age is indicative of premature ovarian insufficiency (ESHRE Guideline Group on POI, 2016). The use of early follicular FSH as a predictor of IVF outcome has several major limitations including the marked cycle-to-cycle fluctuations, the between-assay variability and its poor sensitivity as explained above. Furthermore, a single high FSH value in a woman 35 years and in women with pathological or iatrogenic ovarian damage. Additionally, ORT is used for screening and diagnosis of premature ovarian insufficiency (POI) in women with risk factors such as family history of POI, DOR and autoimmune diseases. ORT has also been used to predict the age onset of menopause. Another utilisation

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for AMH is for the diagnosis of polycystic ovarian syndrome and granulosa cell tumour. The next chapters will provide more details on various clinical applications of ovarian reserve testing.

CONCLUSION Despite its high variability, FSH remains the most used screening test for ovarian reserve. AMH and AFC are gaining increasing popularity as the more reliable (with less variability) and accurate predictors of ovarian response during IVF. Age remains the only reliable predictor of the chance of pregnancy in women undergoing IVF. Therefore, most fertility centres use AMH and age as the main determinants of the success of ART. This is in line with the recent ESHRE guidelines, which recommend individualized strategies for ovarian stimulation based on age and AMH. Similarly, NICE guidelines recommend age as the predictor of chance of conception and one of three OR markers including basal FSH, AMH or AFC as the predictor of ovarian response to gonadotrophin stimulation during IVF (NICE Guidelines number 156, 2013). Both NICE and ESHRE guidelines recommended against the use E2, inhibin B, ovarian volume, ovarian blood flow as predictors of IVF outcome. There is also a consensus amongst fertility specialists that dynamic and combined ovarian reserve tests should be completely abandoned.

REFERENCES Andermann A, Blancquaert I, Beauchamp S, Déry V. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ. 2008; 86:317–319. doi: 10.2471/ blt.07.050112. https://doi.org/10.2471/blt.07.050112. Andersen AN, Witjes H, Gordon K, Mannaerts B. Xpect Investigators. Predictive factors of ovarian response and clinical outcome after

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IVF/ICSI following a rFSH/GnRH antagonist protocol with or without oral contraceptive pretreatment. Hum Reprod 2011; 26:3413-23. Arce JC, La Marca A, Mirner Klein B, Nyboe Andersen A, Fleming R. Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles: prediction of ovarian response and cumulative treatment outcome in good-prognosis patients. Fertil Steril. 2013; 99:1644-1653. Balasch J, Creus M, Fabregues F, Carmona F, Casamitjana R, Ascasco C, et al. Inhibin, follicle-stimulating hormone, and age as predictors of ovarian response in in vitro fertilization cycles stimulated with gonadotropinreleasing hormone agonist-gonadotropin treatment. Am J Obstet Gynecol 1996; 175:1226–1230. Baker TG. A quantitative and cytological study of germ cells in human ovaries. Proc R Soc Lond B Biol Sci. 1963; 158:417-433. doi: 10.1098/ rspb.1963.0055. Bancsi LF, Broekmans FJ, Eijkemans MJ, de Jong FH, Habbema JD, te Velde ER. Predictors of poor ovarian response in in vitro fertilization: a prospective study comparing basal markers of ovarian reserve. Fertil Steril 2002; 77:328–336. Bancsi LF, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Impact of repeated antral follicle counts on the prediction of poor ovarian response in women undergoing in vitro fertilization. Fertil Steril. 2004; 81:35-41. doi: 10.1016/j.fertnstert.2003.06.011. Bhal PS, Pugh ND, Chui DK, Gregory L, Walker SM, Shaw RW: The use of transvaginal power Doppler ultrasonography to evaluate the relationship between perifollicular vascularity and outcome in in-vitro fertilization treatment cycles. Hum Reprod 1999; 14:939–945. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006; 12:685–718. Chang MY, Chiang CH, Hsieh TT, Soong YK, Hsu KH. Use of the antral follicle count to predict the outcome of assisted reproductive technologies. Fertil Steril 1998; 69:505–10.

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Coelho Neto MA, Ludwin A, Borrell A, et al. Counting ovarian antral follicles by ultrasound: a practical guide. Ultrasound Obstet Gynecol. 2018; 51:10-20. doi: 10.1002/uog.18945. Coelho Neto MA, Martins WP, Lima ML, Barbosa MA, Nastri CO, Ferriani RA, Navarro PA. Ovarian response is a better predictor of clinical pregnancy rate following embryo transfer than is thin endometrium or presence of an endometrioma. Ultrasound Obstet Gynecol. 2015; 46: 501–505. Creus M, Peñarrubia J, Fábregues F, Vidal E, Carmona F, Casamitjana R, Vanrell JA, Balasch J. Day 3 serum inhibin B and FSH and age as predictors of assisted reproduction treatment outcome. Hum Reprod. 2000; 15:2341-2346. doi: 10.1093/humrep/15.11.2341. PMID: 11056 129. Csemiczky G, Harlin J, Fried G. Predictive power of clomiphene citrate challenge test for failure of in vitro fertilization treatment. Acta Obstet Gynecol Scand. 2002; 81:954-961. doi: 10.1034/j.1600-0412.2002. 811010.x. Depmann M, Broer SL, van der Schouw YT, Tehrani FR, Eijkemans MJ, Mol BW, Broekmans FJ. Can we predict age at natural menopause using ovarian reserve tests or mother's age at menopause? A systematic literature review. Menopause. 2016; 23:224-232. doi: 10.1097/GME. 0000000000000509. Dewailly D, Andersen CY, Balen A, Broekmans F, Dilaver N, Fanchin R, Griesinger G, Kelsey TW, La Marca A, Lambalk C et al. The physiology and clinical utility of anti-Müllerian hormone in women. Hum Reprod Update 2014a; 20:370–385. doi: 10.1016/j.fertnstert.2014.12.093. Dewailly D, Lujan ME, Carmina E, Cedars MI, Laven J, Norman RJ, Escobar Morreale HF. Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update 2014b; 20: 334–352. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014; 29:400–412. doi: 10.1093/humrep/det457.

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Elter K, Sismanoglu A, Durmusoglu F. Intercycle variabilities of basal antral follicle count and ovarian volume in subfertile women and their relationship to reproductive aging: a prospective study. Gynecol Endocrinol 2005; 20:137–143. Engmann L, Sladkevicius P, Agrawal R, Bekir JS, Campbell S, Tan SL. Value of ovarian stromal blood flow velocity measurement after pituitary suppression in the prediction of ovarian responsiveness and outcome of in vitro fertilization treatment. Fertil Steril. 1999; 71:22-29. doi: 10.1016/s0015-0282(98)00406-3. Esposito MA, Coutifaris C, Barnhart KT. A moderately elevated day 3 FSH concentration has limited predictive value, especially in younger women. Hum Reprod. 2002; 17:118-123. European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016; 31:926‐937. doi: 10.1093/humrep/dew027. Fanchin R, de Ziegler D, Olivennes F, Taieb J, Dzik A, Frydman R. Exogenous follicle stimulating hormone ovarian reserve test (EFORT): a simple and reliable screening test for detecting 'poor responders' in invitro fertilization. Hum Reprod. 1994; 9:1607-1611. doi: 10.1093/ oxfordjournals.humrep.a138760. Fanchin R, Taieb J, Lozano DH, Ducot B, Frydman R, Bouyer J. High reproducibility of serum anti-Mullerian hormone measurements suggests a multistaged follicular secretion and strengthens its role in the assessment of ovarian follicular status. Hum Reprod 2005; 20:923–7. Farquhar CM, Rae T, Thomas DC, Wadsworth J, Beard RW: Doppler ultrasound in the nonpregnant pelvis. J Ultrasound Med 1989; 8:451– 457. Farquhar C, Marjoribanks J, Brown J, Fauser B, Lethaby A, Mourad S, Rebar R, Showell M, van der Poel S. Management of ovarian stimulation for IVF: narrative review of evidence provided for World Health Organization guidance. Reprod Biomed Online 2017; 35:3–16. Garcia JE, Padilla SL, Bayati J, Baramki TA. Follicular phase gonadotropinreleasing hormone agonist and human gonadotropins: a better

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alternative for ovulation induction in in vitro fertilization. Fertil Steril. 1990; 53:302-305. doi: 10.1016/s0015-0282(16)53285-3. Gabreel A, Maheshwara A, Bhattacharya S, Johnson NP. Ultrasound tests of ovarian reserve: A systematic review of accuracy in predicting fertility outcomes. Hum Fertil. 2009; 12:95–106. Gougeon A. Qualitative and quantitative characterization of the follicular population in the adult human ovary [Caracteres qualitatifs et quantitatifs de la population folliculaire dans dans l'ovaire humain adulte]. Contracept Fertil Sex 1984; 12:527–535. Groome NP, Illingworth PJ, O’Brien M, et al. Detection of dimeric inhibin throughout the human menstrual cycle by two-site enzyme immunoassay. Clin Endocrinol. 1994; 40:717–723. Groome NP, Illingworth PJ, O’Brien M, et al. Measurement of dimeric inhibin B throughout the human menstrual cycle. J Clin Endocrinol Metab. 1996; 81:1401–1405. Hadlow N, Longhurst K, McClements A, Natalwala J, Brown SJ, Matson PL. Variation in antimüllerian hormone concentration during the menstrual cycle may change the clinical classification of the ovarian response. Fertil Steril. 2013; 99:1791-1797. doi: 10.1016/j.fertnstert. 2013.01.132. Hannoun A, Abu Musa A, Awwad J, Kaspar H, Khalil A. Clomiphene citrate challenge test: cycle to cycle variability of cycle day 10 follicle stimulating hormone level. Clin Exp Obstet Gynecol. 1998; 25:155-156. Hansen LM, Batzer FR, Gutmann JN, Corson SL, Kelly MP, Gocial B. Evaluating ovarian reserve: follicle stimulating hormone and oestradiol variability during cycle days 2-5. Hum Reprod. 1996; 11:486–9. Hendriks DJ, Broekmans FJ, Bancsi LF, de Jong FH, Looman CW, te Velde ER. Repeated clomiphene citrate challenge testing in the prediction of outcome in IVF: a comparison with basal markers for ovarian reserve. Hum Reprod. 2005; 20:163–169. Hendriks DJ, Mol BW, Bancsi LF, te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta-analysis and comparison with basal folliclestimulating hormone level. Fertil Steril. 2005; 83:291–301.

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Hendriks DJ, Mol BW, Bancsi LF, te Velde ER, Broekmans FJ. The clomiphene citrate challenge test for the prediction of poor ovarian response and nonpregnancy in patients undergoing in vitro fertilization: a systematic review. Fertil Steril. 2006; 86:807–818. Jain T, Soules MR, Collins JA. Comparison of basal follicle-stimulating hormone versus the clomiphene citrate challenge test for ovarian reserve screening. Fertil Steril. 2004; 82:180-185. doi: 10.1016/j.fertnstert. 2003.11.045. Jarvela IY, Sladkevicius P, Kelly S, Ojha K, Campbell S, Nargund G. Quantification of ovarian power Doppler signal with three-dimensional ultrasonography to predict response during in vitro fertilization. Obstet Gynecol. 2003; 102:816–22. Jayaprakasan K, Jayaprakasan R, Al-Hasie HA, Clewes JS, Campbell BK, Johnson IR, Raine-Fenning NJ. Can quantitative three-dimensional power Doppler angiography be used to predict ovarian hyperstimulation syndrome? Ultrasound Obstet Gynecol 2009; 33: 583–591. Jayaprakasan K, Campbell B, Hopkisson J, Johnson I, Raine-Fenning N. A prospective, comparative analysis of Anti-Müllerian hormone, inhibinB, and three dimensional ultrasound determinants of ovarian reserve in the prediction of poor response to controlled ovarian stimulation. Fertil Steril. 2010; 93:855–864. Jayaprakasan K, Chan Y, Islam R, et al. Prediction of in vitro fertilization outcome at different antral follicle count thresholds in a prospective cohort of 1,012 women. Fertil Steril. 2012; 98:657-663. doi: 10.1016/ j.fertnstert.2012.05.042. Jayaprakasan K, Hopkisson JF, Campbell BK, Clewes J, Johnson IR, RaineFenning NJ. Quantification of the effect of pituitary down-regulation on 3D ultrasound predictors of ovarian response. Hum Reprod. 2008; 23:1538-1544. doi: 10.1093/humrep/den128. Järvelä IY, Sladkevicius P, Kelly S, Ojha K, Campbell S, Nargund G. Quantification of ovarian power Doppler signal with three-dimensional ultrasonography to predict response during in vitro fertilization. Obstet Gynecol. 2003; 102:816-822.

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Kim SH, Ku SY, Jee BC, Suh CS, Moon SY, Lee JY. Clinical significance of transvaginal color Doppler ultrasonography of the ovarian artery as a predictor of ovarian response in controlled ovarian hyperstimulation for in vitro fertilization and embryo transfer. J Assist Reprod Genet. 2002; 19:103-112. doi: 10.1023/a:1014776519239. Kissell KA, Danaher MR, Schisterman EF, Wactawski-Wende J, Ahrens KA, Schliep K, Perkins NJ, Sjaarda L, Weck J, Mumford SL. Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women. Hum Reprod. 2014; 29:1764-1772. doi: 10.1093/humrep/ deu142. Klein NA, Illingworth PJ, Groome NP, McNeilly AS, Battaglia DE, Soules MR. Decreased inhibin B secretion is associated with the monotropic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab. 1996; 81:2742–2745. Kupesic S, Kurjak A, Bjelos D, Vujisic S. Three-dimensional ultrasonographic ovarian measurements and in vitro fertilization outcome are related to age. Fertil Steril. 2003; 79:190–197. Kurilo LF. Oogenesis in antenatal development in man. Hum Genet. 1981; 57:86-92. doi: 10.1007/BF00271175. Kwee J, Elting ME, Schats R, McDonnell J, Lambalk CB. Ovarian volume and antral follicle count for the prediction of low and hyper responders with in vitro fertilization. Reprod Biol Endocrinol. 2007; 5:9. Kwee J, Elting MW, Schats R, Bezemer PD, Lambalk CB, Schoemaker J: Comparison of endocrine tests with respect to their predictive value on the outcome of ovarian hyperstimulation in IVF treatment: results of a prospective randomized study. Hum Reprod. 2003; 18:1422-1427. Kwee J, Schats R, McDonnell J, Themmen A, de Jong F, Lambalk C. Evaluation of anti-Müllerian hormone as a test for the prediction of ovarian reserve. Fertil Steril. 2008; 90(3):737-743. doi: 10.1016/j. fertnstert.2007.07.1293. Kwee J, Elting ME, Schats R, McDonnell J, Lambalk CB. Ovarian volume and antral follicle count for the prediction of low and hyper responders

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with in vitro fertilization. Reprod Biol Endocrinol. 2007; 5:9. doi: 10. 1186/1477-7827-5-9. Lass A, Skull J, McVeigh E, Margara R, Winston RM. Measurement of ovarian volume by transvaginal sonography before ovulation induction with human menopausal gonadotrophin for in-vitro fertilization can predict poor response. Hum Reprod. 1997; 12:294–297. Lee DE, Park SY, Lee SR, Jeong K, Chung HW. Diagnostic usefulness of transrectal ultrasound compared with transvaginal ultrasound assessment in young Korean women with polycystic ovary syndrome. J Menopausal Med. 2015; 21:149–154. Licciardi FL, Liu HC, Rosenwaks Z. Day 3 estradiol serum concentrations as prognosticators of ovarian stimulation response and pregnancy outcome in patients undergoing in vitro fertilization. Fertil Steril. 1995; 64:991-994. doi: 10.1016/s0015-0282(16)57916-3. Lorusso F, Vicino M, Lamanna G, Trerotoli P, Serio G, Depalo R. Performance of different ovarian reserve markers for predicting the numbers of oocytes retrieved and mature oocytes. Maturitas. 2007; 56:429–435. Lukaszuk K, Kunicki M, Liss J, Bednarowska A, Jakiel G. Probability of live birth in women with extremely low anti-Müllerian hormone concentrations. Reprod Biomed Online. 2014; 28:64-69. doi: 10.1016/ j.rbmo.2013.09.017. Lukaszuk K, Liss J, Kunicki M, Jakiel G, Wasniewski T, WoclawekPotocka I, Pastuszek E. Anti-Müllerian hormone (AMH) is a strong predictor of live birth in women undergoing assisted reproductive technology. Reprod Biol. 2014; 14:176-181. doi: 10.1016/j.repbio.2014. 03.004. Maheshwari A, Gibreel A, Bhattacharya S, Johnson NP. Dynamic tests of ovarian reserve: a systematic review of diagnostic accuracy. Reprod Biomed Online. 2009; 18:717-734. doi: 10.1016/s1472-6483(10)600193. Morin SJ, Patounakis G, Juneau CR, Neal SA, Scott RT, Seli E. Diminished ovarian reserve and poor response to stimulation in patients 25 IU/l on two occasions >4 weeks apart. Before making the final

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diagnosis of POI, all other conditions that could cause oligo/amenorrhoea should be excluded though proper clinical assessment and relevant investigations. NICE guidelines recommend that diagnosis is made by both a history of oligo/amenorrhoea and elevated serum FSH levels on two blood samples taken 4-6 weeks apart (NICE guideline - NG23, 2015). Other markers of ovarian reserve, such as AMH and AFC are not currently recommended as diagnostic tests for POI. When POI is diagnosed or suspected, further investigations should be undertaken to determine any underlying aetiology, identify possible comorbidities, and evaluate short and long-term health risks. Tests to determine the cause include karyotype analysis, testing for an FMR1 premutation and for measurement of adrenal antibodies. The results of adrenal antibody testing are positive in approximately 4% of women with primary ovarian insufficiency. With the initial assessment of women with POI, measurement of bone mineral density (BMD) should be considered especially when there are additional risk factors (Kanis et al., 2013). If BMD is normal and with adequate estrogen replacement, further repeated BMD scans are of little value (ESHRE guideline group on POI et al., 2016). Women newly diagnosed with POI should be assessed and annually monitored for cardiovascular risk. This should include at least blood pressure measurement, weight, and smoking status. Other measures could also include lipid profile, fasting plasma glucose and HbA1c (ESHRE Guideline Group on POI et al., 2016). In addition, women with Turner Syndrome should be referred to a cardiologist with expertise in congenital heart disease for further evaluation (Bondy, 2008; Sharma et al., 2009).

MANAGEMENT Regardless of the underlying cause, management of POI should include adequate sex hormone (estrogen and progesterone) replacement therapy (HRT) in addition to patient education and emotional support. Women

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should receive advice on risk reducing lifestyle measures and on contraception and fertility. HRT is particularly important in very young women to ensure the development of secondary sex characteristics, normal uterine growth, and acquisition of peak bone mass. Early initiation of HRT is strongly recommended when POI is diagnosed to reduce future risk of osteoporosis and cardiovascular disease. It should be continued at least until the average age of natural menopause (ESHRE guideline group on POI et al., 2016). In women with osteopenia or osteoporosis, BMD measurement should be repeated within 5 years and estrogen replacement therapy should be carefully reviewed accordingly. The two oestrogen preparations widely used for young women with POI are the combined oral contraceptive pill and hormone replacement therapy. These preparations have different estrogen formulations and may have differing benefits and risks.

CONCLUSION Although primary ovarian insufficiency is a rare reproductive disorder affecting 1% of women under 40 years of age, it could have a devastating effect on the wellbeing of affected women due to its associated morbidities as well as loss of fertility. POI reflects a variable degree of impairment of ovarian function, which should be distinguished from premature menopause, which refers to complete and permanent cessation of ovarian function. Most cases of POI are idiopathic with no identifiable cause. Known causes of POI include chromosomal, genetic, autoimmune, pathological, and iatrogenic disorders. Diagnosis of POI should follow ESHRE guideline recommendation. Management of young women with POI should include adequate HRT to prevent long-term skeletal, cardiovascular, and neurological complications of prolonged oestrogen deficiency. In addition, management should include emotional support, education and advice for risk reducing lifestyle measures.

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REFERENCES Aittomäki K, Lucena JLD, Pakarinen P, et al. Mutation in the folliclestimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995; 82:959–968. Albright F, Smith PH, Fraser R. A syndrome characterized by primary ovarian insufficiency and decreased stature: report of 11 cases with a digression on hormonal control of axillary and pubic hair. Am J Med Sci. 1942; 204:625–648. Bachelot A, Rouxel A, Massin N, et al. Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure. Eur J Endocrinol. 2009; 161:179-187. doi: 10.1530/EJE-09-0231. Bakalov VK, Anasti JN, Calis KA, et al. Autoimmune oophoritis as a mechanism of follicular dysfunction in women with 46,XX spontaneous premature ovarian failure. Fertil Steril. 2005; 84:958–965. Bondy CA, Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007; 92:10–25. Bondy CA. Congenital cardiovascular disease in Turner syndrome. Congenit Heart Dis. 2008; 3:2-15. doi: 10.1111/j.1747-0803.2007. 00163.x. Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA, De Jager PL. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology 2014; 82:222–229. Clarkson TB. Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression. Menopause. 2018; 25:1262-1274. doi: 10.1097/GME.0000000000001228. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol. 1986; 67:604-606. de Almeida DM, Benetti-Pinto CL, Makuch MY. Sexual function of women with premature ovarian failure. Menopause. 2011; 18:262-266. doi: 10. 1097/gme.0b013e3181f4318d. De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet. 2010; 376:911-921. doi: 10.1016/S0140-6736(10)60355-8.

Premature Ovarian Insufficiency

187

European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016; 31:926-937. doi: 10.1093/humrep/dew027. Freriks K, Timmermans J, Beerendonk CC, Verhaak CM, Netea-Maier RT, Otten BJ, et al. Standardized multidisciplinary evaluation yields significant previously undiagnosed morbidity in adult women with Turner syndrome. J Clin Endocrinol Metab. 2011; 96:E1517-1526. doi: 10.1210/jc.2011-0346. Han TS, Goswami D, Trikudanathan S, Creighton SM, Conway GS. Comparison of bone mineral density and body proportions between women with complete androgen insensitivity syndrome and women with gonadal dysgenesis. Eur J Endocrinol. 2008; 159:179-185. doi: 10.1530/EJE-08-0166. Hong JS, Yi SW, Kang HC, Jee SH, Kang HG, Bayasgalan G, Ohrr H. Age at menopause and cause-specific mortality in South Korean women: Kangwha Cohort Study. Maturitas. 2007; 56:411–419. Kalantaridou SN, Naka KK, Bechlioulis A, Makrigiannakis A, Michalis L, Chrousos GP. Premature ovarian failure, endothelial dysfunction and estrogen-progestogen replacement. Trends Endocrinol Metab. 2006; 17:101-109. doi: 10.1016/j.tem.2006.02.003. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY; Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2013;24:23-57. doi: 10.1007/s00198-012-2074-y. Knauff EA, Westerveld HE, Goverde AJ, Eijkemans MJ, Valkenburg O, van Santbrink EJ, et al. Lipid profile of women with premature ovarian failure. Menopause. 2008;15(5):919-23. doi: 10.1097/gme.0b013e 31816b4509. Liao KL, Wood N, Conway GS. Premature menopause and psychological well-being. J Psychosom Obstet Gynaecol. 2000; 21:167–174.

188

Saad Ali Kamel S. Amer

Mann E, Singer D, Pitkin J, Panay N, Hunter MS. Psychosocial adjustment in women with premature menopause: a cross-sectional survey. Climacteric. 2012; 15:48–489. Michala L, Goswami D, Creighton SM, Conway GS. Swyer syndrome: presentation and outcomes. BJOG. 2008; 115:737-741. doi: 10.1111/ j.1471-0528.2008.01703.x. Nelson L, Covington S, Rebar R. An update: spontaneous premature ovarian failure is not an early menopause. Fertil Steril 2005; 83:1327-32. Nelson LM, Anasti JN, Flack MR. Premature ovarian failure. In: Adashi EY, Rock JA, Rosenwaks Z, editors. Reproductive endocrinology, surgery, and technology. Philadelphia: Lippincott–Raven; 1996. pp. 1393–410. Nelson LM, Anasti JN, Kimzey LM, et al. Development of luteinized Graafian follicles in patients with karyotypically normal spontaneous premature ovarian failure. J Clin Endocrinol Metab. 1994; 79:1470– 1475. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009; 360:606-614. doi: 10.1056/NEJMcp0808697. NICE. Menopause: diagnosis and management: NICE guideline [NG23]. 2015. Pacello PC, Yela DA, Rabelo S, Giraldo PC, Benetti-Pinto CL. Dyspareunia and lubrication in premature ovarian failure using hormonal therapy and vaginal health. Climacteric. 2014; 17:342-347. doi: 10.3109/13697137. 2013.860116. Phung TK, Waltoft BL, Laursen TM, Settnes A, Kessing LV, Mortensen PB, Waldemar G. Hysterectomy, oophorectomy and risk of dementia: a nationwide historical cohort study. Dement Geriatr Cogn Disord. 2010; 30:43–50. Popat VB, Calis KA, Vanderhoof VH, Cizza G, Reynolds JC, Sebring N, Troendle JF, Nelson LM. Bone mineral density in estrogen-deficient young women. J Clin Endocrinol Metab. 2009; 94(7):2277-2283. doi: 10.1210/jc.2008-1878. Rebar RW, Erickson GF, Yen SSC. Idiopathic premature ovarian failure: clinical and endocrine characteristics. Fertil Steril. 1982; 37:35–41.

Premature Ovarian Insufficiency

189

Rebar RW, Connolly HV. Clinical features of young women with hypergonadotropic amenorrhea. Fertil Steril. 1990; 53:804–10. Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de Andrade M, Melton LJ 3rd. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007; 69:1074– 1083. Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ 3rd. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol 2006; 7:821–828. Rocca W, Bower J, Maraganore D, et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008; 70:200–209. Schmidt PJ, Luff JA, Haq NA, Vanderhoof VH, Koziol DE, Calis KA, Rubinow DR, Nelson LM. Depression in women with spontaneous 46, XX primary ovarian insufficiency. J Clin Endocrinol Metab. 2011; 96:E278–E287. Sharma J, Friedman D, Dave-Sharma S, Harbison M. Aortic distensibility and dilation in Turner's syndrome. Cardiol Young. 2009; 19:568-572. doi: 10.1017/S1047951109990874. van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update. 1999; 5:483–4892. Vearncombe KJ, Pachana NA. Is cognitive functioning detrimentally affected after early, induced menopause? Menopause. 2009; 16:188– 198. Welt CK. Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clin Endocrinol (Oxf). 2008; 68:499–509. Wesevich V, Kellen AN, Pal L. Recent advances in understanding primary ovarian insufficiency. F1000Res. 2020; 9:F1000 Faculty Rev-1101. doi: 10.12688/f1000research.26423.1. Wu X, Cai H, Kallianpur A, Li H, Yang G, Gao J, Xiang YB, Ji BT, Yu T, Zheng W et al. Impact of Premature Ovarian Failure on Mortality and Morbidity among Chinese Women. PloS one. 2014; 9:e89597.

ABOUT THE AUTHOR Saad Ali Kamel S Amer Associate Professor University of Nottingham Saad Amer is an Associate Professor at the University of Nottingham and a Consultant of Gynaecology and Reproductive Medicine at Royal Derby Hospital, UK. He has obtained his Doctorate of Medicine (MD) in Reproductive Medicine from the University of Sheffield, UK in 2003. He has a long-standing research interest in Reproductive Medicine with a focus on polycystic ovarian syndrome (PCOS) and ovarian reserve. He has successfully completed several randomized clinical trials on PCOS and is currently actively engaged in many other studies. He has over 80 publications including original research articles, reviews, book chapters and conference papers. He is an editor and referee for several reputable Journals of Gynaecology and Reproductive Medicine.

INDEX A access, 21, 54, 55, 56, 60, 61 adjustment, 76, 99, 188 adolescents, 72, 74, 86 age, 2, 3, 4, 5, 13, 15, 16, 19, 20, 22, 25, 27, 29, 31, 36, 37, 38, 39, 43, 50, 55, 56, 57, 59, 60, 62, 63, 65, 67, 68, 69, 74, 75, 76, 78, 79, 83, 84, 87, 88, 89, 90, 91, 95, 99, 102, 105, 107, 108, 110, 112, 113, 115, 116, 117, 118, 119, 120, 121, 125, 126, 127, 132, 145, 148, 149, 150, 153, 154, 172, 176, 179, 185 aging, 2, 15, 17, 18, 40, 48, 88, 89, 142, 181 agonist, 4, 19, 20, 32, 38, 40, 46, 50, 66, 118, 135, 151, 152, 155, 156, 157, 158, 162, 163, 166, 168, 172, 173, 175, 176, 177 al-Zarqawi, Abu Musab, 41 amenorrhoea, 116, 117, 118, 179, 180, 183, 184, 189 androgen(s), 2, 12, 45, 62, 66, 70, 71, 80, 81, 159, 160, 169, 174, 187 aneuploidy, 15, 18, 89, 139, 154 antral follicles, 4, 9, 13, 14, 20, 23, 26, 28, 39, 51, 57, 69, 70, 71, 84, 96, 110, 159

apoptosis, 10, 18, 71, 97, 118, 123, 146 arrest, 2, 71, 84 artery/arteries, 31, 43, 47, 50, 113, 114, 128, 133, 186 aspiration, 104, 108, 169 aspirin, 162, 169, 178 ASRM, 1, 20, 23, 24, 28, 29, 30, 47, 73, 85, 87, 110, 142 assay, 21, 27, 47, 53, 54, 55, 57, 59, 60, 61, 65, 67, 72, 73, 75, 76, 77, 95 assessment, 4, 5, 22, 25, 30, 31, 34, 40, 44, 45, 48, 64, 65, 84, 85, 92, 94, 131, 132, 143, 147, 177, 184 asymptomatic, 21, 70, 88 atresia, 11, 12, 13, 14, 71, 85, 93, 134, 166 autocrine, 51, 52 autoimmune, 3, 36, 181, 185, 186 awareness, 90, 100, 121, 165

B benefits, 90, 92, 115, 185 benign, 94, 95, 101, 112, 113, 134, 136, 140, 142, 145 bias, 34, 107, 159

Index

194 bilateral, 93, 94, 100, 102, 105, 106, 112, 113, 115, 124, 125, 126, 141, 144, 146 birth, 2, 11, 12, 44, 46, 47, 55, 60, 78, 85, 91, 104, 110, 138, 148, 149, 151, 156, 157, 158, 159, 160, 164, 172, 174, 176, 177 birth rate, 78, 85, 91, 104, 110, 138, 151, 156, 157, 158, 159, 160, 164 blood, 12, 30, 31, 37, 40, 50, 97, 111, 112, 113, 114, 115, 119, 123, 125, 135, 145, 162, 184 blood flow, 30, 31, 37, 40, 50, 111, 113, 119, 125, 135, 145, 162 blood supply, 12, 98, 111, 112, 113, 114, 115 BMD, 182, 184, 185 BMI, 57, 75, 76, 78, 99, 148, 150 body mass index, 57, 61, 65 bone, 2, 92, 121, 124, 179, 182, 184, 185, 187 bone marrow, 2, 121, 124 breast cancer, 117, 118, 119, 122, 127, 131, 135, 141, 146

C cancer, 115, 116, 118, 119, 120, 123, 134, 139, 142, 144, 145 cardiovascular, 92, 179, 182, 184, 185, 186 cardiovascular disease, 182, 185, 186 chemotherapy, 3, 115, 116, 117, 118, 119, 120, 122, 124, 126, 127, 131, 135, 137, 140, 141, 142, 146, 181 childhood, 2, 13, 123, 124, 126, 131, 135, 136, 144 childhood cancer, 123, 126, 135 children, 3, 53, 63, 115, 144 circulation, 30, 113, 114, 115 classification, 41, 63, 117, 154, 155 clinical application, vii, 5, 37

clomiphene citrate, 4, 19, 32, 39, 41, 42, 48, 49, 75, 77, 82, 83, 86, 131, 141, 152, 166, 175, 176 complexity, 19, 32, 36 conception, 14, 21, 37, 64, 67, 85, 91, 118, 119, 171, 174, 180 consensus, 3, 5, 37, 73, 85, 87, 90, 110, 130, 142, 154, 168 control group, 95, 98, 99, 100, 102, 103, 104, 108, 113, 114, 161, 162 controversial, 12, 70, 148 corpus albicans, 14 corpus luteum, 9, 14 correlation, 4, 20, 23, 30, 31, 57, 70, 72, 73, 74, 75, 77 cortex, 97, 115, 116, 134, 136, 137, 140 cortex cryopreservation, 115, 116 counsel, 4, 36, 115 cross-sectional study, 80, 100, 131 cryopreservation, 90, 91, 115, 116, 128, 140 cycles, 3, 13, 29, 38, 43, 46, 47, 62, 64, 65, 75, 76, 77, 78, 94, 103, 104, 107, 109, 125, 127, 136, 138, 140, 141, 146, 156, 157, 162, 163, 164, 167, 168, 171, 172, 173, 174, 175, 177 cyst, 26, 94, 97, 98, 102, 106, 107, 108, 122, 135, 136, 140, 142 cystectomy, 101, 102, 104, 106, 121, 122, 124, 125, 126, 127, 128, 129, 131, 132, 133, 134, 136, 137, 138, 140, 143, 146

D deficiency, 3, 179, 181, 182, 183, 185 dehydroepiandrosterone, 92, 130, 138, 159, 169, 171, 174 dermoid cyst, 95, 98, 99, 133, 146 dermoid cysts, 95, 98, 99 detection, 21, 22, 25, 48, 53, 54, 55, 73, 90, 123

Index diagnostic, 33, 34, 35, 36, 44, 58, 69, 72, 73, 79, 85, 86, 90, 139, 154, 183, 184 diagnostic criteria, 72, 73, 85, 86, 90, 154, 183 DNA, 118, 130, 145 dosage, 91, 116, 150 DSL, 53, 60, 62, 73 dual stimulation, 163

E ECLIA, 54, 55 education, 4, 88, 184, 185 egg, 131, 132, 140, 164 Elecsys, 54, 55, 56 ELISA, 53, 54, 55, 59, 60, 62, 64, 65, 75 emboli, 114, 115, 128, 133, 143 embolization, 114, 115, 128, 133, 143 embryo cryopreservation, 91 endocrine, 43, 45, 146, 156, 188 endoderm, 10 endometriomas, 3, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 115, 121, 124, 125, 126, 128, 129, 132, 134, 135, 136, 138, 139, 141, 143, 144, 145, 146 endometriosis, 39, 46, 92, 94, 95, 96, 97, 98, 99, 100, 104, 106, 115, 126, 127, 128, 129, 131, 132, 134, 135, 136, 137, 139, 141, 142, 145 energy, 107, 110, 123, 135, 140, 183 environment, 100, 128, 135, 159 environmental factors, 2, 20, 56, 57, 66 enzyme, 41, 60, 63, 65, 181 epiblast, 10 ESHRE, 3, 5, 25, 27, 28, 29, 37, 39, 40, 46, 59, 73, 85, 88, 100, 110, 128, 130, 137, 140, 142, 148, 150, 152, 154, 156, 157, 158, 160, 161, 168, 175, 179, 180, 182, 183, 184, 185, 187

195 estradiol, 4, 22, 27, 28, 44, 46, 47, 62, 81, 130, 138, 141, 143, 144, 161, 168, 176 estrogen, 12, 161, 184, 185, 187, 188 ethnicity, 56, 57, 73 evidence, 2, 7, 12, 18, 19, 21, 22, 28, 32, 33, 35, 36, 40, 52, 70, 73, 74, 85, 93, 97, 98, 106, 109, 110, 119, 120, 134, 152, 155, 156, 159, 160, 161, 162, 164, 165, 172, 177, 178, 182 excision, 94, 101, 102, 103, 104, 105, 106, 107, 108, 112, 115, 122, 125, 129, 138, 139, 141, 144, 146 exposure, 6, 118, 120

F false positive, 21, 35, 148 fecundability, 48, 90, 95, 131 fecundity, 3, 45, 87, 119, 120, 138 fertility, vii, 4, 5, 15, 19, 21, 33, 34, 36, 37, 41, 45, 58, 66, 74, 79, 85, 87, 88, 89, 90, 91, 92, 96, 108, 109, 115, 116, 119, 120, 124, 125, 126, 128, 131, 132, 133, 134, 136, 138, 145, 146, 150, 153, 165, 166, 174, 179, 185 fertility preservation, 115, 116, 120 fertilization, 5, 7, 10, 38, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 62, 64, 65, 86, 118, 122, 123, 124, 127, 128, 129, 130, 133, 136, 138, 140, 141, 142, 143, 145, 146, 165, 166, 168, 170, 171, 172, 174, 176, 177, 178 fibrosis, 93, 94, 97, 119, 120 fluctuations, 22, 27, 52, 66 follicle(s), vii, 1, 2, 3, 4, 5, 7, 9, 11, 12, 13, 14, 15, 16, 17, 18, 20, 22, 23, 24, 25, 26, 28, 30, 33, 38, 39, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50, 51, 52, 57, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 77, 79, 80, 81, 82, 83, 84, 86, 88, 93, 96, 98, 103, 104, 105, 106, 109, 110, 111, 116,

Index

196 118, 120, 122, 125, 129, 130, 133, 135, 138, 144, 145, 146, 153, 159, 160, 165, 166, 167, 168, 169, 170, 171, 175, 176, 180, 186, 188 follicle arrest, 71 follicle dysfunction, 180 follicle loss, 12, 13, 15, 106, 133 follicle pool, 1, 3, 4, 20, 22, 23, 26, 64, 180 follicle selection, 71 follicle stimulating hormone, vii, 4, 40, 41, 49, 129, 138, 166 follicular dynamics, vii, 5, 123 follicular fluid, 51, 60, 66, 70, 81, 166 folliculogenesis, 9, 10, 12, 13, 22, 51, 67, 74, 81, 98, 132, 161, 162, 164, 180 formation, 9, 11, 12 freezing, 131, 132, 163

G gap junctions, 12, 14 gastrulation, 10 Gen II, 53, 54, 55, 56, 60, 65, 67, 73, 76, 77 genetic, 2, 3, 18, 20, 57, 66, 123, 181, 185, 186 genital ridge, 1, 10 germ cells, 1, 10, 11, 16, 17, 18, 38 germline cells, 12 gestation, 1, 10, 11, 51, 55 GnRH, 19, 34, 38, 46, 49, 72, 81, 82, 118, 151, 152, 155, 157, 158, 162, 163, 167, 169, 172, 173, 177 gonadotoxicity, 115, 116, 117, 118 gonadotrophins, 3, 49, 80, 142, 158, 166, 169, 180 gonadotropin-releasing hormone, 40, 46, 47, 50, 135, 166, 168, 174, 175, 176, 177, 178 granulosa cells, 9, 11, 12, 14, 15, 28, 51, 66, 70, 80, 81, 83, 85, 118, 120, 167, 170

growing follicles, 1, 9, 11, 14, 17, 26, 63, 70, 71, 105, 110, 118, 120, 153 growth, 11, 15, 16, 17, 30, 51, 55, 63, 71, 82, 120, 159, 166, 167, 169, 170, 171, 172, 173, 176, 185 growth factor, 30, 159, 166, 169, 170 growth hormone, 160, 167, 169, 170, 171, 172, 173, 176 guidance, 40, 45, 187 guidelines, 25, 29, 37, 139, 148, 150, 152, 156, 157, 158, 179, 184

H health, 3, 5, 21, 85, 91, 92, 119, 179, 180, 184, 188 health risks, 3, 85, 91, 184 heterogeneity, 73, 101, 102, 154, 155, 161 HFEA, 91, 131, 132 hindgut, 10 history, vii, 5, 18, 47, 61, 65, 89, 104, 106, 153, 184 hormonal contraception, 26, 57, 58, 60, 183 hormone(s), vii, 3, 4, 5, 6, 12, 19, 20, 30, 32, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 80, 81, 82, 83, 84, 85, 86, 92, 122, 123, 125, 126, 127, 129, 130, 131, 133, 134, 135, 138, 139, 142, 144, 145, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 178, 184, 185, 186 hormone levels, 45, 48, 49, 50, 59, 61, 62, 63, 64, 65, 66, 84, 85, 123, 125, 126, 127, 129, 134, 135, 139, 142, 144, 145, 168, 171, 175, 178 HRT, 184, 185 human, 7, 16, 17, 18, 38, 40, 41, 44, 46, 47, 50, 54, 63, 64, 67, 71, 72, 81, 82, 85, 109, 134, 144, 146, 165, 166, 167, 169, 170, 172, 176, 177 human chorionic gonadotropin, 50, 169, 172

Index hypothesis, 12, 34, 70, 71, 90, 94, 97, 112, 113, 139, 144 hysterectomy, 111, 113, 114, 123, 130, 135, 143, 145, 146, 188

I iatrogenic, viii, 3, 22, 25, 36, 59, 87, 100, 115, 120, 121, 180, 181, 183, 185 idiopathic, 3, 59, 88, 104, 121, 140, 180, 185, 188 implantation, 14, 67, 78, 85, 137, 156, 164, 173, 178 in vitro, 5, 38, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50, 62, 64, 65, 70, 86, 122, 123, 127, 128, 129, 130, 133, 136, 140, 141, 142, 143, 145, 146, 165, 166, 168, 171, 172, 174, 175, 176, 177, 178 incidence, 74, 89, 105, 151, 152 index, v, 31, 57, 61, 65, 193 individualization, 46, 64, 150, 172, 174 induction, 6, 33, 41, 44, 74, 76, 80, 82, 83, 110, 121, 129, 134, 158, 168, 169, 170 infertility, 48, 69, 82, 83, 96, 99, 122, 123, 127, 131, 134, 136, 137, 138, 142, 145, 169, 172, 183 inflammation, 94, 97, 127 inhibin, 4, 6, 19, 20, 22, 26, 28, 33, 37, 38, 39, 41, 42, 43, 45, 46, 48, 62, 67, 68, 117, 123, 144, 148, 168 inhibitor, 62, 71, 142 initiation, 11, 82, 166, 185 insulin, 65, 159, 169, 170 intervention, 21, 90, 155 intracellular bridges, 10 in-vitro fertilisation, 4, 78, 175 IOT, 53, 72, 73, 75, 77 irregular bleeding, 180 IVF, v, 3, 4, 5, 23, 24, 25, 26, 27, 28, 29, 30, 31, 33, 34, 35, 36, 37, 38, 40, 41, 43, 45, 46, 49, 51, 70, 78, 87, 89, 91, 92, 93, 94,

197 96, 97, 98, 104, 105, 108, 109, 110, 112, 125, 127, 131, 132, 136, 137, 138, 141, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178

K karyotype, 18, 47, 184

L laparoscopic surgery, 107, 132, 134 laser ablation, 107, 108, 141 lead, 26, 71, 118, 159 letrozole, 62, 75, 76, 152, 157, 158, 166, 167, 168, 173 light, 69, 121, 175 lymphoma, 119, 127, 131

M majority, 103, 104, 107 management, 39, 40, 85, 127, 128, 139, 143, 154, 177, 184, 185, 187, 188 measurement, 22, 26, 27, 28, 35, 40, 53, 57, 58, 65, 184, 185 measurements, 26, 27, 32, 40, 43, 47, 53, 55, 90 median, 95, 102, 113 meiosis, 1, 11, 14, 15 menopause, 2, 3, 5, 15, 16, 20, 22, 25, 29, 36, 39, 48, 50, 55, 56, 59, 64, 65, 66, 69, 79, 87, 88, 89, 92, 105, 110, 125, 126, 127, 129, 134, 142, 143, 145, 146, 179, 180, 185, 186, 187, 188, 189 menstrual cycles, 26, 43, 52, 64, 67, 86, 88, 107, 123 menstruation, 116, 117, 118, 144

Index

198 meta-analysis, 24, 29, 30, 36, 41, 49, 57, 65, 67, 78, 83, 85, 94, 95, 96, 101, 102, 103, 104, 109, 110, 111, 112, 114, 122, 128, 131, 137, 138, 139, 141, 143, 146, 151, 156, 157, 158, 160, 161, 162, 166, 169, 171, 172, 178 mice, 18, 64, 71, 72, 125 migration, 10, 16, 18 mitosis, 1, 10, 11 models, 36, 49, 64 mono-ovulation, 51 morphology, 16, 39, 72, 73, 86

N neo-oogenesis, 2, 12 NICE, 37, 59, 100, 139, 150, 174, 184, 188

O obesity, 26, 62, 63, 65, 67 oestrogen, 3, 14, 170, 179, 180, 182, 183, 185 oestrogen deficiency, 3, 179, 182, 183, 185 OHSS, 27, 150, 151, 152, 156 oligomenorrhea, 179 oocyte, 4, 9, 10, 11, 12, 14, 15, 17, 18, 20, 25, 27, 31, 59, 70, 90, 91, 96, 97, 115, 116, 118, 119, 120, 126, 141, 144, 145, 148, 149, 151, 156, 159, 163, 164, 166, 167, 169 oocyte accumulation, 164 oocyte cryopreservation, 90, 91 oocyte nests, 10 oocytes, 1, 2, 3, 7, 11, 14, 15, 16, 17, 22, 24, 29, 30, 44, 46, 91, 93, 94, 96, 97, 98, 103, 104, 105, 110, 118, 120, 122, 127, 142, 146, 148, 149, 151, 153, 154, 155, 156, 157, 158, 161, 162, 163, 164, 167, 176, 177 oogenesis, 2, 7, 12, 17, 43

oogonia, 1, 10 oophorectomy, 102, 109, 110, 123, 125, 133, 146, 188, 189 osteopenia, 182, 185 osteoporosis, 182, 185, 187 ovarian aging, viii, 2, 5, 12, 48, 88, 89, 90, 121, 123, 136 ovarian cancer, 138, 143, 144 ovarian cyst(s), 26, 28, 92, 94, 95, 98, 99, 101, 102, 104, 106, 112, 121, 122, 124, 125, 134, 135, 136, 138, 140, 141, 142, 143 ovarian cystectomy, 101, 102, 104, 106, 121, 122, 125, 134, 136, 138, 143 ovarian doppler, 31 ovarian drilling, 75, 85, 110, 111, 122 ovarian failure, 28, 87, 116, 125, 126, 129, 142, 146, 173, 179, 180, 186, 187, 188, 189 ovarian hyperstimulation, 3, 24, 42, 43, 49, 123, 131, 132, 147, 173, 177 ovarian insufficiency, viii, 3, 5, 21, 27, 36, 40, 59, 87, 89, 179, 181, 183, 184, 185, 186, 187, 188, 189 ovarian response, viii, 3, 4, 5, 22, 24, 25, 26, 27, 33, 36, 37, 38, 39, 41, 42, 43, 45, 46, 47, 63, 77, 86, 89, 92, 96, 103, 110, 112, 115, 125, 128, 129, 132, 136, 138, 142, 147, 148, 150, 151, 153, 154, 165, 166, 168, 170, 171, 173, 175, 176, 177, 178 ovarian responsiveness, 24, 31, 40, 49, 58, 74, 80, 92, 103, 162 ovarian stimulation, 5, 6, 24, 25, 28, 30, 37, 40, 42, 44, 45, 46, 49, 59, 75, 77, 78, 87, 89, 91, 104, 129, 130, 133, 147, 148, 150, 151, 152, 153, 155, 156, 157, 158, 160, 161, 162, 163, 164, 165, 166, 168, 169, 170, 171, 173, 174, 175, 176, 178 ovarian stroma, 30, 31, 40, 50, 97, 106, 119, 120, 145 ovarian surgery, 3, 99, 100, 102, 105, 115, 126, 128, 181

Index ovarian tumor, 126, 133, 146 ovarian volume, 4, 19, 20, 29, 30, 37, 40, 43, 44, 45, 47, 48, 74, 75, 83, 137 ovariectomy, 124, 127, 130, 137 ovaries, 7, 13, 15, 17, 23, 26, 29, 38, 61, 70, 74, 80, 81, 82, 83, 84, 86, 93, 94, 95, 96, 97, 98, 103, 105, 107, 109, 110, 111, 120, 121, 131, 134, 150 ovulation, 3, 9, 13, 14, 20, 33, 41, 44, 51, 74, 75, 76, 77, 80, 82, 83, 85, 95, 107, 110, 121, 124, 126, 129, 132, 134, 137, 158, 168, 169, 170

P paracrine, 15, 51, 52, 71, 79 parenthood, 6, 131, 137, 140 pathogenesis, 71, 81, 153, 182 pathology, 25, 154, 186 pathophysiology, 69, 79, 81, 127, 140 physiology, vii, 5, 39, 61, 81 picoAMH, 54, 55, 59 pilot study, 62, 80, 123 placebo, 138, 159, 166, 174 PM, 18, 86, 130, 138, 172 polycystic ovarian syndrome, vii, 5, 37, 48, 80, 82, 83, 85, 110, 191 population, 3, 13, 17, 41, 45, 48, 50, 56, 59, 61, 63, 72, 83, 90, 105, 106, 110, 125, 132, 180, 189 positive correlation, 31, 71, 72, 75, 78 preantral follicles, 22, 86 predictive, 19, 24, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 43, 46, 48, 49, 58, 79, 83, 119, 127, 131, 145, 148, 149 predictive accuracy, 28, 35, 148 pregnancy, 15, 19, 24, 28, 29, 30, 31, 33, 34, 36, 37, 39, 41, 44, 46, 49, 58, 64, 65, 67, 75, 77, 78, 85, 90, 91, 96, 97, 98, 104, 105, 107, 108, 109, 110, 111, 123, 125, 126, 136, 137, 141, 142, 143, 144,

199 145, 146, 148, 149, 150, 151, 152, 156, 157, 158, 159, 160, 161, 162, 164, 168, 171, 172, 173, 175, 176, 183, 189 prenatal, 2, 10, 18 preservation, 115, 116, 120, 140 prevention, 92, 144, 152 primary follicles, 11, 14, 83 primordial follicles, vii, 1, 5, 9, 11, 13, 15, 51, 111, 116, 118, 120 probability, 27, 149, 172 progesterone, 14, 130, 170, 172, 184 prognosis, 27, 34, 38, 45, 154, 170, 175 prognostic, 28, 45, 46, 69, 74, 79, 90, 136 proliferation, 10, 11, 71 puberty, 2, 12, 13, 14, 55 pulsatility index, 31

R radiation, 3, 120, 128, 137 radiotherapy, 115, 120, 121, 124, 135, 145, 181 receptor(s), 11, 12, 14, 70, 72, 80, 82, 84, 180, 186 recovery, 58, 102, 114, 116, 117, 118, 127, 133, 135, 141, 180 recurrence, 136, 137, 141 regression, 35, 51, 75, 149, 150 regression model, 35, 75, 150 relevance, 62, 81, 139 reliability, 25, 30, 31, 33 reproduction, viii, 5, 18, 39, 47, 60, 62, 86, 130, 137, 141, 146, 171, 172, 174 reproductive age, 3, 5, 65, 67, 68, 69, 83, 84, 87, 121, 127, 132, 142 researchers, 24, 35, 74, 153 response, viii, 3, 4, 5, 6, 19, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 41, 42, 43, 44, 45, 46, 47, 49, 50, 59, 63, 75, 76, 77, 78, 86, 87, 89, 92, 96, 103, 110, 112, 115, 121, 123, 125, 128,

Index

200 129, 130, 131, 132, 134, 136, 138, 141, 142, 145, 146, 147, 148, 150, 151, 153, 154, 165, 166, 168, 170, 171, 173, 174, 175, 176, 177, 178 responsiveness, 24, 31, 40, 49, 58, 74, 80, 92, 103, 141, 162 risk(s), 3, 5, 21, 24, 27, 28, 35, 36, 45, 59, 86, 87, 89, 90, 92, 105, 113, 114, 115, 117, 118, 120, 126, 130, 134, 138, 147, 149, 150, 151, 152, 154, 161, 165, 180, 182, 183, 184, 185, 188, 189 risk factors, 3, 36, 154, 165, 184 ROC, 24, 73, 75, 76, 77

S safety, 53, 65, 152, 157, 158, 159, 162 salpingectomy, 111, 112, 113, 125, 129, 130, 134, 137, 138, 144, 146 screening, 7, 19, 21, 22, 25, 36, 37, 40, 42, 48, 50, 87, 89, 90, 131, 143 secondary follicles, 12 secretion, 14, 40, 43, 51, 52, 70, 71, 72, 81, 169, 170 sensitivity, 21, 24, 27, 29, 30, 33, 35, 51, 53, 54, 71, 72, 73, 74, 75, 77, 101, 117, 148, 149, 159 serum, vii, 20, 26, 32, 34, 39, 40, 43, 44, 46, 48, 53, 54, 56, 57, 58, 59, 60, 61, 62, 64, 65, 66, 67, 69, 71, 72, 73, 74, 75, 77, 78, 79, 80, 81, 83, 84, 85, 86, 95, 99, 100, 101, 102, 103, 104, 111, 112, 113, 114, 123, 125, 126, 127, 133, 134, 135, 138, 139,143, 144, 145, 150, 153, 167, 168, 175, 176, 180, 184 showing, 29, 31, 35, 57, 70, 77, 92, 98, 112, 149, 162 signs, 92, 119, 144 smoking, 56, 57, 61, 62, 66, 67, 115, 181, 182, 184

sperm, 17, 47, 78, 129, 139, 141, 165, 168, 172 spontaneous pregnancy, 19, 96, 108 stability, 22, 52, 53, 54 standardization, 62, 74, 125 stem cells, 2, 6, 7, 12, 17, 18 steroidogenesis, 159, 160, 170, 180 stimulation, 3, 4, 5, 6, 11, 19, 20, 22, 24, 25, 28, 30, 37, 40, 42, 44, 45, 46, 47, 49, 50, 59, 62, 75, 77, 78, 86, 87, 89, 91, 103, 104, 129, 130, 133, 136, 137, 138, 145, 147, 148, 150, 151, 152, 153, 154, 155, 156, 157, 158, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 173, 174, 175, 176, 178 stroma, 12, 31, 97, 106, 120 subfertility, 4, 56, 87, 89, 90, 183 subgroups, 102, 154, 155 success rate, 91, 151, 153, 156, 159 Sun, 7, 23, 48, 127, 178 supplementation, 130, 162, 169 suppression, 31, 34, 40, 47, 122 surgical technique, 107, 115, 139 survivors, 119, 123, 124, 126, 135 syndrome, 24, 42, 44, 47, 61, 66, 69, 80, 81, 82, 83, 84, 85, 86, 129, 142, 143, 144, 177, 181, 182, 183, 186, 187, 188, 189 systolic velocity, 31

T techniques, 25, 115, 116, 120, 177 technology/technologies, viii, 5, 19, 30, 38, 44, 45, 46, 48, 58, 62, 73, 74, 85, 124, 127, 136, 155, 164, 172, 175, 188 telangiectasia, 119, 130, 181 testing, vii, 4, 5, 19, 21, 35, 36, 41, 45, 49, 52, 61, 87, 92, 100, 121, 147, 184 testosterone, 75, 76, 130, 159, 160, 166, 171, 174 theca, 12

Index therapeutic interventions, 2, 121, 189 therapy, 46, 80, 84, 92, 121, 137, 166, 168, 174, 184, 185, 188 tissue, 3, 96, 97, 106, 120, 128, 134, 138, 140 transforming growth factor, 28, 51, 97 transvaginal ultrasound, 44, 49, 74 treatment, 3, 4, 21, 24, 27, 28, 32, 33, 34, 36, 38, 39, 40, 43, 45, 46, 58, 75, 76, 78, 79, 81, 91, 92, 104, 110, 116, 117, 118, 119, 120, 123, 125, 127, 131, 132, 136, 138, 141, 142, 143, 144, 146, 147, 150, 151, 153, 154, 155, 157, 159, 160, 161, 163, 165, 167, 168, 169, 170, 175, 177, 178 trial, 124, 130, 138, 156, 165, 166, 169, 171, 173, 174, 176, 177, 178 tumours/tumors, 59, 134, 138, 144 Turner syndrome, 181, 182, 184, 186, 187 twinning, 89, 134, 143

U ultrasensitive AMH, 54 ultrasonography, 38, 42, 43, 45, 46, 48, 49, 137 ultrasound, 4, 6, 20, 21, 23, 25, 26, 32, 39, 40, 42, 44, 45, 47, 48, 49, 50, 61, 70, 72, 73, 74, 81, 83, 123

201 V validation, 74, 90, 113 variability, 21, 22, 25, 27, 28, 30, 33, 37, 41, 43, 52, 54, 57, 67, 142 variations, 16, 25, 31, 34, 35, 36, 53, 57, 89 vaso-motor symptoms, 183

W WMD, 101, 109, 111, 112, 114 workers, 91, 150, 153 World Health Organization (WHO), 27, 40, 50

Y yield, 59, 110, 148, 149, 151, 156, 159, 164 yolk sac, 1, 10 young women, 3, 21, 36, 87, 89, 90, 91, 111, 115, 119, 121, 123, 127, 146, 149, 165, 179, 185, 188, 189

Z zona pellucida, 11, 15