Clinical Reproductive Medicine and Surgery: A Practical Guide [4th ed. 2022] 9783030995959, 9783030995966, 303099595X

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Clinical Reproductive Medicine and Surgery A Practical Guide Tommaso Falcone William W. Hurd Editors Fourth Edition

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Clinical Reproductive Medicine and Surgery

Tommaso Falcone  •  William W. Hurd Editors

Clinical Reproductive Medicine and Surgery A Practical Guide Fourth Edition

Editors

Tommaso Falcone Cleveland Clinic London Cleveland Clinic Lerner College of Medicine Cleveland, OH, USA

William W. Hurd Division of Reproductive Endocrinology and Infertility University of Alabama School of Medicine Birmingham, AL, USA

ISBN 978-3-030-99595-9    ISBN 978-3-030-99596-6 (eBook) https://doi.org/10.1007/978-3-030-99596-6 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2007, 2013, 2017, 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

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The editors would like to dedicate the fourth edition of this textbook to all enthusiastic students of reproductive medicine, particularly the fellows, residents, and new clinicians for whom this book was created.

Preface to the Fourth Edition Fifteen years have elapsed since we first asked a group of clinical experts from throughout the world to help create a comprehensive textbook of clinical reproductive medicine and surgery that was straight forward, up to date, and worth reading. We have been gratified to hear that the subsequent editions of this book have continued to be useful to fellows and residents in training, and specialists and subspecialists in practice. The fourth edition includes a number of changes, including two new chapters and several new authors. All chapter from the previous edition have been updated and edited for clarity. Questions have been added to the end of each chapter to help readers self-test their knowledge. We have also added two chapters to address topics made prominent by technological advances. The third-party reproduction chapter addresses the unique clinical and regulatory challenges accompanying the use of donor gametes and gestational carriers. The uterine transplant chapter describes the medical and surgical challenges involved in this cutting-­ edge approach. We hope readers find the information about the latest developments in our fast-evolving field interesting. More importantly, we hope this book continues to provide easy access to the essential information about the clinical practice of reproductive medicine and surgery. Tommaso Falcone

London, England



William W. Hurd

Birmingham, AL, USA

VII

Contents 1

 ypothalamic-Pituitary-­Ovarian Axis and Control of the H Menstrual Cycle..................................................................................................1 Julian A. Gingold, Meaghan Jain, and Cyrus Jalai

2

Female and Male Gametogenesis..........................................................23 Nina Desai, Jenna M. Rehmer, Jennifer Ludgin, Rakesh Sharma, Raj Kumar Anirudh, and Ashok Agarwal

3

Normal Puberty and Pubertal Disorders...........................................55 Siddhi Mathur, Joseph S. Sanfilippo, and M. Jonathon Solnik

4

Fertilization and Implantation.................................................................79 Christopher K. Arkfeld and Hugh S. Taylor

5

Reproductive Imaging...................................................................................109 Laura Detti

6

Amenorrhea..........................................................................................................139 Alexander M. Kotlyar and Eric Han

7

Polycystic Ovary Syndrome.......................................................................157 Tommaso Falcone and William W. Hurd

8

Abnormal Uterine Bleeding.......................................................................171 Sonia Elguero, Bansari Patel, Anna V. Jones, and William W. Hurd

9

Menopause............................................................................................................201 Tara K. Iyer and Holly L. Thacker

10

Osteoporosis........................................................................................................235 Tiffany M. Cochran and Holly L. Thacker

11

Male Infertility....................................................................................................265 Scott Lundy and Sarah C. Vij

12

Female Infertility...............................................................................................281 Elizabeth J. Klein, Roxanne Vrees, and Gary N. Frishman

13

Fertility Preservation.....................................................................................303 Pasquale Patrizio, Emanuela Molinari, Tommaso Falcone, and Lynn M. Westphal

14

Ovarian Reserve Testing...............................................................................323 Paula Amato

15

Recurrent Early Pregnancy Loss..............................................................335 Krystle Y. Chong and Ben W. Mol

VIII

16

Contents

Ovulation Induction........................................................................................353 Ginevra Mills and Togas Tulandi

17

Assisted Reproductive Technology: Clinical Aspects................367 Pardis Hosseinzadeh, M. Blake Evans, and Karl R. Hansen

18

ART: Laboratory Aspects..............................................................................393 Charles L. Bormann

19

Preimplantation Genetic Testing............................................................409 Jason M. Franasiak, Katherine L. Scott, and Richard T. Scott Jr.

20

 ysteroscopic Management of Intrauterine Disorders: H Polypectomy, Myomectomy, Endometrial Ablation, Adhesiolysis, and Removal of Uterine Septum.............................429 Michelle G. Park and Keith B. Isaacson

21

Gynecologic Laparoscopy...........................................................................459 Mohamed A. Bedaiwy, Howard T. Sharp, Tommaso Falcone, and William W. Hurd

22

Uterine Leiomyomas.......................................................................................491 Gregory M. Christman

23

Tubal Disease and Ectopic Pregnancy.................................................515 Mabel Lee, Rebecca Flyckt, and Jeffrey M. Goldberg

24

Endometriosis.....................................................................................................535 Dan I. Lebovic and Tommaso Falcone

25

Contraception: Evidence-­Based Practice Guidelines and Recommendations.................................................................................553 Ashley Brant, Rachel Shin, and Pelin Batur

26

 urgical Techniques for Management of Anomalies of the S Müllerian Ducts..................................................................................................573 Marjan Attaran

27

Third-Party Reproduction...........................................................................601 Alexander Quaas

28

Uterus Transplantation.................................................................................613 Elliott G. Richards and Jenna M. Rehmer

Supplementary Information Glossary......................................................................................................................630 Index............................................................................................................................ 635

IX

Contributors Ashok  Agarwal, PhD  American Center for Reproductive Medicine, Department of Urology, Cleveland Clinic, Cleveland, OH, USA [email protected] Paula Amato, MD, MCR  Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA [email protected] Raj Kumar Anirudh, BA  University of Miami, College of Arts and Sciences, Coral Gables, FL, USA Christopher K. Arkfeld, MD  Department of Obstetrics and Gynecology, Yale School of Medicine, New Haven, CT, USA [email protected] Marjan Attaran, MD  Department of Obstetrics and Gynecology, Section of Pediatric and Adolescent Gynecology, Cleveland Clinic, Cleveland, OH, USA [email protected] Pelin  Batur, MD  Department of Obstetrics & Gynecology, Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA [email protected] Mohamed A. Bedaiwy, MD, PhD  Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada [email protected] Charles L. Bormann, PhD, HCLD  Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA [email protected] Ashley  Brant, DO, MPH  Department of Obstetrics & Gynecology, Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA [email protected] Krystle Y. Chong, MBBS (Hons)  Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia [email protected] Gregory  M.  Christman, MD  Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Florida, Gainesville, FL, USA

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Contributors

[email protected] Tiffany M. Cochran, MD, MHA  OB/GYN & Women’s Health Institute, Center for Specialized Women’s Health, Cleveland Clinic Foundation, Cleveland, OH, USA [email protected] Nina  Desai, PhD, HCLD  IVF Laboratory, Department of Obstetrics and Gynecology, Cleveland Clinic Fertility Center, Beachwood, OH, USA [email protected] Laura  Detti, MD  Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Baylor College of Medicine, Houston, TX, USA [email protected] Sonia Elguero, MD  Boston IVF-The Albany Center, Albany, NY, USA [email protected] M.  Blake  Evans, DO  Section of Reproductive Endocrinology and Infertility, Department of Ob/Gyn, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA [email protected] Tommaso Falcone, MD  Cleveland Clinic London, London, UK Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA Obstetrics, Gynecology and Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA [email protected] Rebecca Flyckt, MD  Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility, University Hospitals Cleveland Medical Center, Cleveland, OH, USA [email protected] Jason M. Franasiak, MD, HCLD/ALD (ABB)  Reproductive Medicine Associates of New Jersey, Marlton, NJ, USA [email protected] Gary  N.  Frishman, MD  Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI, USA [email protected] Julian A. Gingold, MD, PhD  Albert Einstein College of Medicine, The Bronx, NY, USA [email protected] Jeffrey  M.  Goldberg, MD  Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility, Cleveland Clinic, Cleveland, OH, USA

Contributors

[email protected] Eric  Han, MD  Section of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA [email protected] Karl  R.  Hansen, MD, PhD  Section of Reproductive Endocrinology and Infertility, Department of Ob/Gyn, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA [email protected] Pardis  Hosseinzadeh, MD  Section of Reproductive Endocrinology and Infertility, Department of Ob/Gyn, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA [email protected] William  W.  Hurd, MD, MSc, MPH  Division of Reproductive Endocrinology and Infertility, University of Alabama School of Medicine, Birmingham, AL, USA [email protected] Keith B. Isaacson, MD  Newton Wellesley Hospital, Harvard Medical School, Newton, MA, USA [email protected] Tara  K.  Iyer, MD  Center for Specialized Women’s Health, Department of Obstetrics and Gynecology and Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA [email protected] Meaghan Jain, MD  Albert Einstein College of Medicine, The Bronx, NY, USA [email protected] Cyrus Jalai, MD  Albert Einstein College of Medicine, The Bronx, NY, USA [email protected] Anna V. Jones, BS  University of Alabama School of Medicine, Birmingham, AL, USA [email protected] Elizabeth  J.  Klein, MD  Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI, USA [email protected] Alexander M. Kotlyar, MD  Section of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA [email protected]

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Contributors

Dan I. Lebovic, MD  Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Washington University School of Medicine, St. Louis, MO, USA [email protected] Mabel  Lee, MD  Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility, University Hospitals Cleveland Medical Center, Cleveland, OH, USA [email protected] Jennifer Ludgin, BA  OB/GYN/IVF Research Intern, Department of Obstetrics and Gynecology, Cleveland Clinic Fertility Center, Beachwood, OH, USA Scott  Lundy, MD, PhD  Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA [email protected] Siddhi Mathur, MSc, MD  Department of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto, ON, Canada [email protected] Ginevra  Mills, MD  Department of Obstetrics and Gynecology, McGill University, Montréal, QC, Canada [email protected] Ben W. Mol, MD, PhD  Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia [email protected] Emanuela Molinari, PhD  Center for Human Reproduction, New York, NY, USA Michelle  G.  Park, MD  Southern California MIGS Collaborative, AAGL, ACOG, Los Angeles, CA, USA [email protected] Bansari Patel, MD  Atlanta Center for Reproductive Medicine, Atlanta, GA, USA Pasquale Patrizio, MD  Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Endocrinology and Infertility, University of Miami, Miller School of Medicine, Miami, FL, USA [email protected] Alexander  Quaas, MD, PhD  Division of Reproductive Endocrinology and Infertility, University of California, San Diego, CA, USA Reproductive Partners San Diego, San Diego, CA, USA University Hospital Basel, Basel, Switzerland [email protected]

Contributors

Jenna M. Rehmer, MD  Reproductive Endocrinology and Infertility Division, Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA [email protected] Elliott G. Richards, MD  Reproductive Endocrinology and Infertility Division, Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA [email protected] Joseph S. Sanfilippo, MD, MBA  Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Endocrinology and Infertility, Magee-Womens Hospital, Pittsburgh, PA, USA Department of Obstetrics and Gynecology, University of Pittsburgh, Pittsburgh, PA, USA [email protected] Katherine L. Scott, MS, TS (ABB)  Division of Reproductive Clinical Science, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA Richard T. Scott Jr., MD, HCLD/ALD (ABB)  Reproductive Medicine Associates of New Jersey, Basking Ridge, NJ, USA [email protected] Rakesh Sharma, PhD  American Center for Reproductive Medicine, Department of Urology, Cleveland Clinic, Cleveland, OH, USA [email protected] Howard T. Sharp, MD  Department of Obstetrics and Gynecology, University of Utah Hospitals and Clinics, Salt Lake City, UT, USA [email protected] Rachel  Shin, MD, MPH  Department of Obstetrics & Gynecology, Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA [email protected] M. Jonathon Solnik, MD  Department of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto, ON, Canada Head of Gynaecology and Minimally Invasive Surgery, Sinai Health System and Women’s College Hospital, Toronto, ON, Canada [email protected] Hugh S. Taylor, MD  Department of Obstetrics and Gynecology, Yale School of Medicine, New Haven, CT, USA [email protected] Holly L. Thacker, MD  Center for Specialized Women’s Health, Department of Obstetrics and Gynecology and Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA [email protected]

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Contributors

Togas  Tulandi, MD, MHCM  Department of Obstetrics and Gynecology, McGill University, Montréal, QC, Canada [email protected] Sarah C. Vij, MD  Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA [email protected] Roxanne Vrees, MD  Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI, USA [email protected] Lynn M. Westphal, MD  Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA [email protected]

1

Hypothalamic-Pituitary-­ Ovarian Axis and Control of the Menstrual Cycle Julian A. Gingold , Meaghan Jain, and Cyrus Jalai Contents 1.1

Introduction – 2

1.2

The Menstrual Cycle – 2

1.2.1 1.2.2 1.2.3

T he Follicular Phase – 3 Early Luteal Phase – 3 Mid- to Late Luteal Phase – 4

1.3

Anatomy of the Menstrual Cycle – 5

1.3.1 1.3.2 1.3.3 1.3.4

 ypothalamus – 5 H Pituitary – 5 Ovaries – 8 Uterus – 9

1.4

Endocrinology of the Menstrual Cycle – 10

1.4.1 1.4.2 1.4.3 1.4.4 1.4.5 1.4.6 1.4.7

 nRH Agonists and Antagonists – 11 G Control of GnRH Pulsatility – 12 Structure of Gonadotropins – 12 Biological Sources of Sex Steroids – 12 Follicular Phase Endocrinology – 13 Luteal-Phase Endocrinology – 14 Additional Mediators – 16

1.5

Review Questions – 17

1.6

Answers – 18 References – 18

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 T. Falcone, W. W. Hurd (eds.), Clinical Reproductive Medicine and Surgery, https://doi.org/10.1007/978-3-030-99596-6_1

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J. A. Gingold et al.

Key Points 55 The menstrual cycle is divided into follicular and luteal phases, with the follicular phase starting with onset of menses and ending with onset of the LH surge, and the luteal phase starting with onset of the LH surge and ending with onset of menses. 5 5 The hypothalamic-pituitary-ovarian (HPO) axis is a tightly regulated system controlling the menstrual cycle and female reproduction through multiple positive and negative feedback loops. 55 Pulsatile GnRH release into hypophyseal portal circulation stimulates pituitary LH and FSH production. LH and FSH are gonadotropins that stimulate ovarian follicular development and hormone production, leading to a slow rise in estradiol production during the follicular phase and the onset of high progesterone production in the luteal phase. 55 The LH surge brings about resumption of meiosis in the oocyte, production of prostaglandins to facilitate follicular rupture, and the formation of the corpus luteum, which produces the hormones required to prepare the endometrium for implantation.

1.1

Introduction

The menstrual cycle is the product of a cascade of hormones from many interacting endocrine glands coordinating a cyclic ovarian and uterine response. Ovarian production of estrogens and progestins is largely regulated by the hypothalamus and anterior pituitary gland, both of which are also regulated by serum hormone levels. The interplay between these endocrine systems forms the basis of the hypothalamic-pituitary-ovarian (HPO) axis.

This chapter will cover how the time-, location-, and dose-dependent interactions between the central nervous system, endocrine, and pelvic organs coordinate to reliably grow and release one egg each month while simultaneously preparing the endometrium for a pregnancy. The first section details the stages of the menstrual cycle. The second section covers the functional anatomy of the hypothalamus, anterior pituitary, ovaries, and uterus. The third section discusses neuroendocrine regulation of the menstrual cycle. The last section also reviews the key hormones driving the menstrual cycle, with a particular focus on gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone (. Table 1.1).  

1.2

The Menstrual Cycle

The menstrual cycle is conventionally divided into two different stages of ovarian activity as well as two phases of uterine response. The ovarian cycle includes the follicular phase and the luteal phase, separated by ovulation. The uterine cycle includes the proliferative phase and the secretory phase. Each menstrual cycle spans from the first full day of menstrual bleeding to the first full day in the following menstrual period. On average this cycle lasts 28  days, though a cycle length between 24 and 38  days is considered within normal range [1, 2]. This range is based on variation on the length of the follicular/proliferative phase, with the luteal/secretory phase remaining relatively constant at 14  days. Normal menses last 3–8 days [1]. Bleeding quantity on average during menses is 30  mL, and blood loss greater than 80  mL is considered heavy menstrual bleeding [3]. While a wide variety of conditions may lead to abnormal uterine bleeding, deviations from these parameters in the menstrual cycle may suggest a breakdown in regulation of the hypothalamic-pituitary-ovarian axis or a structural abnormality involving the pelvic organs [1, 4].

3 Hypothalamic-Pituitary-­O varian Axis and Control of the Menstrual Cycle

..      Table 1.1  Major hormones of the hypothalamic-­pituitary-ovarian axisa Hormone

Structure

Gene location

Major site(s) of production

Half-life

Serum concentration

GnRH

Decapeptide

8p21–8p11.2

Arcuate nucleus of hypothalamus

2–4 min

N/A

FSH

Glycoprotein with α- and β-subunits

α: 6q12.21 β: 11p13

Gonadotrophs of anterior pituitary

1.5–4 h

5–25 mIU/mL

LH

Glycoprotein with α- and β-subunits

α: 6q12.21 β: 19q12.32

Gonadotrophs of anterior pituitary

20– 30 min

5–25 mIU/mL

Estradiol

18 carbon steroid

NA

Granulosa cells

2–3 h

20–400 pg/mL

Progesterone

21 carbon steroid

NA

Theca-lutein cells

5 min

0.1–30 ng/mL

Inhibin

Peptide with α- and β-subunits Inhibin A = α + βA Inhibin B = α + βB

α: 2q33 βA: 2q13 βB: 7p15

Granulosa cells

30– 60 min

A: 10–60 B: 10–150 pg/ mL

aReproduced

1.2.1

with permission from Falcone and Hurd [110]

The Follicular Phase

During the follicular (proliferative) phase of the menstrual cycle, the dominant hormone, FSH, stimulates folliculogenesis. Folliculogenesis involves recruitment of a cohort of immature antral follicles in the ovary, one of which becomes the dominant follicle for the menstrual cycle. Antral follicles are visible on transvaginal ultrasound around menses as homogeneous hypoechoic cysts measuring 2–10 mm in mean diameter across two dimensions. After receiving appropriate signals, one or more follicles from the cohort of antral follicles grow to maturation. The follicle that goes on to ovulate is often recognizable several days prior to ovulation as the so-called dominant follicle and is typically the largest diameter follicle, growing to 17–25 mm prior to ovulation [5]. The dominant follicle is the most responsive to FSH, owing to its expression of the highest concentration of FSH receptors on its surface among the growing antral follicles [6]. Surrounding the dominant follicle is a bed of granulosa cells expressing aromatase, the final enzyme involved in estra-

diol biosynthesis. Increased estradiol production influences uterine response in the follicular phase by stimulating proliferation of the endometrial glands. Rising estradiol also provides negative feedback to reduce GnRH production from the hypothalamus and decrease FSH production from the pituitary in the early follicular phase, thereby leading to apoptosis of the other more FSH-­sensitive follicles recruited in that cycle and limiting multifollicular ovulation. 1.2.2

Early Luteal Phase

The luteinizing hormone surge marks the beginning of the luteal phase and triggers ovulation. The LH surge is mediated by a switch from negative pituitary feedback to estradiol levels during the early follicular phase to positive feedback in response to rising estradiol levels in the late follicular phase, with a level > 200 pg/mL for over 50 hours being sufficient to promote the LH surge [4]. It is also accompanied by a shift from inactive, glycosylated to biologically active, non-­glycosylated

1

4

1.2.3

Mid- to Late Luteal Phase

Estrogen levels fall and progesterone levels dramatically rise during the luteal phase. While progesterone production from the follicle begins to rise late in the follicular phase, it is predominantly produced following the LH surge, which transforms the granulosa cells in the basement membrane into progesterone-­producing luteal cells. The combined cystic structure following follicular rupture is called the corpus luteum, literally “yellow body” in Latin. These luteal cells are vacuolated and filled with lutein, a straw-colored fluid. By day 7 or 8 of the luteal phase, peak progesterone levels and vascularization of the corpus luteum are reached (. Fig. 1.1) [13]. Progesterone induces dramatic changes on the endometrium, including cessation of proliferation of endometrial glands, leading to increased glandular tortuosity, and appearance of vacuoles in the endometrial glands that soon secrete a range of proteins and peptides into the endometrial cavity. These processes prepare the endometrium for embryo  

a

Follicular

Ovulation

40

Secretory

FSH and LH

50 FSH LH

IU/L

30 20 10 0

b

300 250 200

PG/ML

LH isoforms as estradiol levels rise [7]. For granulosa cells to achieve this level of estradiol, the dominant follicle typically has grown to >15 mm [5, 8]. Animal studies on the nature of the switch from negative to positive feedback of estradiol on LH production point to increased estradiol inducing increased transmission of glutamate and gamma-aminobutyric acid (GABA) in GnRH neurons [9, 10]. The LH surge promotes the first meiotic division of the oocyte in the dominant follicle, previously arrested at the diplotene phase, and the ultimate rupture of the follicle leading to oocyte release. Meiosis is not completed until fertilization. Rupture occurs secondary to LH-influenced production of prostaglandins and eicosanoid signaling molecules that culminate in an ordered release of proteolytic enzymes [11]. Ovulation occurs about 36 hours after the start of the LH surge and 12 hours after the peak of the LH surge, leading to follicular rupture and oocyte release [12]. The fallopian tube, the typical site of fertilization, will then sweep up the oocyte.

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 Cycle Day Estradiol and Inhibin Estradiol Inhibin B Inhibin A

150 100 50 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 Cycle Day

c

16

Progesterone

14 12 10 NG/ML

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J. A. Gingold et al.

8 6 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Cycle Day

..      Fig. 1.1  Hormone fluctuations during the menstrual cycle. a Mean values of FSH and LH throughout the cycle. b Mean values of estradiol and inhibin. c Mean values of progesterone during the menstrual cycle. (Reproduced with permission from Falcone and Hurd [110])

implantation. If embryo implantation occurs, human chorionic gonadotropin (hCG), produced by the early embryo as early as 8–9 days after fertilization, will cause the corpus luteum to continue its production of progesterone via its action on the LH/hCG receptor [14].

5 Hypothalamic-Pituitary-­O varian Axis and Control of the Menstrual Cycle

If implantation does not occur, decreasing LH levels late in the luteal phase, induced by negative pituitary feedback, will cause a drop in progesterone levels. Declining estrogen and progesterone levels lead to enzymatic degradation of the functionalis layer of the endometrium, inflammatory infiltration, and vasoconstriction, thus beginning the process of menses. During the late luteal phase, the declining levels of estrogen and progesterone reduce their negative feedback on FSH production, enabling FSH levels to rise and begin the menstrual cycle again.

1.3

Anatomy of the Menstrual Cycle

This section will cover the anatomy of the hypothalamus, pituitary, ovary, and uterus and highlight the endocrinological connections between them that underpin the HPO axis. 1.3.1

Hypothalamus

The central nervous system is the primary regulator of the menstrual cycle. Menstrual cycle control originates from the hypothalamus and pituitary gland. The hypothalamus is located at the base of the brain, below the third ventricle and above the pituitary gland (. Fig. 1.2) [15]. It is bordered anteriorly by the optic chiasm and inferiorly by the mammillary bodies. The hypothalamus is a master regulator of the menstrual cycle via its signals to the anterior pituitary gland, but it also controls many other essential functions, including homeostasis, management of emotion and behavior in connection with the limbic system, circadian rhythms, the sleep-wake cycle, electrolyte balance, and food intake. The hypothalamus consists of three zones – lateral, medial, and periventricular. Each of these zones contains several nuclei. The arcuate nucleus, located in the periventricular zone, produces GnRH and is the hypothalamic regulator of the HPO axis and reproduction. During development, GnRH neurons originating at the olfactory area migrate to the arcuate nucleus along olfactory axon fibers, at which  

point they become hormonally active [15, 16]. The GnRH neurons synthesize GnRH from a larger 92 amino-­acid precursor [17]. GnRH, which is released into the hypophyseal portal vessels, reaches the hypothalamus, thus allowing the arcuate nucleus of the hypothalamus to control the pituitary gland [18]. The hypothalamus also transmits several other hormones via the hypophyseal portal system to communicate with the anterior pituitary. These hypothalamic hormones include growth hormone-releasing hormone (GHRH), which prompts the anterior pituitary to release growth hormone (GH); prolactin-­ releasing hormone (PRH), which prompts the anterior pituitary to stimulate milk production through release of prolactin; thyrotropin-releasing hormone (TRH), which modulates thyroid function by stimulating the anterior pituitary to release thyroid-­ stimulating hormone (TSH); and corticotropin-­releasing hormone (CRH), which regulates adrenal function via anterior pituitary production of adrenocorticotropic hormone (ACTH). 1.3.2

Pituitary

The pituitary gland is a small ovular structure suspended in the underside of the brain by the pituitary stalk (infundibulum). It sits in a bony cradle in the sphenoid bone called the sella turcica (. Figs. 1.2 and 1.3) [16]. Due to the location of the pituitary in the anatomically confined sella turcica, significant enlargement of the pituitary, as may occur with pituitary tumors such as prolactinomas, may cause headache and compression of adjacent cranial nerves involved in vision, leading to bilateral hemianopsia, though most patients with pituitary tumors are initially asymptomatic. There are two parts of the pituitary gland (anterior and posterior) which have separate embryonic origins and functions. The anterior lobe, the relevant pituitary component of the hypothalamic-pituitary-ovarian axis, derives from an outpouching of the pharynx known as Rathke’s pouch. The anterior lobe of the pituitary can be further divided into three smaller parts  – the pars anterior, pars intermedia, and pars tuberalis [18]. The pars ante 

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1

..      Fig. 1.2  Illustration of the hypothalamus, pituitary, sella turcica, and portal system. The arcuate nucleus is the primary site of GnRH-producing neurons. GnRH is released from the median eminence into the portal system. The blood supply of the pituitary gland derives from the internal carotid arteries. In addition to the arcuate nucleus, the other hypothalamic nuclei are SO supraoptic nucleus, SC suprachiasmatic nucleus, PV

paraventricular nucleus, DM dorsal-medial nucleus, VM ventromedial nucleus, PH posterior hypothalamic nucleus, PM premammillary nucleus, LM lateral mammillary nucleus, MM medial mammillary nucleus. The three hypothalamic areas are PA preoptic area, AH anterior hypothalamic area, and DH dorsal hypothalamic area. (Reproduced with permission from Falcone and Hurd [110])

rior lobe consists of glandular epithelium and secretes six major hormones: prolactin, GH, ACTH, FSH, LH, and TSH. The secretion of these hormones is controlled by the hypothalamus via hormones that travel through the hypophyseal portal vessels to act on the specialized cells responsible for secretion of each of the six hormones. The hypophyseal portal vessels originate with a branch of the internal carotid artery, known as the superior hypophyseal artery. The hypophyseal artery forms a capillary plexus around the hypothalamus, where it picks up

neurotransmitters, such as GnRH, and transports them to the next capillary plexus that surrounds the anterior pituitary [18]. In the case of the HPO axis, GnRH produced by the hypothalamus reaches pituitary gonadotropes to stimulate FSH and LH release. The other hypothalamic hormones transmitted through the hypophyseal portal system act on their own specific cell types in the anterior pituitary, including thyrotropes, which produce TSH; somatotrophs, which produce GH; lactotrophs, which secrete prolactin; and corticotrophs, which secrete ACTH (. Table 1.2).  

7 Hypothalamic-Pituitary-­O varian Axis and Control of the Menstrual Cycle

a

b

c

d

..      Fig. 1.3  X-ray and T1-weighted MRI images of the pituitary gland. a Lateral skull film with the sphenoidal sinus and sella turcica. b Sagittal section demonstrating the relationship between the sphenoidal sinus and the pituitary gland. The normal posterior pituitary is brighter on MRI compared to the anterior pituitary. The sella tur-

cica is not well seen on MRI. c Coronal section demonstrating the relationship of the pituitary to the optic chiasm and the pituitary stalk. d Coronal section after gadolinium contrast, demonstrating the close proximity of the pituitary to the internal carotid arteries. (Reproduced with permission from Falcone and Hurd [110])

..      Table 1.2  Major cell types of the anterior pituitary glanda Cell type

Appearance on light microscopy

Cellular frequency (%)

Hormone products

Somatotrophs

Acidophilic

50

Growth hormone

Lactotrophs

Acidophilic

20

Prolactin

Corticotrophs

Basophilic

20

Adrenocorticotrophic hormone (ACTH)

Thyrotrophs

Basophilic

5

Thyroid-stimulating hormone (TSH) and free α-subunit

Gonadotrophs

Basophilic

5

Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and free α-subunit

aReproduced

with permission from Falcone and Hurd [110]

1

8

1

J. A. Gingold et al.

The posterior lobe of the pituitary is embryonically derived from the forebrain as an extension of the hypothalamus. The posterior lobe secretes two hormones – antidiuretic hormone (responsible for regulation of blood osmolarity) and oxytocin (secreted during labor and with breastfeeding and involved in milk release into lactiferous ducts, uterine contractions, and social bonding). 1.3.3

Ovaries

The female gonads, the ovaries, are paired ovular structures which embryologically originate in the mesonephric ridge and descend into the pelvis [19]. The ovaries are the site of development and maturation of oocytes, the female gametes, and production of estradiol (E2) and progesterone in response to LH and FSH. The ovary can be divided histologically into three components: 1. Surface  – comprised of a single layer of cuboidal epithelium 2. Cortex  – comprised of connective tissue stroma and ovarian follicles containing oocytes 3. Medulla – comprised of connective tissue and a neurovascular network In the ovarian cortex, granulosa and theca cells surround each follicle. Prior to birth, these follicles are initially referred to as primordial follicles, each containing an oogonium, which is derived from a primary germ cell. All primary oocytes in these primordial follicles remain arrested in the prophase stage of meiosis I until puberty. Immature follicles, not yet recruited, are surrounded by a thin layer of granulosa cells [20]. With the onset of puberty and a rise in FSH and LH during each menstrual cycle, a cohort of about 20 primordial follicles are recruited to undergo the first stage of meiosis and become primary follicles. Once the first meiotic division is completed, the follicle is termed a secondary follicle (. Fig. 1.4) [20]. During this stage of early follicular maturation, stromal cells surrounding the follicle differentiate into theca cells to produce androgens under the influence of LH signals.  

..      Fig. 1.4  Stages of follicular development. Each primordial follicle contains an oogonium arrested in the first meiotic division in prophase. The primordial follicle is surrounded by a single layer of squamous granulosa cells. With each menstrual cycle, a small number of primordial follicles are recruited to become primary follicles. Granulosa cells develop a second layer and become cuboidal. The zona pellucida, a layer of glycoproteins separating the oocyte and granulosa cells, develops. Upon completion of the first meiotic division, the primary follicle becomes a secondary follicle. During this transition, a pool of follicular fluid known as the antrum coalesces and is surrounded by androgen-­ producing theca cells

The androgens, androstenedione, and testosterone, produced by the theca cells, diffuse to the nearby granulosa cells, which express the aromatase enzyme under the influence of FSH signals and convert the androgens to estrogens (. Table  1.3). Theca cells express LH receptors but not FSH receptors, while granulosa cells express FSH receptors but not LH receptors [21]. For this reason, although FSH is the only signal required for early folliculogenesis, LH is essential for producing the androgens that form the substrate of estrogen biosynthesis to promote follicle maturation.  

9 Hypothalamic-Pituitary-­O varian Axis and Control of the Menstrual Cycle

..      Table 1.3  Site of synthesis of major steroidogenic products of the ovary Cell type

Major steroid hormone products

Theca cells

Androgens (androstenedione, DHEA, testosterone)

Granulosa cells

Estrogens (estradiol, estrone, inhibin, AMH)

Theca-lutein cells

Progestogens (progesterone, 17-hydroxyprogesterone)

Granulosa-­ lutein cells

Estrogens (estradiol, estrone)

Granulosa cells within each follicle are responsible for the final stages of estrogen production, primarily estradiol and, to a lesser extent, estrone. Granulosa cells are also the source of anti-Mullerian hormone (AMH) and inhibin. AMH levels in reproductive-aged women reflect granulosa cell quantity, which is itself correlated with the primordial follicle pool. [22, 23] Thus, AMH is used clinically in the prediction of ovarian reserve for women undergoing infertility evaluation [24]. Once ovulation has occurred, the corpus luteum secretes estradiol and progesterone initially under support of luteal-phase LH.  If implantation occurs, embryonic hCG allows the corpus luteum to continue producing these hormones. Progesterone is primarily produced by the corpus luteum during early pregnancy until around 10  weeks gestational age and is essential for maintaining the pregnancy through around 7 weeks gestational age, after which placental production is sufficient to maintain the pregnancy [25]. If there is no pregnancy or hCG to rescue the corpus luteum, it will develop into a white fibrous streak in the ovary known as the corpus albicans [19]. Each ovary has two peritoneal attachments. The ovarian ligament attaches the ovary to the uterus and supplies secondary blood supply to the ovary. The suspensory ligament of the ovary (infundibulopelvic ligament) contains the primary neurovascular structures and connects the hilum of the ovary to the pelvic sidewall. Additionally, the ovary is attached to the broad ligament via the mesovarium [26].

The ovarian arteries, which directly branch from the abdominal aorta, provide the primary vascular supply to the ovaries. Anastomotic contribution from the uterine arteries, which branch from the anterior division of the internal iliac artery, provides collateral ovarian blood supply. Venous return occurs directly to the inferior vena cava from the right ovarian vein and via the left renal vein from the left ovarian artery [26]. Identification of the hilum at the anterolateral aspect of the ovary is particularly important in surgical planning, for example, during excision of ovarian cysts or endometriomas adjacent to the hilum. Surgical injury to the hilum or thermal injury from use of electrosurgery can disrupt ovarian blood supply and jeopardize remaining healthy ovarian tissue [27]. Ovarian vascular anatomy is also particularly important during ovarian transposition surgery, in which the ovary is relocated with its suspensory ligament blood supply in order to move the ovaries out of the pelvis and protect them from damage during therapeutic pelvic radiation.

1.3.4

Uterus

While it does not directly regulate the HPO axis, the uterus cyclically responds to the fluctuating hormones produced by it. The hormonal response of the endometrium is critical for normal menstrual function and to prepare the endometrium for embryonic implantation. The uterus lies in the pelvis, between the rectum and bladder. It consists of two parts, the corpus (body) and the cervix. The uterine wall contains three distinct layers: 1. The perimetrium  – the outermost layer consisting of connective tissue. 2. The myometrium  – the middle smooth muscular layer. The myometrium distends during pregnancy and contracts secondary to hormonal stimuli. 3. Endometrium – the inner mucosal layer constituting the primary hormonally responsive tissue affected by the menstrual cycle (see 7 Sect. 1.2).  

1

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The endometrium consists of two anatomic layers  – the functionalis and basalis. The functionalis layer constitutes the cellular interface with the endometrial cavity and undergoes cyclic change with the menstrual cycle. The basalis layer is primarily responsible for regenerating the functionalis layer in each cycle [28]. Increasing estrogen levels lead to glandular proliferation, increase in stromal matrix, and elongation of terminal arterioles within the functionalis of the endometrium. Progesterone, which rises most dramatically following the LH surge, causes the endometrium to undergo secretory changes characterized by terminal artery lengthening, superficial stromal edema, and glandular tortuosity. If implantation does not occur, falling estrogen/progesterone levels lead to cessation of glandular activity and stromal development, ultimately ending with enzymatic degradation and vasoconstriction within the functionalis [29]. The functionalis layer becomes unstable and sloughs off with menses. Inappropriately coordinated hormonal influences on the endometrium and lack of cyclic hormonal response will result in pathological endometrial findings. For example, in cases of unopposed estrogen due to anovulatory cycles, as frequently seen in patients with obesity, polycystic ovarian syndrome, or other metabolic disorders, endometrial tissue can respond with continuous proliferation, and potentially progress to hyperplasia or malignancy [29].

pyro-Glu1-His2-Trp3-Ser4-Tyr5-Gly6-Leu7-Arg8-Pro9-Gly10-NH2

..      Fig. 1.5  Structure of GnRH-1. (Reproduced with permission from Falcone and Hurd [110])

First sequenced and characterized in 1971, GnRH is a decapeptide (pGlu-His-Trp-SerTyr-­ Gly-Leu-Arg-Pro-Gly-NH2) and is the key regulator in the pituitary-gonadal axis (. Fig.  1.5) [30]. It is located as a single gene copy on the short arm of chromosome 8 and is secreted into the hypophyseal portal circulation to act chiefly on the anterior pituitary gland. GnRH synthesis occurs in a small subset of hypothalamic neurons which secrete it in pulsatile fashion into the hypophyseal portal blood system, through which it is transported to the anterior pituitary gland. Binding and activation of GnRH receptors triggers LH and FSH synthesis and release, ultimately leading to gametogenesis and gonadal steroidogenesis for sexual maturation and reproductive function [31]. The approximately 1000–3000 GnRH-­ producing cells found in the arcuate nucleus of the hypothalamus arrive there via neuroendocrine cell migration during embryogenesis from the olfactory placode. Abnormalities in this migratory pathway have clinical ramifications: Kallmann syndrome (KS) represents a failure in olfactory and GnRH neuronal migration from the olfactory placode to the hypothalamus resulting in GnRH deficiency. A number of distinct genetic causes for defects in GnRH migration have been 1.4 Endocrinology identified, including variants with X-linked, autosomal dominant, and autosomal recesof the Menstrual Cycle sive inheritance patterns, though the X-linked Human reproduction hinges on an intact form is the most common. Because KS genetic HPO axis demanding an ordered response mutations impair cell migration in nasal areas, across multiple organ systems. First, GnRH-­ patients experience both hypothalamic amensecreting neurons direct gonadotrophs to pro- orrhea and anosmia (inability to smell) [32, duce LH and FSH. These hormones primarily 33]. The clinical spectrum of other isolated act on ovarian tissue to promote synthesis of gonadotrophic-release hormone deficiencies the major female sex hormones estradiol and also includes constitutional delay of puberty progesterone. Finally, the sex hormones act and adult-onset hypothalamic hypogonadism. At least two GnRH isoforms have been on steroid receptors throughout the body to produce dramatic changes in gene transcrip- identified in humans and additional GnRH tion, including dramatic effects on the endo- isoforms exist in fish, amphibians, and protochordates [31, 34]. In humans, GnRH-I is metrium.  

1

11 Hypothalamic-Pituitary-­O varian Axis and Control of the Menstrual Cycle

the “classical” GnRH isoform that regulates synthesis and secretion of FSH and LH [35]. The other main GnRH isoform in humans is the “chicken-GnRH/GnRH-II” isoform. GnRH-­II is conserved from fish to mammals and differs from the classical GnRH-I by only three amino acids. However, its expression is localized to specific nuclei (supraoptic, paraventricular, suprachiasmatic) of the central nervous system and peripheral tissues (medial basal hypothalamus and female reproductive tissues including ovaries/placenta/endometrium) but has a limited role in the menstrual cycle. Its role appears to be in regulating sexual behavior [36–38]. GnRH pulse control is regulated by multiple hormones and neurotransmitters. Among them, dopamine, secreted directly into portal blood via the hypothalamic tuberoinfundibular pathway, suppresses arcuate GnRH production. In contrast, norepinephrine cell bodies located in the mesencephalon and lower brainstem stimulate GnRH production.

1.4.1

GnRH Agonists and Antagonists

The half-life of GnRH is approximately 2–4  minutes, due to rapid cleavage of the bonds between amino acids 5–6, 6–7, and 9–10. Chemical alteration of the amino acids in GnRH at these positions, combined with carboxyl- and amino-terminal modifications, has enabled the synthesis of an array of GnRH peptide analogues with distinct properties, including longer half-life, pure agonist activity, and pure antagonist activity (. Table 1.4). A number of these peptide analogues have found clinical applications. Continuous use of GnRH agonists leads to high-affinity binding to and occupancy of the GnRH receptor. GnRH agonist binding to its receptor induces initial gonadotroph activation and FSH/LH synthesis (the so-called “flare” effect), followed by desensitization and downregulation of the GnRH receptor, leading to suppressed FSH and LH levels within 1–3  weeks [15, 39–41]. GnRH antagonists do not produce this initial  

..      Table 1.4  Properties of commercially available GnRH agonistsa Structure and substitutions at positions 6 and 10

Half-­life

Relative potency

Route of administration

GnRH

Native decapeptide

2–4 min

1

IV, SC

Nafarelin

Decapeptide 6: D-Naphthylalanine for Gly

3–4 h

200

Intranasal

Triptorelin

Decapeptide 6: D-Trp for Gly

3–4 h

36–144

SC, IM depot

Leuprolide

Nonapeptide 6: D-Leu for Gly 10: NHEt for Gly

1.5 h

50–80

SC, IM depot

Buserelin

Nonapeptide 6: Ser(OtBu) for Gly 10: NHEt for Gly

1.5 h

20–40

SC, intranasal

Goserelin

Decapeptide 6: Ser(OtBu) for Gly 10: AzaGly for Gly

4.5 h

50–100

SC implant

Histrelin

Decapeptide 6: DHis for Gly 10: AzaGly for Gly

50 min

100

SC

aReproduced

with permission from Falcone and Hurd [110]

12

1

J. A. Gingold et al.

agonistic activity, and instead lead to immediate suppression of LH and FSH production via competitive inhibition [42–44]. Non-peptide, small molecular GnRH antagonists have also been developed. These drugs mechanistically work as peptide GnRH antagonists do but offer oral bioavailability, which is not possible with peptides. Elagolix, a competitive non-peptide GnRH receptor antagonist, has FDA approval for treatment of moderate to severe endometriosis [45, 46]. Another oral GnRH antagonist, relugolix, has been approved in Japan for treatment of uterine myomas. 1.4.2

Control of GnRH Pulsatility

GnRH neurons retain the ability to synchronize GnRH release into the hypothalamic-­ hypophyseal portal vessels as pulses. Variations in the GnRH pulse frequency and amplitude lead to differential production of FSH and LH, thus allowing one hormone to simultaneously regulate the levels of its two primary targets. Direct measurement of GnRH production is technically challenging because the hormone has a 2–4-minute half-­life and is restricted to the hypophyseal portal vessels, though direct measurement via portal blood collection under anesthesia has been performed in animal models [47, 48]. Because LH has a much shorter half-life than FSH (20 minutes versus 3 hours), serum LH levels primarily reflect recent LH production under GnRH control. Thus, human studies attempting to measure GnRH levels have used serial measurements of LH levels as surrogate for GnRH production. Such studies have demonstrated that low-frequency GnRH pulses ( Literature > Cytokine Bulletin [cited 21 2012]. http:// www.­r ndsystems.­c om/cb_detail_objectname_ FA01_BMPs.­aspx. 77. Young JM, McNeilly AS. Theca: the forgotten cell of the ovarian follicle. Reproduction. 2010;140: 489–504. 78. Carlsson IB, Laitinen MP, Scott JE, Louhio H, Velentzis L, Tuuri T, et al. Kit ligand and c-Kit are expressed during early human ovarian follicular development and their interaction is required for the survival of follicles in long-term culture. Reproduction. 2006;131(4):641–9. 79. Hutt KJ, McLaughlin EA, Holland MK. Kit ligand and c-Kit have diverse roles during mammalian oogenesis and folliculogenesis. Mol Hum Reprod. 2006;12(2):61–9. 80. Zuckerman S.  The number of oocytes in the mature ovary. Recent Prog Horm Res. 1951;95(6): 63–108. 81. 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(1):2–12. 82. Virant-Klun I, Stimpfel M, Skutella T.  Stem cells in adult human ovaries: from female fertility to ovarian cancer. Curr Pharm Des. 2012;18(3): 283–92. 83. 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):145–50. 84. White YA, Woods DC, Takai Y, Ishihara O, Seki H, Tilly JL. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-­age women. Nat Med. 2012;18(3):413–21. 85. Virant-Klun I, Stimpfel M, Skutella T.  Ovarian pluripotent/multipotent stem cells and in  vitro oogenesis in mammals. Histol Histopathol. 2011;26(8):1071–82. 86. Tilly JL, Telfer EE.  Purification of germline stem cells from adult mammalian ovaries: a step closer towards control of the female biological clock? Mol Hum Reprod. 2009;15(7):393–8. 87. Rienzi L, Gracia C, Maggiulli R, LaBarbera AR, Kaser DJ, Ubaldi FM, et  al. Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-­freezing versus vitrification to produce evidence for the development of global guidance. Hum Reprod Update. 2017;23(2):139–55. 88. Noyes N, Boldt J, Nagy ZP.  Oocyte cryopreservation: is it time to remove its experimental label? J Assist Reprod Genet. 2010;27(2–3):69–74.

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Goldman RH, Racowsky C, Farland LV, Munné S, Ribustello L, Fox JH. Predicting the likelihood of live birth for elective oocyte cryopreservation: a counseling tool for physicians and patients. Hum Reprod. 2017;32(4):853–9. 90. Fuchs Weizman N, Baram S, Montbriand J, Librach CL.  Planned oocyte cryopreservation (planned OC): systematic review and meta-­analysis of cost-efficiency and patients' perspective. BJOG. 2021;128(6):950–62. 91. Hoekman EJ, Louwe LA, Rooijers M, van der Westerlaken LAJ, Klijn NF, Pilgram GSK, et  al. Ovarian tissue cryopreservation: low usage rates and high live-birth rate after transplantation. Acta Obstet Gynecol Scand. 2020;99(2):213–21. 92. Rivas Leonel EC, Lucci CM, Amorim CA. Cryopreservation of human ovarian tissue: a review. Transfus Med Hemother. 2019;46(3):173–81. 93. Telfer EE.  Future developments: in  vitro growth (IVG) of human ovarian follicles. Acta Obstet Gynecol Scand. 2019;98(5):653–8. 94. Desai N, Alex A, AbdelHafez F, Calabro A, Goldfarb J, Fleischman A, et  al. Three-­ dimensional in vitro follicle growth: overview of culture models, biomaterials, design parameters and future directions. Reprod Biol Endocrinol. 2010;8:119. 95. Middendorff R, Muller D, Mewe M, Mukhopadhyay AK, Holstein AF, Davidoff MS. The tunica albuginea of the human testis is characterized by complex contraction and relaxation activities regulated by cyclic GMP.  J Clin Endocrinol Metab. 2002;87:3486–99. 96. de Kretser DM, Temple-Smith PD, Kerr JB. Chapter 16: Anatomical and functional aspects of the male reproductive organs. In: Bandhauer K, Fricks J, editors. Handbook of urology. Berlin: Springer; 1982. p. 1–31. 97. de Kretser DM, Kerr JB. The cytology of the testis. In: Knobill E, Neil JD, editors. The physiology of reproduction. New York: Raven; 1994. p. 1177–290. 98. Christensen AK.  Leydig cells. In: Hamilton DW, Greep RO, editors. Handbook of physiology. Baltimore: Williams & Wilkins; 1975. p. 57–94. 99. Clermont Y. The cycle of the seminiferous epithelium in man. Am J Anat. 1963;112:35–51. 100. Clermont Y. Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonial renewal. Physiol Rev. 1972;52:198–236. 101. Huckins C. The spermatogonial stem cell population in adult rats. I. Their morphology, proliferation and maturation. Anat Rec. 1971;169:533–57. 102. Dym M, Fawcett DW. Further observations on the numbers of spermatogonia, spermatocytes, and spermatids connected by intercellular bridges in the mammalian testis. Biol Reprod. 1971;4:195–215. 103. Paulson JR, Laemmli UK.  The structure of histone-­ depleted metaphase chromosomes. Cell. 1977;12:817–28. 104. Izaurralde E, Kas E, Laemmli UK.  Highly preferential nucleation of histone H1 assem-

bly on scaffold-­ associated regions. J Mol Biol. 1989;210:573–85. 105. Adachi Y, Kas E, Laemmli UK. Preferential cooperative binding of DNA topoisomerase II to scaffold-associated regions. EMBO J. 1989;13:3997. 106. Giroux CN.  Meiosis: components and process in nuclear differentiation. Dev Genet. 1992;13: 387–91. 107. Auger J, Dadoune JP.  Nuclear status of human sperm cells by transmission electron microscopy and image cytometry: changes in nuclear shape and chromatin texture during spermiogenesis and epididymal transit. Biol Reprod. 1993;49: 166–75. 108. Miller D, Brinkworth M, Iles D.  Paternal DNA packaging in spermatozoa: more than the sum of its parts? DNA, histones, protamines and epigenetics. Reproduction. 2010;139:287–301. 109. Braun RE. Packaging paternal chromosomes with protamine. Nat Genet. 2001;28:10–2. 110. Balhorn R. The protamine family of sperm nuclear proteins. Genome Biol. 2007;8:227. 111. Bedford JM, Calvin H, Cooper GW. The maturation of spermatozoa in the human epididymis. J Reprod Fertil Suppl. 1973;18:199–213. 112. Russell L. Morphological and functional evidence for Sertoli-germ cell relationship. In: Russell LD, Griswold MD, editors. The Sertoli cell. Clearwater: Cache Press; 1993. p. 365–90. 113. Breucker H, Schafer E, Holstein AF.  Morpho genesis and fate of the residual body in human spermiogenesis. Cell Tissue Res. 1985;240: 303–9. 114. Heller CG, Clermont Y.  Spermatogenesis in man: an estimate of its duration. Science. 1963;140(3563):184–6. 115. Clermont Y, Perey B.  The stages of the cycle of the seminiferous epithelium of the rat: practical definitions in PA-Schiff-hematoxylin and hematoxylin-­eosin stained sections. Rev Can Biol. 1957;16:451–62. 116. Perey B, Clermont Y, LeBlonde CP. The wave of seminiferous epithelium in the rat. Am J Anat. 1961;108:47–77. 117. Heller CH, Clermont Y.  Kinetics of the germinal epithelium in man. Recent Prog Horm Res. 1964;20:545–75. 118. Schulze W, Rehder U. Organization and morphogenesis of the human seminiferous epithelium. Cell Tissue Res. 1984;237:395–407. 119. World Health Organization. Laboratory manual for the examination of human semen and sperm– cervical mucus interaction. 4th ed. New  York: Cambridge University Press; 1999. 120. World Health Organization. Laboratory manual for the examination of human semen and sperm– cervical mucus interaction. 5th ed. New  York: Cambridge University Press; 2010. 121. WHO laboratory manual for the examination and processing of human semen. 6th ed. Geneva. 2021.

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Significance of timing for the postcoital evaluation of cervical mucus. Am J Obstet Gynecol. 1975;121:387–93. 134. Mortimer D. Objective analysis of sperm motility and kinematics. In: Keel BA, Webster BW, editors. Handbook 35. Katz DF, Drobnis E, Overstreet JW.  Factors regulating mammalian sperm migration through the female reproductive tract and oocyte vestments. Gamete Res. 1989;22:443–69. 135. Mortimer D.  Sperm transport in the human female reproductive tract. In: Finn CA, editor. Oxford reviews of reproductive biology. Oxford, UK: Oxford University Press; 1983. p.  30–61. Chapter 5. 136. Yanagamachi R.  Mammalian fertilization. In: Knobill E, O’Brien NJ, editors. The physiology of reproduction. New York: Raven; 1994. 137. Thomas P, Meizel S.  Phosphatidylinositol 4,5-bisphosphate hydrolysis in human sperm stimulated with follicular fluid or progesterone is dependent upon Ca2+ influx. Biochem J. 1989;264:539–46. 138. Overstreet JW, Katz DF, Yudin AI. Cervical mucus and sperm transport in reproduction. Semin Perinatol. 1991;15:149–55. 139. Parks JE, Ehrenwald E.  Cholesterol efflux from mammalian sperm and its potential role in capacitation. In: Bavister BD, Cummins J, Roldan ERS, editors. Fertilization in mammals. Norwell: Serono Symposia; 1990. 140. Benoff S, Hurley I, Cooper GW, Mandel FS, Hershlag A, Scholl GM, et  al. Fertilization potential in  vitro is correlated with head-specific mannose-­ ligand receptor expression, acrosome status and membrane cholesterol content. Hum Reprod. 1993;8:2155–66.

55

Normal Puberty and Pubertal Disorders Siddhi Mathur, Joseph S. Sanfilippo, and M. Jonathon Solnik Contents 3.1

Introduction – 57

3.2

Normal Puberty – 57

3.3

Onset of Puberty – 58

3.4

Characteristics of Sexual Development – 59

3.5

Thelarche – 60

3.6

Adrenarche – 61

3.7

Growth Spurt – 61

3.8

Menarche – 61

3.9

Precocious Puberty – 62

3.9.1 3.9.2

E ffects of Precocious Puberty on Adult Height – 63 Central Precocious Puberty (See Central Precocious Puberty) – 63 Laboratory Findings – 63 Treatment – 64 Hypothalamic Suppression – 64 Recombinant Growth Hormone – 66 GnRH-Independent Precocious Puberty (See GnRH-Independent Precocious Puberty) – 66 Autonomous Ovarian Estrogen Production – 66 McCune–Albright Syndrome – 67

3.9.3 3.9.4 3.9.5 3.9.6 3.9.7 3.9.8 3.9.9

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 T. Falcone, W. W. Hurd (eds.), Clinical Reproductive Medicine and Surgery, https://doi.org/10.1007/978-3-030-99596-6_3

3

3.9.10 3.9.11 3.9.12

T reatment – 67 Premature Thelarche – 67 Premature Adrenarche – 67

3.10

Delayed Puberty and Primary Amenorrhea – 68

3.10.1 3.10.2 3.10.3 3.10.4 3.10.5 3.10.6

 ypergonadotropic Hypogonadism – 68 H Hypogonadotropic Hypogonadism – 69 Primary Amenorrhea with Otherwise Normal Sexual Development – 69 Evaluation – 70 Imaging – 71 Treatment of Delayed Puberty – 72

3.11

Review Questions – 74

3.12

Answers – 75 References – 75

57 Normal Puberty and Pubertal Disorders

Key Points 55 Timing of puberty and its trajectory is determined by genetic, environmental, and neurobehavioural factors. The typical span is from age 8 to 13 years. 55 Adrenarche is the first biochemical change seen in puberty and the initiating signals arise from hypothalamic–adrenal pathways rather than gonaladal pathways. 55 Adolescents with central precocious puberty can be successfully suppressed with GnRH agonists. The addition of recombinant growth hormone may be of benefit in select individuals, but overall, has not been shown to increase final adult height. 55 In adolescents with delayed puberty who require induction with estrogen administration, titrate slowly over a longer period of time to avoid abnormal breast development. 55 Exploring gender identity and experience with youth and adolescents can be an important aspect of pubertal development.

3.1

Introduction

Sexual development involves a complex series of events that, if orchestrated in an appropriate sequence, results in the normal transition from childhood to young adulthood. Although from an evolutionary perspective, the ultimate goal is procreation, puberty represents a monumental time in the life of an adolescent, one of biological and psychological challenges, potentially heightened even when subtle variances to societal norms occur. This segment will first describe normal pubertal development, and then focus on mechanisms that result in both precocious and delayed development, emphasizing presentation and pattern recognition for generating differential diagnoses, and providing useful algorithms and treatment strategies for a wide range of specialists who can bring a unique per-

spective when caring for such young patients when normal puberty drifts awry.

3.2

Normal Puberty

The activation of the hypothalamic–pituitary–gonadal (HPG) axis represents the beginning of reproductive life in the adolescent female, originally described by Ernst Knobil in 1980 at the University of Pittsburgh [1]. In the higher cortical centers, from the arcuate nucleus of the hypothalamus, gonadotropin-­ releasing hormone (GnRH) is synthesized and released [2]. Through its effect on the anterior pituitary, GnRH regulates the synthesis, storage, and release of the pituitary gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). These hormone levels approach that of an adult in the fetal circulation by mid-­ gestation. However, with increasing maternal steroid hormone production toward term, gonadotropin levels decline. Shortly after delivery, as the maternal source of estrogen is withdrawn, gonadotropin levels are noted to increase as a result of the release from the negative-feedback circuit [3]. This sequence of events demonstrates the functional capability of the hypothalamicpituitary-ovarian (HPO) axis early in development and results in follicular growth in the prepubertal ovary and an increase in circulating estradiol. This effective and exquisitely sensitive negative-feedback system, often referred to as the gonadostat, develops rapidly. In the years preceding puberty, gonadotropin levels remain low in response to suppression by low levels of circulating estrogen (10 pg/mL). It is thought that the two primary inhibitory influences on the pulsatile release of GnRH and the downregulation of the HPO axis during childhood are the (1) intrinsic central nervous system (CNS) inhibition via γ(gamma)-aminobutyric acid (GABA) and the (2) negative-feedback system driven by ovarian steroid hormones [4, 5]. With continued maturation of the CNS after birth, a more profound internal inhibitory effect can be noted in reference to GnRH-secreting neurons. In premature

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infants with less developed neuronal pathways, for example, pituitary gonadotropins are higher than in term counterparts, presumably due to a weaker inhibitory influence [6]. The presence of a nonsteroidal regulator of these pathways is further substantiated by the ability of patients with gonadal agenesis to secrete moderate levels of gonadotropins in response to GnRH [7]. The normal age range of puberty is 7–13 years for white girls and 6–13 for Black girls [8]. Mean age at menarche is 12.9 (+/−1.2) years in white girls and 12.1 (+/−1.2) years in Black girls [7]. On average, thelarche occurs 1.2 years before pubarche. Menarche usually correlates with pubarche Stage IV and generally is 2–2.5 years after thelarche [9].

3.3

Onset of Puberty

Pulsatile secretion of GnRH from the arcuate nucleus of the hypothalamus leads to gonadarche, documented by profound increases in sex steroid hormone production [2]. Early pubertal changes are temporally associated with an increase in GnRH pulse frequency, primarily during the sleep cycle [10]. As menarche approaches, GnRH pulses increase in amplitude and can be detected throughout the day, similar to that of an adult [11, 12]. Both genetic and environmental effects may play a role with the initiation of pubertal development. It has been suggested that appropriate weight gain and percent body fat are required for these events to occur [13]. This concept is substantiated by data from adolescent females who suffer from chronic illness, and malnutrition or have low body mass indices due to vigorous exercise. These young girls frequently experience delays in sexual maturation and may present with primary amenorrhea, resulting from hypothalamic hypogonadism. Accordingly, normal menstrual cycles resume with reversal of their nutritional status [14]. Investigators who followed healthy females throughout puberty found that body composition did not change prior to, but rather along with, the increase in GnRH secretion [15].

Plasma concentrations of leptin, an adipocyte-derived hormone, correlate well with body composition and have been shown to rise throughout puberty in female patients [16]. Specific leptin deficiencies have been shown to prevent sexual maturation, which can then be triggered by restoring normal levels [17]. Nevertheless, the role of leptin in pubertal development has not been clearly elucidated. The concept of intrauterine growth restriction, imprinting, and subsequent developmental disorders follows a common thread, since early exposure to a spendthrift, “lowcalorie” environment may have a contrary effect in childhood, as suggested by the Barker hypothesis, resulting in early onset menarche and adrenarche [18–20]. Another molecule that may play a role in the reversal of the HPO downregulation is neuropeptide Y (NPY). Circulating levels are regulated by steroid hormones as well as nutritional status, with a net influence in gonadotropin synthesis through an alteration in GnRH pulsatility and pituitary response to GnRH [21]. Increased levels of NPY have been documented in females with eating disorders such as anorexia nervosa and bulimia [22], representing another possible correlation with percent body fat and reproductive potential. Kisspeptin is a strong stimulator of the HPO axis, acting through GnRH neuronal activity, and may be a key player in early pubertal development [23]. Although the exact mechanisms on the gonadotropic axis are not well defined, receptor mutations have been identified in women with precocious puberty, and when administered to women with hypothalamic amenorrhea, kisspeptin agonists have successfully stimulated gonadotropin secretion. Insulin-like growth factor I plays a role and appears to be under the control of gonadotropin releasing hormone (GnRH); furthermore, this appears to be tied into the growth hormone axis [24, 25]. Low levels of estrogen appear to stimulate bone growth in part through the growth hormone-insulin-like growth factor I axis [26]. Please see . Fig. 3.1 outlining the neuroendocrine basis for pubertal development [27].  

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59 Normal Puberty and Pubertal Disorders

Hypothalamus

GHRH

GnRH

CRH

HPG axis

GH axis Anterior Pituitary

FSH & LH

GH ACTH

Testes

Liver & Epiphyses

IGF-1 IGF-2

HPA axis

Ovaries Adrenal gland zona reticularis ST DHEAS

pulsatile secretion

3β DHEA 17β

A4 AT

Testosterone Estradiol

..      Fig. 3.1  Simplified diagram of the hypothalamic– pituitary–gonadal (HPG) axes, hypothalamic–pituitary– adrenal (HPA) axes, and growth hormone (GH) axes. The hypothalamus releases gonadotropin-­releasing hormone (GnRH), corticotropin-releasing hormone (CRH), and growth hormone-releasing hormone (GHRH), which stimulate the anterior pituitary gland to release folliclestimulating hormone (FSH) and luteinizing hormone (LH), adrenocorticotropic hormone (ACTH), and growth hormone (GH), respectively. GnRH, LH, GHRH, and GH are released in a pulsatile fashion that varies with pubertal stage. In the HPG axis, FSH stimulates the ovarian follicles to produce estrogen (from androgenic precursors produced from theca cells), inhibin, progesterone, and ova. Estrogen provides both a positive and negative feedback on GnRH.  In females, a critical amount

3.4

Characteristics of Sexual Development

The predictable and ordered series of events, which have historically been referred to as the standard for sexual development and somatic growth, were initially described by Tanner and Marshall more than 30  years ago (Sexual

FSH FSH Ovarian follicles Estrogen progesterone Inhibin Ova

LH

LH Interstitial cells (theca cells) Androgens (testosterone)

Leydig cells

Sertoli cells & seminiferous tubules Estrogen Inhibin sperm

Androgens (testosterone)

of estrogen is needed to produce a positive feedback to stimulate the LH surge that leads to ovulation. In males, FSH stimulates Sertoli cells and seminiferous tubules to produce estrogen, inhibin, and sperm. LH stimulates theca cells in females and Leydig cells in males to produce androgens. On the HPA axis, ACTH stimulates the zona reticularis of the adrenal gland to secrete dehydroandrosterone (DHEA). DHEA is then converted to dehydroandrosterone sulfate (DHEAS) via sulfotransferase (ST), and to androstenedione (A4) via 3b-hydroxysteroid dehydrogenase (3b). A4 is then converted to testosterone via 17b-hydroxysteroid dehydrogenase (17b) and estradiol via aromatase (AT). In the GH axis, GH stimulates the liver and epiphyses of bone to produce insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2)

Maturity Rating (SMR) Scale) [28] (. Fig. 3.2). These publications raise the notion of endocrinedisrupting chemicals, and although there is little doubt that persistent exposure may adversely affect developmental pathways and promote disease progression, the association with pubertal development remains tentative and weakly causative from an epidemiological perspective.  

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..      Fig. 3.2  Timing of events of puberty. 1969 data from a study of British schoolchildren. 1997 data from a study of American schoolchildren. (Reproduced with permission from Solnik and Sanfilippo [29]; adapted from [28])

Breast

Prepubertal

Breast and papilla are elevated as a small mound. Areolar diameter increases

Further enlargement of the breast bud with loss of the contour separation between breast and areola

Areola and papilla form a secondary mound

Mature areola is part of the general breast contour

3.5

Thelarche

The first clinical sign of development in the majority of white females is breast budding, denoted by Tanner Stage II. According

Pubic Hair

I

II

III

IV

V

Prepubertal

Spare, lightly pigmented chiefly along the medial border of the labia majora

Darker, beginning to curl, increased amount spreading over the mons

Increased amount of, coarse, curly but limited to the mons

Adult feminine triangle with spread to the medial surface of the thighs

to Tanner and Marshall, this initial event occurs between 8 and 13 years of age in most females, with a mean of 10.6 years. The transition period from Stage II to Stage V breast development may last 4.2 years [28].

61 Normal Puberty and Pubertal Disorders

3.6

Adrenarche

Adrenal activation occurs independent of the hypothalamic–pituitary–gonadal axis and typically occurs between 6 and 81 years of age, reaching adult hair distribution by age 14, and preceding gonadal activation by approximately 2  years. Since adrenarche may occur before thelarche and at a fairly young age in normally developing females, it can result in undue stress for parents. While early onset may be associated with hyperandrogenism, it may be more familial and not represent pathological development.

3.7

Growth Spurt

The growth spurt (peak growth velocity), during which adolescents achieve approximately 20% of their adult final height, occurs with the onset of puberty [28]. Peak growth velocity (2–3  cm/year) precedes menarche and typically occurs earlier in girls than in boys. Rapid growth of the extremities occurs first, followed by a gradual lengthening within the vertebral column. The timing of the growth spurt varies according to ethnicity. Predicted final height has traditionally been based on the methodology described by Bayley and Pinneau [30]. Target height (cm) considers genetic potential and is calculated from the averages of the height of the child’s parents: male— [father’s height  +  mother’s height  +  13]/2 and female: [father’s height − 13 + mother’s height]/2.

3.8

Menarche

According to Tanner, girls in the UK in 1969 had their first menses at the average age of 13.5  years, with a range of 9–16  years [28]. The mean age of menarche for a white adolescent in the USA is approximately 12.7 years. At the time of menarche, most have achieved Tanner Stage IV breast development, and the interval from initial breast development to menarche on average is 2.3 years [28]. There seems to have been a decline in the average age of menarche in the first half of the

twentieth century, in part due to the improvement in general health and nutrition [31]. Nonetheless, few reports have documented any further changes since the mid-­twentieth century. There is good evidence that African– American girls have an earlier onset of puberty compared to white girls [32, 33]. This was well demonstrated by the Pediatric Research in Office Settings (PROS) study published by Herman-Giddens in 1999 [32]. This multicenter, cross-sectional study evaluated over 17,000 female patients between 3 and 12 years of age [32]. On average, African–American females show early signs of puberty up to 1.5 years earlier than their white counterparts. By 7 years of age, 27.2% of African-American girls and 6.7% of white girls showed breast or pubic hair development. Menarche was achieved almost a year earlier. The mean age for onset of breast development was 8.87  years in African–American girls and 9.96  years in white girls. At each consecutive stage of development, African– Americans were more advanced per year than white. Girls of other ethnic backgrounds may also have a characteristic difference in onset of pubertal maturation. However, only white and African–American girls were included in this study. Please see . Fig. 3.3 for a visual representation of pubertal timelines. PROS was the first large publication to address current and demographically relevant standards for assessing normal and abnormal onset of puberty. Updated guidelines have since been proposed and recommend a formal evaluation for precocious puberty be initiated in African–American girls who present before the age of 6 and white girls who present before the age of 7. Although this provocative investigation has drawn much criticism, it does invite us to reconsider the current standards (. Fig.  3.2). As recent as 2016, authors reported on findings from 5839 girls from the UK Millennium Cohort Study, a cohort born between 2000 and 2002. They evaluated variables that were associated with menstruation at age 11  years in this longitudinal study: disadvantaged minorities (especially from Pakistan, Bangladesh, and Black African descent), higher BMI, and exposure to psychosocial stress were more linked to early onset of menarche [34] (. Fig. 3.3).  

 

 

1

Reference? Previous notation 11–12 years

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Adrenarche Thelarche Growth Spurt

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Pubarche Menarche Age (years)

6

7

8

9

10

..      Fig. 3.3  Anticipated timelines for mean onset and duration of pubertal trajectories [7 https://pedsinreview-­ aappublications-­org.­myaccess.­library.­utoronto.­ca/content/pedsinreview/37/7/292.­full.­pdf]. Typical age range  

3.9

Precocious Puberty

The definition of precocious puberty has since remained stable, such that any female who presented prior to 8  years of age was observed, if not evaluated, for progression of

11

12

13

14

15

of puberty is 7–13 years. Thelarche occurs 1.2 years before pubarche. Mean age at menarches is 12.9(+/– 1.2) years, 2–2.5 years after thelarche. *Ages may vary based on ethnicity., BMI, nutritional status

sexual characteristics [28]. As referred to earlier, the traditional definition was challenged by Herman-­Giddens, who strongly suggested that normal pubertal development may begin as early as 6 years of age [32]. Causes of precocious puberty are listed in 7 Box 3.1.  

Box 3.1  Causes of Precocious Puberty Central precocious puberty (GnRH dependent) 1. Idiopathic 2. Central nervous system tumors (a) Craniopharyngioma (b) Trauma (c) Infection (d) Primary hypothyroidism 3. Syndromes associated with elevated gonadotropins (a) Silver’s syndrome (dwarf-­like characteristics)

(a) Granulosa cell (b) Functional cyst 3. Adrenal tumors 4. McCune–Albright syndrome Heterosexual precocious puberty 1. Exogenous steroid hormone exposure (androgens) 2. Adrenal and ovarian androgen-­producing tumors aUrgent

Peripheral precocious puberty (GnRH independent) 1. Exogenous steroid hormone exposure (estrogens) 2. Ovarian tumors

assessment in girls with precocious puberty presenting with rapid onset symptoms, contrasexual development (i.e., virilization), vaginal bleeding without other secondary sexual characteristics, and focal neurological findings suggestive of space-occupying lesion

63 Normal Puberty and Pubertal Disorders

zz Environmental Factors

Although the activation of the HPO axis results in normal onset of sexual development, alternate sources of steroid hormone production may signal abnormally early development in adolescent girls. Such agents include organic pesticides, soy-based products, and shampoos containing placental extract. Investigators have suggested several possible pathways by which these agents influence development, including direct activation of the HPO axis and steroid hormone-like activity [35–37]. An area of upcoming study is endocrine-disrupting chemicals that are a group of exogenous chemical (EDS) or a combination of chemicals that interfere with any hormone action. They can affect any component of the hypothalamic–pituitary axis. Examples of EDCs include herbicides, plastics, parabens, plastics, and fungicides. Many of these EDCs are estrogen/androgen agonists. In animal models, they have been shown to affect menstrual cycle, development of the Müllerian tract, and risk of developing breast cancer [38]. These associations are to be further studied in human models. zz Neurobehavioral Factors

Puberty timing has been shown to be influenced by demographic, ethnic, genetic, endocrine, and environmental factors. The transition from youth to adolescence can also be affected by biobehavioral factors and neurodevelopmental disorders such as autism spectrum disorders (ASD). ASD is a complex neurodevelopmental disorder with an estimated prevalence of 2% among children 6–17 years of age. Research on the effect of ASD on pubertal timing has been limited. Corbett et al., in one of the largest longitudinal studies to study the impact of ASD on pubertal timing, reported that females with ASD showed earlier pubertal onset than males with ASD [39].

3.9.1

 ffects of Precocious Puberty E on Adult Height

Low levels of estrogens have been shown to promote bone growth, as is manifest by rapid

growth velocity during the growth spurt. Conversely, high levels promote closure of the epiphyseal plates. Girls who present early in the course of precocious puberty are generally taller than their age-respective cohorts due to increased levels of steroids and the actions of IGF-I. This growth is premature and limited, so that the final height in untreated patients will likely be less than 155  cm [30]. As a result, by the time most adolescents achieve menarche, they have likely reached their final height. Notwithstanding the apparent risk for short stature, a significant number of untreated patients with idiopathic disease will likely attain relatively normal adult height, greater than the third percentile [30]. Some specialists in the field believe that the diagnosis of precocious puberty cannot be assigned unless symptoms are also associated with an accelerated growth spurt. 3.9.2

 entral Precocious Puberty C (See Central Precocious Puberty)

CPP is more frequently noted among girls, with an incidence of 1:5000–1:10,000 [40]. It results from the premature activation of the hypothalamic GnRH neurons. Approximately 70–95% of such cases are idiopathic in nature; however, other potential etiologies must first be considered, since the level of urgency and need for management of individual causes will vary [41, 42]. For a full list of etiologies, see 7 Box 3.1.  

3.9.3

Laboratory Findings

Baseline gonadotropin levels in the pubertal range with a predominant LH response are suggestive of CPP. Random daytime levels may be of less use in early central pubertal development because the initial increase in pulsatility occurs at night. To help distinguish CPP from GnRHindependent forms of precocious puberty, a GnRH stimulation test should be performed. To accomplish this, 100 μg of GnRH (gonadorelin acetate) is administered intravenously,

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and gonadotropin levels are drawn at baseline and at 20, 40, and 60 min. One of the earliest signs of physiologic puberty is the nocturnal, pulsatile secretion of GnRH with a subsequent increase in serum LH. There is a corresponding rise in LH for each pulse of GnRH secreted. These same events occur with early onset, and an LH:FSH ratio > 1 would be expected. Serum estradiol levels would be detected in the pubertal range as well. In order to maintain the diagnosis of CPP, androgen (DHEA, DHEA-S, testosterone) and 17-­hydroxyprogesterone (17OHP) levels should be drawn. 3.9.3.1

Physical Exam

Physical findings suggestive of central precocious puberty (CPP) include Tanner Stage II breast development with darkening of the areola, labial fullness with a dullness of the vaginal mucosa, and leukorrhea. Coarse pubic hair, acne, oily skin, clitoromegaly, and deepening of the voice are signs of androgen production, which may occur in the setting of heterosexual development and should likewise be investigated. Tall stature and adulttype body odor are other indications for the evaluation of precocious puberty. A complete neurological exam, psychological evaluation, and skin assessment should be performed initially and with subsequent visits as well. Simple findings such as elevated blood pressure, suggestive of nonclassic congenital adrenal hyperplasia (CAH), or skin changes consistent with café au lait spots are most helpful and easy to notice. 3.9.3.2

Imaging Studies

Imaging studies play a key role in the evaluation of children with precocious puberty, because a rapid increase in growth and bone age are typically seen in children with rapidly increasing levels of sex steroid hormones. Linear growth and skeletal maturation are often a more accurate assessment of pubertal development than progression of secondary sexual characteristics. Bone age is typically evaluated by radiographic plain films of the left hand and wrist. This is a simple and noninvasive test that is well tolerated by most children. Bone age advance over chronological age is diagnostic

for precocious puberty, and a disparity of greater than 2 years is more suspicious for a progressive disorder [43]. Given the higher prevalence of CNS abnormalities, especially in girls who present with particularly early onset or who have a known history of childhood seizures, neuroimaging is always indicated to rule out space-occupying lesions, malignant neoplasms, and other CNS anomalies, even in the absence of neurological complaints. Pelvic ultrasound, however, is typically one of the easiest and most useful studies since it provides a good picture of ovarian function (developing follicles capable of producing estradiol, increased cortical volume suggestive of excess androgen production) or neoplastic processes. Ultrasound may also demonstrate subsequent steroid hormone influence on other reproductive organs. A diagnostic approach to precocious puberty is given in . Fig. 3.4.  

3.9.4

Treatment

The ultimate therapeutic goal with central precocious puberty is to suppress the HPO axis and return the hormonal environment to that of the prepubertal state (serum estradiol 30–40 IU/L) on two occasions more than a month apart meet the criteria for primary ovarian insufficiency (POI). POI, which arises from follicular dysfunction and depletion, comprises 4–18% of cases of secondary amenorrhea.

The vast majority (90%) of POI cases are idiopathic. However, it can be associated with a myriad of underlying pathologies, as outlined in . Table  6.2. For example, many instances of POI have genetic causes/chromosomal abnormalities such as fragile X syndrome [59]. In the case of fragile X syndrome, a family history of early menopause and especially of male developmental delay is typically found. For patients experiencing POI before the age of 30, a karyotype is warranted to rule out Turner’s syndrome and to determine if a Y chromosome is present, which would necessitate gonadectomy to reduce the risk of gonadal malignancy [60]. It must be noted that POI patients have a 6% chance of achieving a spontaneous pregnancy. Hence, contraceptive counseling should be performed [61]. Autoimmune disease accounts for approximately 5% of cases of POI [62]. In particular, POI is associated with autoimmune adrenal and thyroid conditions. While antithyroid antibodies (anti-thyroglobulin and anti-TPO)  

..      Table 6.2  Causes of primary ovarian insufficiency [3] X chromosomal causes

Structural alterations or mutations in or absence of an X chromosome

With the stigmata of Turner syndrome (45,X or mosaic) Without the stigmata of Turner syndrome

Mutations in premature ovarian failure 1 (Xq26-q28) Mutations in premature ovarian failure1 in association with Fragile X premutation (Xq27.3) Mutations in premature ovarian failure 2A (Xq22) Mutations in premature ovarian failure 2B (Xq21) Mutations in premature ovarian failure 4 in association with mutations in bone morphogenetic protein 15 (Xp11.2

Trisomy X with or without mosaicism (continued)

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..      Table 6.2 (continued) Mutations associated with a 46,XY karyotype

Mutations in Xp22.11-p21.2 (Swyer syndrome)

Autosomal causes

Mutations involving enzymes important for reproduction

Galactosemia (galactose-1-phosphate uridyltransferase deficiency) (9p13)

Mutations involving reproductive hormones, their receptors, and action

Mutations of luteinizing hormone or follicle-stimulating hormone or both rendering them biologically inactive (theoretical)

6

Mutations in 5 cen

17α-Hydroxylase deficiency (CPY17A1) (10q24.3)

Mutations of inhibin (theoretical) Receptor mutations

Follicle-stimulating hormone receptor (2p21-p16) Luteinizing hormone/ human chorionic gonadotropin receptor (2p21)

Mutations in the hormone action pathways Other mutations

Blepharophimosis, ptosis, and epicanthus inversus, type 1 (BPES) (premature ovarian failure 3) (3q23) Premature ovarian failure 5 (newborn ovary homeobox) (7q35) Autoimmune polyendocrine syndrome, type 1(APS1) (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, APECED) (autoimmune regulator gene, AIRE) (21q22.3) Vanishing white matter leukodystrophy with ovarian failure (genes encoding the translation initiation factor E1F2B) (14q24, Chr 12, 1p34.1, 3q27, 2p23.3) Congenital disorders of glycosylation, type 1a (CDG1a) (genes encoding phosphomannomutase-2, PMM2) (16p13.3-p13.2)

Environmental insults

Chemotherapeutic (especially alkylating) agents Ionizing radiation Viral infection (documented for mumps) Surgical injury or extirpation

Immune disturbances

In association with other autoimmune diseases Isolated In association with congenital thymic aplasia

Idiopathic causes

153 Amenorrhea

A. Obtain an ultrasound to assess for are the most common autoimmune antiboda uterus. ies seen in POI patients, those that have anti-­ B. Obtain a karyotype. adrenal/anti-steroidogenic enzyme antibodies C. Recommend that she proceed to (e.g., 21-hydroxylase) are at greater risk of gonadectomy. developing autoimmune oophoritis [62, 63]. D. Perform a brain MRI. Therefore, any patients with such positive E. All of the above. antibodies should have their adrenal function assessed. Addison’s disease patients can also experience POI 8–14 years prior to the devel- ?? 2. A 28-year-old G2P1 presents to your clinic with 3 weeks of nipple discharge, opment of adrenal insufficiency [64]. Any and menses have been absent for the patient positive for anti-adrenal antibodies past 4  months (previously monthly). should have an AM serum cortisol checked Her primary care physician obtained and, if less than 18 mg/dL, should undergo an a random prolactin level which was ACTH stimulation test [65]. 96 ng/mL; beta-HCG was negative. Her A key point to note is that POI and early mother had breast cancer and her sister menopause are associated with higher all-­ is BRCA1 positive. What is the next best cause mortality in numerous studies. In parstep in management? ticular, there is a higher risk of cardiovascular A. Proceed with a breast exam. disease and osteoporosis [66, 67]. Hence, judi B. Obtain a morning, fasting prolaccious use of hormone replacement therapy is tin. essential for these patients at least up until the C. Perform a brain MRI. age of natural menopause [68].

6.4.6.1

 ther Causes of Primary O Ovarian Insufficiency

Patients with FSH abnormalities and defects in steroidogenesis, such as 17-hydroxylase deficiency, can also lead to POI [69]. Patients with these conditions typically exhibit an elevated FSH level. In addition, metabolic disorders, such as galactosemia resulting from a deficiency of galactose-1-phosphate uridyl transferase, can lead to POI.  Fortunately, galactosemia is typically diagnosed shortly after birth due to intolerance of milk and signs of galactose excess [70].

6.5

Review Questions

?? 1. A 15-year-old G0 is seen for primary amenorrhea. Her exam is notable for Tanner stage 5 breast development, an absence of pubic hair, and truncal obesity. She has been sexually active for the past year, but intercourse remains painful. She also complains of persistent headaches over the past 6 months. What is your next step in management?

D. Perform a mammogram. ?? 3. Your new patient is a 19-year-old G2P0 who present with missed menses for the past 3  months. This patient is also experiencing increasing vaginal dryness. She also has a maternal male cousin with developmental delay. Her history is notable for two surgical pregnancy terminations. All pregnancy tests have been negative. The remainder of her history is unremarkable. Which test is the most helpful in determining the diagnosis? A. Saline-infusion sonography B. TSH C. FSH D. Karyotype E. All of the above ?? 4. In the course of evaluating an 18-year-old for primary amenorrhea, you note that her karyotype is 45 XO consistent with Turner’s syndrome. Her cardiac evaluation is unremarkable, and you counsel her on her reproductive outlook. Her AMH is 0.04 ng/mL. What is the best characterization of her ability to conceive?

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A. While unlikely, she still has a 6% chance of conceiving. B. It will be impossible for her to conceive. C. She will need in  vitro fertilization to achieve conception.

6.6

Answers

vv 1. A

6

vv 2. A vv 3. C vv 4. A

References 1.

Fritz M, Speroff L.  In: Taylor HS, Seli E, Pal L, editors. Clinical gynecologic endocrinology and infertility. Philadelphia: Wolters Kluwer Health/ Lippincott Williams & Wilkins; 2020. 2. Marsh CA, Grimstad FW.  Primary amenorrhea: diagnosis and management. Obstet Gynecol Surv. 2014;69(10):603–12. 3. Practice Committee of American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2008;90(5 Suppl): S219–25. 4. Sims J, Lutz E, Wallace K, Kassahun Yimer W, Ngwudike C, Shwayder J.  Depomedroxyprogesterone acetate, weight gain and amenorrhea among obese adolescent and adult women. Eur J Contracept Reprod Health Care. 2020;25(1):54–9. 5. Luciano AA.  Clinical presentation of hyperprolactinemia. J Reprod Med. 1999;44(12 Suppl): 1085–90. 6. Miller KK, Rosner W, Lee H, Hier J, Sesmilo G, Schoenfeld D, et  al. Measurement of free testosterone in normal women and women with androgen deficiency: comparison of methods. J Clin Endocrinol Metab. 2004;89(2):525–33. 7. Kamilaris TC, DeBold CR, Manolas KJ, Hoursanidis A, Panageas S, Yiannatos J. Testosterone-­secreting adrenal adenoma in a peripubertal girl. JAMA. 1987;258(18):2558–61. 8. Robbins JB, Broadwell C, Chow LC, Parry JP, Sadowski EA.  Müllerian duct anomalies: embryological development, classification, and MRI assessment. J Magn Reson Imaging. 2015;41(1): 1–12.

9. Chandler TM, Machan LS, Cooperberg PL, Harris AC, Chang SD.  Mullerian duct anomalies: from diagnosis to intervention. Br J Radiol. 2009;82(984):1034–42. 10. Timmreck LS, Reindollar RH.  Contemporary issues in primary amenorrhea. Obstet Gynecol Clin N Am. 2003;30(2):287–302. 11. Allybocus ZA, Wang C, Shi H, Wu Q. Endocrinopathies and cardiopathies in patients with Turner syndrome. Climacteric. 2018;21(6): 536–41. 12. McDonough PG, Byrd JR.  Gonadal dysgenesis. Clin Obstet Gynecol. 1977;20(3):565–79. 13. Committee on Adolescent Health Care. ACOG Committee Opinion No. 728: Müllerian agenesis: diagnosis, management, and treatment. Obstet Gynecol. 2018;131(1):e35–42. 14. Simpson JL.  Genetics of the female reproductive ducts. Am J Med Genet. 1999;89(4):224–39. 15. Bjørsum-Meyer T, Herlin M, Qvist N, Petersen MB. Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-­ Rokitansky-­ Küster-Hauser syndrome in co-­ occurrence: two case reports and a review of the literature. J Med Case Rep. 2016;10(1):374. 16. Stamou MI, Georgopoulos NA.  Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism. Metabolism. 2018;86:124–34. 17. Beneduzzi D, Trarbach EB, Min L, Jorge AA, Garmes HM, Renk AC, et  al. Role of gonadotropin-­ releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. Fertil Steril. 2014;102(3):838–46.e2. 18. Fourman LT, Fazeli PK.  Neuroendocrine causes of amenorrhea--an update. J Clin Endocrinol Metab. 2015;100(3):812–24. 19. Desai SS, Roy BS, Mahale SD.  Mutations and polymorphisms in FSH receptor: functional implications in human reproduction. Reproduction. 2013;146(6):R235–48. 20. Gromoll J, Simoni M, Nordhoff V, Behre HM, De Geyter C, Nieschlag E. Functional and clinical consequences of mutations in the FSH receptor. Mol Cell Endocrinol. 1996;125(1–2):177–82. 21. Toledo SP, Brunner HG, Kraaij R, Post M, Dahia PL, Hayashida CY, et  al. An inactivating mutation of the luteinizing hormone receptor causes amenorrhea in a 46,XX female. J Clin Endocrinol Metab. 1996;81(11):3850–4. 22. Harrington J, Palmert MR.  Clinical review: distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available ­ diagnostic tests. J Clin Endocrinol Metab. 2012; 97(9):3056–67. 23. Jagiello J.  Prevalence of testicular feminization. Lancet. 1962;1:329.

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24. Hughes IA, Werner R, Bunch T, Hiort O. Androgen insensitivity syndrome. Semin Reprod Med. 2012;30(5):432–42. 25. Deans R, Creighton SM, Liao LM, Conway GS. Timing of gonadectomy in adult women with complete androgen insensitivity syndrome (CAIS): patient preferences and clinical evidence. Clin Endocrinol. 2012;76(6):894–8. 26. Amitai E, Lior Y, Sheiner E, Saphier O, Leron E, Silberstein T.  The impact of hymenectomy on future gynecological and obstetrical outcomes. J Matern Fetal Neonatal Med. 2020;33(8):1400–4. 27. Williams CE, Nakhal RS, Hall-Craggs MA, Wood D, Cutner A, Pattison SH, et al. Transverse vaginal septae: management and long-term outcomes. BJOG. 2014;121(13):1653–8. 28. Meczekalski B, Katulski K, Czyzyk A, Podfigurna-­ Stopa A, Maciejewska-Jeske M.  Functional hypothalamic amenorrhea and its influence on women’s health. J Endocrinol Investig. 2014;37(11): 1049–56. 29. Golden NH, Carlson JL. The pathophysiology of amenorrhea in the adolescent. Ann N Y Acad Sci. 2008;1135:163–78. 30. Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et  al. Functional hypothalamic amenorrhea: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(5):1413–39. 31. Berga SL.  Behaviorally induced reproductive compromise in women and men. Semin Reprod Endocrinol. 1997;15(1):47–53. 32. Hergenroeder AC, Smith EO, Shypailo R, Jones LA, Klish WJ, Ellis K.  Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months. Am J Obstet Gynecol. 1997;176(5):1017–25. 33. Jacobs HS, Knuth UA, Hull MG, Franks S. Post“pill” amenorrhoea--cause or coincidence? Br Med J. 1977;2(6092):940–2. 34. Steele SJ, Mason B, Brett A.  Amenorrhoea after discontinuing combined oestrogen-progestogen oral contraceptives. Br Med J. 1973;4(5888):343–5. 35. Schwallie PC, Assenzo JR.  The effect of depo-­ medroxyprogesterone acetate on pituitary and ovarian function, and the return of fertility following its discontinuation: a review. Contraception. 1974;10(2):181–202. 36. Fotherby K, Howard G.  Return of fertility in women discontinuing injectable contraceptives. J Obstet Gynaecol (Lahore). 1986;6 Suppl 2:S110–5. 37. Lauritsen MP, Bentzen JG, Pinborg A, Loft A, Forman JL, Thuesen LL, et al. The prevalence of polycystic ovary syndrome in a normal population according to the Rotterdam criteria versus revised criteria including anti-Mullerian hormone. Hum Reprod. 2014;29(4):791–801. 38. Rebar R, Judd HL, Yen SS, Rakoff J, Vandenberg G, Naftolin F. Characterization of the inappropri-

ate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest. 1976;57(5):1320–9. 39. Lobo RA, Carmina E.  The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med. 2000;132(12):989–93. 40. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et  al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-­ Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97(1):28–38.e25. 41. Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et  al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565–92. 42. Franik S, Eltrop SM, Kremer JA, Kiesel L, Farquhar C.  Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2018;5(5):Cd010287. 43. Practice Committee of the American Society for Reproductive Medicine. Electronic address: [email protected]; Practice Committee of the American Society for Reproductive Medicine. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril. 2017;108(3):426–41. 44. Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS.  A metaanalysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update. 2006;12(6):673–83. 45. Barnett R.  Cushing’s syndrome. Lancet. 2016; 388(10045):649. 46. El-Maouche D, Arlt W, Merke DP.  Congenital adrenal hyperplasia. Lancet. 2017;390(10108): 2194–210. 47. Schlechte J, Dolan K, Sherman B, Chapler F, Luciano A.  The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab. 1989;68(2):412–8. 48. Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med. 1977;296(11):589–600. 49. Schlechte J, Sherman B, Halmi N, VanGilder J, Chapler F, Dolan K, et al. Prolactin-secreting pituitary tumors in amenorrheic women: a comprehensive study. Endocr Rev. 1980;1(3):295–308. 50. Chen L, White WL, Spetzler RF, Xu B. A prospective study of nonfunctioning pituitary adenomas: presentation, management, and clinical outcome. J Neuro-Oncol. 2011;102(1):129–38. 51. Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, et  al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273–88. 52. Sheehan HL, Murdoch R. Postparum necrosis of the interior pituitary: pathological and clinical aspects. J Obstet Gynaecol Br Emp. 1938;45:456.

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53. Kilicli F, Dokmetas HS, Acibucu F. Sheehan’s syndrome. Gynecol Endocrinol. 2013;29(4):292–5. 54. Briet C, Salenave S, Bonneville JF, Laws ER, Chanson P.  Pituitary apoplexy. Endocr Rev. 2015;36(6):622–45. 55. Barkhoudarian G, Kelly DF.  Pituitary apoplexy. Neurosurg Clin N Am. 2019;30(4):457–63. 56. VanKoevering KK, Sabetsarvestani K, Sullivan SE, Barkan A, Mierzwa M, McKean EL. Pituitary dysfunction after radiation for anterior skull base malignancies: incidence and screening. J Neurol Surg B Skull Base. 2020;81(1):75–81. 57. March CM.  Management of Asherman’s syn drome. Reprod Biomed Online. 2011;23(1):63–76. 58. Yang X, Liu Y, Li TC, Xia E, Xiao Y, Zhou F, et al. Durations of intrauterine balloon therapy and adhesion reformation after hysteroscopic adhesiolysis: a randomized controlled trial. Reprod Biomed Online. 2020;40(4):539–46. 59. Nelson LM.  Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606–14. 60. De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet. 2010;376(9744):911–21. 61. Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014;124(1):193–7. 62. Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr Rev. 1997;18(1):107–34. 63. Bakalov VK, Vanderhoof VH, Bondy CA, Nelson LM.  Adrenal antibodies detect asymptomatic

auto-immune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Reprod. 2002;17(8):2096–100. 64. Turkington RW, Lebovitz HE.  Extra-adrenal endocrine deficiencies in Addison’s disease. Am J Med. 1967;43(4):499–507. 65. Kim TJ, Anasti JN, Flack MR, Kimzey LM, Defensor RA, Nelson LM.  Routine endocrine screening for patients with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol. 1997;89(5 Pt 1):777–9. 66. Gong D, Sun J, Zhou Y, Zou C, Fan Y. Early age at natural menopause and risk of cardiovascular and all-cause mortality: a meta-analysis of prospective observational studies. Int J Cardiol. 2016;203: 115–9. 67. Faubion SS, Kuhle CL, Shuster LT, Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric. 2015;18(4):483–91. 68. Committee opinion no. 698 summary: hormone therapy in primary ovarian insufficiency. Obstet Gynecol. 2017;129(5):963–4. 69. Kovanci E, Schutt AK.  Premature ovarian failure: clinical presentation and treatment. Obstet Gynecol Clin N Am. 2015;42(1):153–61. 70. Spencer JB, Badik JR, Ryan EL, Gleason TJ, Broadaway KA, Epstein MP, et  al. Modifiers of ovarian function in girls and women with classic galactosemia. J Clin Endocrinol Metab. 2013;98(7):E1257–65.

157

Polycystic Ovary Syndrome Tommaso Falcone and William W. Hurd Contents 7.1

Introduction – 159

7.2

Epidemiology – 159

7.3

Diagnosis of PCOS – 159

7.3.1 7.3.2

 iagnostic Criteria – 159 D Exclude Other Etiologies – 160

7.4

Pathophysiology – 161

7.5

Conditions Associated with PCOS – 161

7.5.1 7.5.2 7.5.3 7.5.4 7.5.5 7.5.6

I nsulin Resistance – 162 Diabetes Mellitus – 162 Obesity – 162 Metabolic Syndrome – 162 Infertility – 162 Endometrial Cancer – 163

7.6

Initial Evaluation – 163

7.6.1 7.6.2 7.6.3

 istory – 163 H Physical Examination – 164 Pelvic Ultrasound – 164

7.7

Laboratory Evaluation – 164

7.7.1 7.7.2 7.7.3

 ndrogens – 164 A Detecting Other Underlying Diseases – 165 Less Useful Laboratory Tests – 165

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 T. Falcone, W. W. Hurd (eds.), Clinical Reproductive Medicine and Surgery, https://doi.org/10.1007/978-3-030-99596-6_7

7

7.8

Management – 166

7.8.1 7.8.2

 eriodic Testing – 166 P Treatment – 166

7.9

Review Questions – 168

7.10

Answers – 168 References – 168

159 Polycystic Ovary Syndrome

Key Points 55 Several different phenotypes of polycystic ovary syndrome (PCOS) exist based on the presence or absence of androgen excess, ovulatory dysfunction, and polycystic ovarian morphology. 55 Exclusion of other hyperandrogenic disorders is necessary before diagnosing PCOS. 55 Women with PCOS should be assessed for commonly associated mood, body image, and eating disorders. 55 As many as 30% of women with PCOS will not be overweight or obese. 55 Lifestyle changes, such as diet and exercise, should be included in the management plans of obese women with PCOS. 55 Metabolic abnormalities associated with PCOS should be actively managed to decrease the risk of cardiovascular disease. 55 Combined estrogen-progestin contraceptives are the most useful and frequently used pharmacologic intervention for women with PCOS not currently pursuing fertility.

7.1

Introduction

Polycystic ovary syndrome (PCOS) is one of the most common hormonal conditions diagnosed in reproductive-aged women with some combination of androgen excess, ovulatory dysfunction, and/or ovaries with polycystic morphology, in the absence of other causal disease processes. The underlying etiologies of this complex gynecologic-endocrine disorder vary among individuals, and manifest as at least four heterogeneous phenotypes that include metabolic and reproductive components. Women with PCOS are at increased risk for a number of morbidities, including infertility, obesity, type 2 diabetes mellitus, endometrial cancer, and metabolic disorders that increase the risk of cardiovascular disease. In this chapter, we will briefly present PCOS epidemiology and pathophysiology followed by a cogent approach to diagnosis, treatment, and long-term follow-up.

Case Vignette

A 24-year-old woman consults for irregular periods. She has noticed slow increase in facial hair since puberty and mild acne. She used electrolysis to remove unwanted facial hair. She has never used the oral contraceptive agent. On physical examination, her body mass index (BMI) is 35  kg/m2, her Ferriman-Gallwey score is 6, and she has no signs of virilization. Initial laboratory evaluation reveals a normal serum prolactin and TSH, and mildly elevated total testosterone. You order a test to exclude an adrenal cause of her condition.

7.2

Epidemiology

PCOS is the single most common endocrine disorders among reproductive-aged women throughout the world, with an estimated prevalence ranging from 6% to 15% [1]. Prevalence estimates vary as a result of the diagnostic criteria used and ethnicity of the population, as well as the study design used. The worldwide incidence of PCOS has somewhat increased over the last decades. However, this increase appears to be much less than the increased incidence of obesity. This supports the concept that, although obesity and related insulin resistance play a causal role in many women with PCOS, obesity results in PCOS only in women that are metabolically predisposed to this condition. 7.3

Diagnosis of PCOS

7.3.1

Diagnostic Criteria

PCOS is defined by three conditions, clinical or hormonal evidence of androgen excess, ovulatory dysfunction, and polycystic morphology on ultrasound, after other underlying conditions have been excluded. These three conditions form the basis of commonly used diagnostic criteria: (a) US National Institutes of Health (NIH) criteria, (b) Androgen Excess-Polycystic Ovary Syndrome (AE-­PCOS) Society Criteria, and (c) Rotter-

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dam criteria developed by a consensus panel of the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) (. Table 7.1). The broadest and per-

haps most commonly used of these is the Rotterdam criteria, which requires the presence of any two of these three conditions.

 

7.3.2

Any of the three conditions used to diagnose PCOS can be the result of other underlying conditions (. Table  7.2). Androgen excess can be the result of congenital adrenal enzyme deficiency (nonclassical congenital adrenal hyperplasia) or neoplasm originating in the ovary or adrenal gland. Ovulatory dysfunction can result from a number of diseases specific to the hypothalamic-pituitary-ovarian axis (e.g., hyperprolactinemia) or systemic disease such as hypothyroidism or Cushing syndrome. Polycystic ovary morphology (i.e., >12 antral follicles visualized by ultrasound) is a normal finding in women under 25  years of age, and common in women with hypothalamic amenorrhea. A diagnosis of PCOS should be made with caution in adolescents, since most will have polycystic ovary morphology on ultrasound, and many will have puberty-related anovulatory cycles and signs of androgen excess (acne) which resolve with maturation. Screening tests for these conditions are discussed below.

..      Table 7.1  Most commonly used PCOS diagnostic criteria Criteria

Necessary conditions for diagnosis

NIH

Must include hyperandrogenism

 

and

7

Oligo- or anovulation AE-PCOS Society

Must include hyperandrogenism and either Oligo-ovulation/anovulation or Polycystic ovary morphology

Rotterdam

Exclude Other Etiologies

Must include two of the following: Hyperandrogenism Oligo-ovulation/anovulation Polycystic ovary morphology

..      Table 7.2  Common conditions that can mimic PCOS Associated conditions Androgen excess Ovulatory dysfunction Nonclassical CAH

X

X

Ovarian tumors

X

X

Adrenal tumors

X

X

Polycystic ovary morphology

Hypothyroidism

X

Hyperprolactinemia

X

Hypothalamic amenorrhea

X

X

X

X

Adolescence

X

Women 35 kg/ m2. Oral agents are the primary fertility treatment for anovulatory women with PCOS, with the primary risk of multiple gestations occurring in >5% if pregnancies [11]. Clomiphene citrate is the only FDA-approved oral medication for ovulation induction and is reasonably effective for women with PCOS.  The aromatase inhibitor letrozole has been shown in several studies to have improved pregnancy and live birth rates compared to clomiphene citrate [11]. However, letrozole has yet to be FDA approved for ovulation induction. Injectable human gonadotropins have been used for ovulation induction for women with PCOS resistant to oral agents. However, the risk of multiple gestations is increased compared to oral agents, even when used with the utmost of care [12]. In vitro fertilization can lower the risk of multiple gestations by appropriately limiting the number of embryos transferred. Although significantly more expensive per cycle, the ability to freeze embryos for subsequent pregnancies make this a suitable option for some women with PCOS who do not conceive with oral ovulation induction agents. 7.5.6

Endometrial Cancer

It is well established that women with PCOS have an increased risk of developing endometrial hyperplasia and an approximately threefold increased risk of endometrial cancer [13]. The most obvious link between PCOS and endometrial cancer is anovulation resulting in prolonged endometrial exposure to unopposed estrogen. However, hyperandrogenism and prolonged elevated LH levels have also been proposed to play a role. Prevention of endometrial hyperplasia and cancer consists of progestin therapy as discussed below when not trying to conceive. Early detection consists of surveillance with transvaginal ultrasound and the liberal use of endometrial biopsy for women with thickened endometrium and/or abnormal uterine

bleeding, particularly after prolonged period of amenorrhea in the absence of progestin therapy. 7.6

Initial Evaluation

The investigation of women who present with symptoms and signs of PCOS serves three important goals: confirmation the diagnosis of PCOS, exclusion other underlying diagnoses (. Table 7.2), and assessment for associated disorders (7 Box 7.1). The evaluation consists of history and physical examination, transvaginal ultrasonography, and laboratory evaluation. A tentative PCOS diagnosis can often be made on the basis of history and physical examination in women with irregular menses and hirsutism [7].  

 

7.6.1

History

A thorough history should include a careful family and past medical histories. PCOS is often a familial problem, and many women with PCOS will have multiple first or second relatives with similar problems. It is important to characterize the presence and onset of menstrual abnormality and any clinical signs of androgen excess. Menstrual irregularity can begin in women with PCOS immediately after menarche during adolescence or later in life concurrent with weight gain. However, the use of oral contraceptives can obscure menstrual irregularity. Additionally, some women with PCOS will report regular uterine bleeding despite chronic anovulation. These women will be unable to detect a mid-cycle luteal surge, and mid-luteal serum progesterone will be low. The most common clinical manifestation of androgen excess is hirsutism, with gradual increasing midline body hair on the face and/or lower abdomen. Acne can also be a symptom of androgen excess, although the high incidence of acne during puberty makes this symptom less helpful before the age of 20. Rapid progression of hirsutism or signs of virilization (e.g., male-pattern hair loss, clitoromegaly, deepening of the voice) are

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uncommon for women with PCOS, increasing the concern for an androgen-secreting tumor.

7.6.2

7

Physical Examination

Two important aspects of the physical exam are detecting clinical signs of androgen excess and signs of other underlying illness or of comorbidities. Body mass index (BMI), blood pressure, and abdominal girth should be assessed at every visit. Signs of androgen excess should be documented, including hirsutism, acne, clitoromegaly, male-pattern hair loss, and voice deepening. Acanthosis nigricans (i.e., darkened velvety skin of the neck or inner thigh) can result from hyperinsulinemia, but is a relatively nonspecific finding that can be associated with excess corticosteroids, pineal tumors, and a number of other endocrine disorders [14]. Hirsutism can be quantified using the Ferriman-­Gallwey score. A score >4–6 is considered suggestive of hyperandrogenism. However, the diagnosis of hirsutism can be made difficult by the use of hair removal methods, and ethnicity. Hair follicle concentration varies greatly according to ethnicity. Consequently, hirsutism is less common in women of East/Southeast Asian, Native American, or Ashkenazi Jewish descent, whereas it is more common in Hispanic women and those with ethnic origins in the Middle Eastern, South Asian, or African [15].

7.6.3

Pelvic Ultrasound

Typical polycystic ovary morphology on ultrasound is present in the majority of women with PCOS [7]. The Rotterdam criteria definition for polycystic ovary morphology is an antral follicle count (AFC) ≥12 and/or an ovarian volume >10  cm3. However, modern high-resolution ultrasound transducers will visualize AFC >12  in a large percentage of reproductive-aged women. As a result, newer PCOS diagnostic criteria use an AFC >20 follicles in at least one ovary and/or an ovarian volume of >10 cm3 [7] (. Fig. 7.1).  

..      Fig. 7.1  This is the classical image of PCOS with an enlarged ovary containing an increased number of small follicles around the periphery of the cortex, resembling a string of pearls, along with a bright echogenic stroma

Antral follicle count (AFC) is relatively subjective, and an increased number of antral follicles are normal in young women. For this reason, the diagnosis of PCOS should not be made based on an isolated ultrasound finding of polycystic ovary morphology in the absence of other diagnostic criteria. This is particularly important for adolescents and women within 8  years of menarche, since most of them will have polycystic ovary morphology using these definitions [16].

7.7

Laboratory Evaluation

Laboratory evaluation can confirm the diagnosis of PCOS in women without clinical signs of androgen excess and is essential for excluding other underlying diagnoses (. Table 7.2) or associated disorders (7 Box 7.1). Androgen assessment is important both for anovulatory women with no clear demonstration of clinical hyperandrogenism and for those with symptoms suggestive of an androgen-­ secreting tumor.  

 

7.7.1

Androgens

Androgens routinely measured include testosterone (both free and total), dehydroepiandrosterone sulfate (DHEAS), and 17-hydroxyprogesterone. For women with-

165 Polycystic Ovary Syndrome

out clinical signs of hyperandrogenism, mild elevation of free or total testosterone or DHEAS fulfills one of the three diagnostic criteria for PCOS.  However, marked elevation of testosterone (e.g., >150  ng/dL) is often the result of an ovarian or adrenal tumor, and marked DHEAS elevation (e.g., >800 mcg/dL) warrants further evaluation of an adrenal tumor. Several commonly used medications can suppress ovarian androgen secretion, including hormonal contraception (both oral and parenteral), spironolactone, and metformin. This makes the diagnosis of PCOS using serum androgen levels less useful in women taking any of these medications. However, there is little clinical advantage to discontinuing these medications for 3  months before repeat androgen testing in women who already meet the diagnostic criteria for PCOS. Early morning follicular phase17-hydroxyprogesterone can be elevated in women with nonclassical congenital adrenal hyperplasia (NCCAH), most commonly resulting from a 21-hydroxylase deficiency. However, some women with milder forms of NCCAH will have normal basal 17-­ hydroxyprogesterone that becomes abnormally elevated only after stimulation with an ACTH analog. Thus, an ACTH stimulation test is indicated if there is a high index of ­suspicion for this familial condition. DHEAS is not elevated in women with NCCAH [17]. 7.7.2

 etecting Other Underlying D Diseases

Amenorrhea and oligomenorrhea have a number of causes other than PCOS (. Table 7.2). Pregnancy is certainly the most important, and HCG should be measured, even in women with years of menstrual abnormalities. Other subtle causes include hypothyroidism and hyperprolactinemia, and thus serum TSH and prolactin are important screening tests in these women. In women who appear to be hypoestrogenic, measuring FSH and estradiol can help detect women with ovulation dysfunction on the basis of ovarian insufficiency or hypogonadal hypogonadism.  

Cushing syndrome is a relatively uncommon condition that can be confused with PCOS.  However, this syndrome should be considered in women with physical findings suggestive of increased cortisol, such as central obesity, purple abdominal striae, hypertension, and proximal muscle weakness. DHEAS levels can be normal or elevated in the presence of an ACTH-secreting pituitary tumor (Cushing disease) and normal or low in women with a steroid-secreting adrenal tumor. The most sensitive screening test for Cushing syndrome is a 24-hour urine cortisol measurement, since cortisol is normally highest during the day and low at night. 7.7.3

Less Useful Laboratory Tests

Anti-Mullerian hormone (AMH) strongly correlates with AFC and is usually elevated in women with PCOS.  As a result, elevated AMH has been suggested as a new criterion to diagnose PCOS.  Although AMH has not become a part of any of the standard PCOS diagnostic criteria, it remains a useful part of a fertility evaluation, particularly for those considering IVF.  Markedly elevated AMH (range 4.9–8.4  ng/mL) is supportive of the diagnosis of PCOS.  However, assay variability and lack of consensus on the threshold for diagnosis have resulted in AMH being used as supportive of the diagnosis rather than replacing ultrasound. COC suppresses AMH and makes the determination equivocal. As with the limited utility of ultrasound in adolescent patients suspected of having PCOS, AMH also shows a similar weak association with PCOS in this age group. Therefore, the diagnosis of PCOS in adolescent age group should rely solely on the presence of a menstrual disorder and hyperandrogenism. It has been long appreciated that the ratio of LH to FSH and the estrone level are often elevated in women with PCOS. However, like AMH, this ratio and the estrone level are not part of any of the standard PCOS diagnostic criteria. Since the results of these lab values rarely if ever help in the diagnosis or management, measuring them is not helpful in the diagnosis of PCOS.

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Management

Long-term management of women with PCOS consists of regular surveillance of comorbidities associated with this syndrome and active treatment of associated abnormalities and diseases. 7.8.1

7

Periodic Testing

Women with PCOS should be seen annually to detect and/or monitor associated comorbidities. Physical examination should focus on blood pressure and weight. A transvaginal ultrasound is indicated in women with abnormal uterine bleeding, particularly if they are not being treated with long-term hormonal suppression with progestins or COC. Annual laboratory evaluation for obese women with PCOS should include a fasting lipid profile and, for those not already determined to be prediabetic or diabetic, a glucose intolerance screening test. It has been appreciated for years that a fasting blood glucose is not an adequate screening test for women with PCOS, and for this reason, a 2-hour oral glucose tolerance test (2hOGTT) has been recommended as both a screening and diagnostic test in these women. More recently, a HbA1C has been recognized as a less expensive and accurate screening test for glucose intolerance in the general population. Small studies have demonstrated that Hb1C and the 2hGTT provide similar results in the PCOS population [6]. However, in high-risk patients with PCOS, the 75  g OGTT is still recommended [7]. Patients with sleep apnea should be referred to specialized sleep medicine centers. There are no special tests or imaging recommended for screening patients for endometrial cancer. Anovulation and chronic estrogen exposure without progesterone are associated with increased risk of endometrial cancer. Furthermore obesity and increased insulin levels are independent risk factors for endometrial cancer. The strategy should be to prevent chronic estrogen exposure by exposing the endometrium to progesterone including the use of progestin intrauterine devices.

All women should be assessed for mood disorders such as anxiety and depression with simple questionnaires. The approach to contraception in women with PCOS should be the same as other women, considering their risk factors and prevention of chronic exposure to unopposed estrogen. For this reason the estrogen-progestin contraceptives are ideal as they can also help with management of the hyperandrogenic problems. Management of infertility secondary to anovulation associated with PCOS is covered in a separate chapter. However, the general principles are that weight loss is important and that letrozole is the agent of choice for ovulation induction. 7.8.2

Treatment

For women with PCOS not currently desiring pregnancy, management focuses on preventing, detecting, and adequately treating comorbidities to optimize quality of life and minimize long-term morbidity and mortality. Anovulation can be managed with cyclic combined oral contraceptives, progestin-only contraceptives (e.g., oral, progestin-releasing IUD, progestin depot, or implant) or cyclic progestin with an alternate contraception plan. Long-term treatment of women with PCOS with oral contraceptives has been shown to decrease the risk of endometrial cancer by at least 50% [13]. Although less well studied, it is likely that other forms of chronic progestin therapy are also effective. Such therapy should be continued until pregnancy is desired or until the natural age of menopause to decrease the risk of abnormal uterine bleeding and endometrial cancer. Type 2 DM and prediabetes can be managed with an oral insulin sensitizer (e.g., metformin), diet, increased exercise, and weight loss when appropriate. Some patients will become insulin-dependent. Hypertension and lipid disorders should be managed using standard algorithms. Hirsutism can be managed cosmetically and medically with oral contraceptives to increase SHBG production and, if necessary, spironolactone to block androgen receptors. Women with refractory hirsutism can be

7

167 Polycystic Ovary Syndrome

referred to a dermatologist who specializes in treating hirsutism. The management of hyperandrogenic phenotypes such as acne, hirsutism, and hair loss requires long-term intervention [7, 18]. The initial medical intervention is with an oral combined estrogen-progesterone contraceptive agent (COC). A low-dose estrogen (20  mcg) progestin formulation containing a low androgen profile progestin such as norethindrone is recommended. If suppression is not achieved with a low-dose COC, a higher dose (30–35 mcg) formulation can be offered. Formulations with progestins with lower androgen profile such as cyproterone acetate, and drospirenone, are acceptable in women with very low risk for venous thromboembo-

lism (VTE) but are not be considered first line. Anti-androgens can be added after 6 months if no acceptable response is seen. The most commonly used anti-androgen is spironolactone. The starting dose is typically 50–100 mg twice daily. Other anti-androgens can be ­considered in women with severe androgenic manifestations. These drugs should never be used without appropriate counseling and contraception. Mechanical methods such as electrolysis and laser treatment are effective. The use of topical cream with eflornithine hydrochloride (13.9%) can help, but recurrence is high after discontinuing the treatment. Insulin sensitizers such as metformin are not effective. 7 Box 7.2 lists some general concepts of management of patients with PCOS.  

Box 7.2  International Evidence-Based Guideline for the Assessment of Polycystic Ovary Syndrome [7] 55 Evidence-based recommendation–– Serum total and free testosterone is used for biochemical confirmation of hyperandrogenism –– Serum AMH is not part of the diagnostic criteria for PCOS –– Combined oral contraceptives is recommended for management of irregular menstrual cycles and hyperandrogenism 55 Clinical consensus recommendation –– Documentation of anovulation –– Documentation of hyperandrogenism

The cornerstone of treatment for overweight and obese women with PCOS is weight management via diet and exercise. The goal is to decrease the long-term health risks associated with PCOS, including type 2 DM, cardiovascular risk, and endometrial cancer, and to optimize the chances of pregnancy for those desiring children. Obesity is a challenge to manage and involves a multidisciplinary approach with dieticians and other specialists. Standard medical therapy with calorie restriction and exercise

–– Pelvic ultrasound should not be used for diagnosis of PCOS in adolescents –– Endovaginal ultrasound diagnosis of PCOS is made with a cut-off follicle number between 2 and 9 mm per ovary of >20 and/or an ovarian volume of > of 10 mL –– Screening for lipid disorders in overweight and obese women –– Screen for glucose intolerance –– Lifestyle modifications with diet and exercise should be part of all management strategies

is effective but compliance is low [19]. Bariatric surgery should be considered in obese women with other serious comorbidities such as type 2 DM, hypertension, sleep apnea, nonalcoholic fatty liver disease, and heart disease. Women with PCOS seeking fertility can usually be managed with an oral agent for ovulation induction (OI), with the addition of metformin for those with IR (see 7 Chap. 16). Those who do not conceive with oral OI agents can be treated with either injectable gonadotropins for OI or in vitro fertilization  

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(IVF), the latter of which has the advantage of a lower risk of multiple gestations. Risks of adverse maternal-fetal complications such as gestational diabetes should be discussed. In addition to the maternal complications associated with obesity and other metabolic problems such as gestational diabetes, there are data that show that the children of women with PCOS are at increased risk of offspring obesity from early age and diabetes in female offspring from late adolescence [20].

7.9

7

Review Questions

?? 1.  A 24-year-old woman consults for irregular periods. She has noticed slow increase in facial hair since puberty and mild acne. She used electrolysis to remove unwanted facial hair. She has never used the oral contraceptive agent. On examination her body mass index (BMI) is 35 kg/m2. Her Ferriman-­ Gallwey score is 6. There are no signs of virilization. Initial investigation included normal serum prolactin and TSH, and mildly elevated total testosterone. Which test will rule out a congenital adrenal cause for this disorder? A. Cortisol B. DHEAS C. DHEA D. Androstenedione E. 17-hydroxprogesterone ?? 2. A 30-year-old woman presents with rapidly increasing facial and body hair and irregular periods over the last 6 months. On examination she has male-pattern baldness and enlarged clitoris. A pelvic ultrasound revealed a solid mass of approximately 4  cm on the left ovary. Adrenal CT scan was normal. Which hormone is most likely to be elevated in a serum sample? A. Testosterone B. DHEAS C. 17(OH) progesterone D. DHEA E. Estradiol

?? 3. A 30-year-old woman presents with rapidly increasing facial and body hair and irregular periods over the last 6 months. On examination she has male-pattern baldness and enlarged clitoris. A pelvic ultrasound is normal. Which blood test would be most accurate to identify the cause? A. DHEAS B. Cortisol C. Free- Testosterone D. Aldosterone

7.10

Answers

vv 1. E vv 2. A vv 3. A

References 1.

Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO.  The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2016;31(12):2841–55. https://doi.org/10.1093/humrep/dew218. Epub 2016 Sep 22. PMID: 27664216. 2. Legro RS.  Obesity and PCOS: implications for diagnosis and treatment. Semin Reprod Med. 2012;30(6):496–506. https://doi.org/10.1055/s-­0032-­1328878. Epub 2012 Oct 16. PMID: 23074008; PMCID: PMC3649566. 3. Chen YH, Heneidi S, Lee JM, Layman LC, Stepp DW, Gamboa GM, Chen BS, Chazenbalk G, Azziz R. miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes. 2013;62(7):2278–86. 4. Taylor AE, McCourt B, Martin KA, Anderson EJ, Adams JM, Schoenfeld D, Hall JE. Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1997;82(7):2248. 5. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins— Gynecology. ACOG practice bulletin no. 194: polycystic ovary syndrome. Obstet Gynecol. 2018;131(6):e157–71. https://doi.org/10.1097/ AOG.0000000000002656. 6. Hurd WW, Abdel-Rahman MY, Ismail SA, Abdellah MA, Schmotzer CL, Sood A. Comparison

169 Polycystic Ovary Syndrome

7.

8.

9.

10.

11.

12.

of diabetes mellitus and insulin resistance screening methods for women with polycystic ovary syndrome. Fertil Steril. 2011;96(4):1043–7. https://doi. org/10.1016/j.fertnstert.2011.07.002. Epub 2011 Aug 3. PMID: 21813121. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ, International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364. Azziz R.  Polycystic ovary syndrome. Obstet Gynecol. 2018;132(2):321–36. https://doi.org/10. 1097/AOG.0000000000002698. Behboudi-Gandevani S, Amiri M, Bidhendi Yarandi R, Noroozzadeh M, Farahmand M, Rostami Dovom M, Ramezani Tehrani F.  The risk of metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Clin Endocrinol. 2018;88(2):169–84. https://doi. org/10.1111/cen.13477. Epub 2017 Oct 16. PMID: 28930378. Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, Stener-Victorin E, Fauser BC, Norman RJ, Teede H.  The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update. 2016;22(6):687–708. https://doi.org/10.1093/humupd/dmw025. Epub 2016 Aug 10. Franik S, Eltrop SM, Kremer JA, Kiesel L, Farquhar C.  Aromatase inhibitors (letrozole). Cochrane Database Syst Rev. 2018;5(5):CD010287. Published 2018 May 24. https://doi.org/10.1002/14651858. CD010287.pub3. Costello MF, Misso ML, Balen A, Boyle J, Devoto L, Garad RM, Hart R, Johnson L, Jordan C, Legro RS, Norman RJ, Mocanu E, Qiao J, Rodgers RJ, Rombauts L, Tassone EC, Thangaratinam S, Vanky E, Teede HJ; International PCOS Network. Evidence summaries and recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome: assessment and treatment of infertility.

Hum Reprod Open. 2019;2019(1):hoy021. https:// doi.org/10.1093/hropen/hoy021. PMID: 31486807; PMCID: PMC6396642. 13. Dumesic DA, Lobo RA.  Cancer risk and PCOS.  Steroids. 2013;78(8):782–5. https://doi. org/10.1016/j.steroids.2013.04.004. Epub 2013 Apr 24. PMID: 23624028. 14. Phiske MM.  An approach to acanthosis nigri cans. Indian Dermatol Online J. 2014;5(3):239–49. https://doi.org/10.4103/2229-­5178.137765. 15. Afifi L, Saeed L, Pasch LA, et  al. Association of ethnicity, Fitzpatrick skin type, and hirsutism: a retrospective cross-sectional study of women with polycystic ovarian syndrome. Int J Womens Dermatol. 2017;3(1):37–43. Published 2017 Mar 13. https://doi.org/10.1016/j.ijwd.2017.01.006. 16. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS.  Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36(5):487–525. https://doi.org/10.1210/er. 2015-­1018. 17. Papadakis G, Kandaraki EA, Tseniklidi E, Papalou O, Diamanti-Kandarakis E. Polycystic ovary syndrome and NC-CAH: distinct characteristics and common findings. A systematic review. Front Endocrinol (Lausanne). 2019;10:388. https://doi. org/10.3389/fendo.2019.00388. PMID: 31275245; PMCID: PMC6593353. 18. Martin KA, Anderson RR, Chang RJ, Ehrmann DA, Lobo RA, Murad MH, Pugeat MM, Rosenfield RL. Evaluation and treatment of hirsutism in premenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(4):1233. 19. Harrison CL, Lombard CB, Moran LJ, Teede HJ.  Exercise therapy in polycystic ovary syndrome: a systematic review. Hum Reprod Update. 2011;17(2):171–83. 20. Chen X, Koivuaho E, Piltonen TT, Gissler M, Lavebratt C.  Association of maternal polycystic ovary syndrome or anovulatory infertility with obesity and diabetes in offspring: a population-­based cohort study. Hum Reprod. 2021;36(8):2345–57.

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Abnormal Uterine Bleeding Sonia Elguero, Bansari Patel, Anna V. Jones, and William W. Hurd Contents 8.1

Introduction – 173

8.1.1 8.1.2

 revalence – 174 P Terminology – 174

8.2

Normal Menstrual Cycle and Menstruation – 174

8.3

Diagnostic Classifications – 175

8.4

Systemic Causes of AUB – 175

8.4.1 8.4.2 8.4.3 8.4.4 8.4.5

 vulatory Dysfunction – 175 O Mechanisms of Bleeding in Anovulatory Patients – 176 Causes of Ovulatory Dysfunction – 177 Hormonal Therapy and AUB – 179 Coagulopathies – 180

8.5

Pregnancy – 180

8.5.1 8.5.2 8.5.3 8.5.4

 iable Intrauterine Pregnancy – 181 V Early Pregnancy Loss – 181 Ectopic Pregnancy – 181 Molar Pregnancy – 181

8.6

Infection – 181

8.6.1 8.6.2 8.6.3 8.6.4

 elvic Inflammatory Disease – 181 P Endometritis – 182 Cervicitis – 182 Vaginitis – 183

8.7

Neoplasms – 183

8.7.1

Benign Uterine Neoplasms – 183

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 T. Falcone, W. W. Hurd (eds.), Clinical Reproductive Medicine and Surgery, https://doi.org/10.1007/978-3-030-99596-6_8

8

8.7.2 8.7.3 8.7.4

 alignant and Premalignant Uterine Neoplasms – 184 M Ovarian Malignancies – 184 Vaginal Malignancies – 185

8.8

 linical Evaluation of Abnormal C Vaginal Bleeding – 185

8.8.1 8.8.2 8.8.3 8.8.4 8.8.5 8.8.6 8.8.7 8.8.8 8.8.9

E xclude Pregnancy – 185 Characterize Bleeding – 185 Medical History – 187 Physical Examination – 187 Laboratory Testing – 187 Papanicolaou Smear – 188 Endometrial Biopsy – 189 Imaging – 189 Hysteroscopy – 190

8.9

Acute Management of AUB – 190

8.9.1

E mergency AUB Treatment for Hemodynamically Unstable Patients – 190 Acute Outpatient Treatment of AUB – 191

8.9.2

8.10

L ong-Term Management of Ovulatory Dysfunction – 191

8.10.1 8.10.2

 vulation Induction – 192 O Hormonal Treatment of Anovulatory Bleeding – 192

8.11

Treatment of AUB in Ovulatory Patients – 193

8.11.1 8.11.2

 edical Treatment – 193 M Surgical Treatment of AUB – 194

8.12

Review Questions – 195

8.13

Answers – 196 References – 196

173 Abnormal Uterine Bleeding

Key Points 55 Abnormal vaginal bleeding is one of the most common gynecologic problems of reproductive-aged women. 55 Abnormal uterine bleeding (AUB) is an important subset of abnormal vaginal bleeding defined as bleeding that occurs in nonpregnant, reproductive-aged women originating from the uterine fundus or cervix. 55 The PALM-COEIN classification system advocated by ACOG includes many of the most common causes of AUB. 55 The SPIN (Systemic, Pregnancy, Infection, Neoplasms) classification system offers a comprehensive system for managing women with abnormal vaginal bleeding. 55 Pregnancy should be excluded in all reproductive-aged women presenting with presumed AUB. 55 The most common cause of AUB is anovulatory bleeding, often related to polycystic ovary syndrome, but also commonly occurring in the healthy peri-menarcheal and perimenopausal women. 55 AUB related to structural abnormalities is most commonly treated surgically; AUB in women with normal pelvic anatomy can usually be managed medically with hormones, antibiotics, antifibrinolytics, nonsteroidal anti-inflammatory drugs, or a combination of these.

8.1

Introduction

Vaginal bleeding that occurs outside the parameters of normal menstruation is one of the most common clinical problems confronting women and their gynecologists. The possible etiologies of abnormal vaginal bleeding range from a temporary interruption of the normal menstrual cycle to the earliest symptom of a potentially life-threatening condition. Chronic abnormal vaginal bleeding impairs quality of life as a result of significant physical, emotional, sexual, social, and financial burdens [1].

Abnormal uterine bleeding (AUB) is a subset of abnormal vaginal bleeding where vaginal bleeding originates from either the uterine fundus or cervix and does not include bleeding related to pregnancy or that originating in the lower genital tract [2]. AUB can be described according to bleeding pattern using terms such as heavy menstrual bleeding; non-­ menstrual bleeding that is irregular, intermenstrual, or prolonged; or any combination of these bleeding patterns. Experienced clinicians are well aware that what appears to be AUB has a broad spectrum of possible causes and can be related to pregnancy or originate from non-uterine sources, including the vagina, bladder, or rectum. With this in mind, every gynecologist must develop a thorough and cost-effective approach to the diagnosis and management of abnormal vaginal bleeding. The ability to expediently evaluate and treat women with abnormal vaginal bleeding depends on a broad understanding of its various causes and their diverse presentations. Case Vignette

A 37-year-old G0 P0 presents to her gynecologist’s office with profuse vaginal bleeding that began the prior evening. Her gynecologic history is significant for a diagnosis of polycystic ovary syndrome (PCOS) and only 3–4 menses per year. She is not using any contraceptive method but has not been able to get pregnant for 3  years. Her vital signs are stable, and she has no symptoms other than bleeding. Her pelvic exam reveals clots in the vagina and blood actively coming from a normal-appearing cervix. Bimanual pelvic examination, made difficult by her obesity, does not reveal uterine or adnexal masses or tenderness. Pelvic ultrasound shows a normal-sized anteverted uterus with a 16  mm endometrial stripe and what appear to be clots in the uterine cavity. Laboratory evaluation includes a negative urine pregnancy test, white blood cell count of 9500 per mcL, hemoglobin of 8.8 g/dL, and platelet count of 250,000 per mcL.  Other laboratory results are pending.

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8.1.1

Prevalence

Abnormal vaginal bleeding is one of the most common chief complaints for which women see obstetrician-gynecologists. AUB accounts for approximately 30% of all gynecology visits [3]. Despite its frequency, AUB remains a difficult diagnostic and therapeutic challenge and still accounts for 10–20%of all hysterectomies performed in the USA [4]. In years past, approximately 20% of hysterectomy specimens removed for AUB have no discernible pathology [5]. More recently, the use of hysterectomy to treat AUB has decreased as more of these patients are treated using effective medical or minimally invasive surgical modalities.

ing that can almost always be identified using the more sophisticated diagnostic techniques available today [7]. The ability of clinicians to identify a specific etiology for the vast majority of AUB has resulted in an increased likelihood of effective treatment for AUB without having to resort to hysterectomy.

8.2

A solid understanding of the normal menstrual cycle is essential to effectively evaluate and treat women with abnormal vaginal bleeding. Complex interactions between the hypothalamus, pituitary, and ovary (see 7 Chap. 1) result in monthly ovulation, which leads to either pregnancy or menstruation within approximately 2  weeks. Each month, the endometrium of normally ovulating women is exposed to physiologic levels of estradiol (50–250 pg/mL), accompanied in the last 12–14 days of each cycle by progesterone (mid-luteal phase progesterone >12  nmol/L). The result is a structurally stable endometrium 5–16  mm thick as measured by transvaginal ultrasound. Menstruation is the universal breakdown and uniform shedding of the endometrial functional layer. Unless pregnancy occurs, involution of the corpus luteum results in rapid decreases in both progesterone and estrogen. This hormonal withdrawal activates matrix metalloproteinases, which enzymatically dissolve the endometrium [8]. Hemostasis is achieved by a combination of vasoconstriction of the spiral arterioles and normal coagulation mechanisms. Normal menstruation occurs every 28  ±  7  days with duration of flow of 4 ± 2 days and a blood loss of 40 ± 40 mL [9]. Normal menstruation should not cause severe pain or include passage of large clots. However, what constitutes “normal” menstruation is subjective and varies between individual women and between cultures. In most women, 90% of blood loss per cycle occurs within the first 3  days of menstruation [10]. The amount of blood lost during a normal menstrual period should be 40 years of age –– Endometrial biopsy 55 New-onset heavy menstrual bleeding –– Prothrombin time –– Activated partial thromboplastin time –– Bleeding time 55 Heavy menstrual bleeding since menarche –– Above plus –– Iron profile, serum creatinine –– Factor VII level –– von Willebrand factor (vWF) antigen –– Ristocetin cofactor –– Platelet aggregation studies 55 If the above are negative, consider –– Factor XI level –– Euglobulin clot lysis time

8.8.5.1

Urine Tests

The most important test for all reproductive-­ aged women complaining of AUB is an hCG test for pregnancy. This can be readily obtained through urine testing as a preliminary qualitative test. If positive, quantitative serum HCG testing can be completed.

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8.8.5.2

8

Blood Tests

For all cases, except the most insignificant bleeding, a CBC (including platelets) is important to detect significant anemia and disorders of platelet production or survival. Unless precluded by extremely heavy bleeding, a Papanicolaou smear should be performed on any woman who has not had recent screening as per the current screening guidelines. For patients with apparent oligo- or anovulation, thyroid-stimulating hormone (TSH) and prolactin testing will detect subtle pituitary function disorders that might present with AUB as the earliest symptom. Since cervical and uterine infections are common, nucleic acid amplification tests for gonorrhea and chlamydia are helpful in women with intermenstrual spotting, as well as any woman at risk for these infections. Several patient groups may require additional ancillary tests. Obese patients with apparent AUB are at increased risk for type 2 diabetes. Several authors recommend measurement of hemoglobin A1c (HbA1c) as a good diabetes screen that does not require fasting or a return visit for provocative testing. Patients with hirsutism or other evidence of androgen excess should be screened for ovarian and adrenal malignancies with total testosterone and DHEAS.  All women >45  years old should have an endometrial biopsy to rule out endometrial hyperplasia or cancer. Similarly, women younger than 45 with persistent abnormal bleeding or chronic unopposed estrogen exposure should have an endometrial biopsy after pregnancy has been excluded. PCOS and nonclassic CAH may sometimes be indistinguishable by clinical presentation, since both disorders are often characterized by hirsutism, acne, menstrual abnormalities, and infertility [61]. Unfortunately, no discriminatory screening test exists for this heterologous condition, which is most commonly caused by 21-­hydroxylase or 11-beta-hydroxylase deficiency. Measuring baseline serum 17-­hydroxyprogesterone will detect nonclassic CAH in the majority of women with this condition. However, as many as 10% of women

with nonclassic CAH will have normal baseline levels of 17-­ hydroxyprogesterone and demonstrate elevated levels only after stimulation with an ACTH analogue. If ovulation dysfunction and signs of androgen excess begin at the time of puberty, such women should be investigated appropriately (see 7 Chap. 7).  

8.8.5.3

Evaluation for Hemostatic Disorders

Patients with new onset of significant menorrhagia should be evaluated for bleeding disorders with a CBC, prothrombin time, activated partial thromboplastin time, and bleeding time [62]. Any patient with a history of menorrhagia since menarche, especially with a history of surgical or dental-related bleeding or postpartum hemorrhage, should be evaluated for heritable bleeding disorders. These tests include specific tests for von Willebrand disease, such as von Willebrand factor antigen, von Willebrand factor functional activity (ristocetin cofactor activity), and factor VIII level. These levels can fluctuate; therefore, these tests should be repeated if clinical suspicion is high. Normal ranges should be adjusted for the observation that von Willebrand factor levels are 25% lower in women with blood type O compared with other blood groups. Further studies, such as platelet aggregation studies, may also be required [62]. If these studies are negative, factor XI level and euglobulin clot lysis time can be evaluated. 8.8.6

Papanicolaou Smear

In the setting of mild vaginal bleeding, a Pap smear should be performed to rule out bleeding from cervical carcinoma. It is important to not delay this sampling due to the bleeding, and a large cotton-tipped swab can be used to carefully clear the bleeding before obtaining sampling. Importantly, other forms of cervical bleeding such as cervical polyps and ectropion can be ruled out through physical examination.

189 Abnormal Uterine Bleeding

8.8.7

Endometrial Biopsy

For premenopausal women over the age of 40 years old, AUB is often the result of anovulatory bleeding, which is a normal physiological response to declining ovarian function. However, the risk of endometrial hyperplasia and carcinoma also increases with age. For this reason, once pregnancy has been excluded, an endometrial biopsy should be obtained in all women older than 45 years of age who present with AUB. Endometrial biopsy should also be performed in all women who are younger than 45 years of age who have a history of persistent AUB, unopposed estrogen exposure, or failed medical management [11]. 8.8.8

Imaging

the nature of both palpable and nonpalpable adnexal masses. Knowledge about the size and location of leiomyoma and the potential that an ovarian mass might be malignant is invaluable prior to surgery. 8.8.8.2

Sonohysterogram

Sonohysterography can be used to accurately visualize most intrauterine abnormalities once pregnancy has been excluded. Accurate evaluation of the uterine cavity is of the utmost importance for the evaluation and treatment of AUB.  This procedure involves injection of sterile saline into the uterus while a transvaginal sonogram is performed. It may cause a small amount of discomfort to the patient. When the uterine cavity is distended with saline, intracavitary lesions (e.g., polyps, fibroids, cancer) as small as 3 mm can be clearly seen (. Fig. 8.2).  

Over the last two decades, our ability to visualize the uterine cavity and adnexa has dramatically increased. In addition to the bimanual pelvic examination, the only other available methods were hysterosalpingogram (HSG) and dilation and curettage. Although the radiation exposure and discomfort associated with HSG are both considered acceptable, this technique effectively identifies only marked abnormalities of the uterine cavity. Lesions 60% of these patients. Anovulatory patients who continue to hemorrhage despite treatment with intravenous estrogens will usually respond to uterine dilation and curettage. Concomitant hysteroscopy, when possible, is an important adjuvant to diagnose and treat intrauterine pathology such as polyps or leiomyomas.

191 Abnormal Uterine Bleeding

8.9.1.2

Arterial Embolization for Pelvic Malignancies

Women with AUB related to cervical or endometrial malignancies can present with massive arterial hemorrhage. When pelvic examination reveals a tumor mass as the bleeding source, the initial approach is vaginal packing and intravenous resuscitation with fluid and blood products. When pressure and clotting factors do not control hemorrhage, intravascular arterial embolization by an interventional radiologist can be lifesaving. Embolization has been reported to result in complete or partial hemorrhage control in up to 90% of these patients [66]. Once these patients are stabilized, irradiation or surgical intervention can be utilized as indicated. 8.9.2

Acute Outpatient Treatment of AUB

8.9.2.1

at three tablets per day will often decrease or stop bleeding quickly, although many women experience nausea with this high-dose regimen [67]. Alternatively, medroxyprogesterone acetate, at a dose of 10  mg per day for 10–14 days, usually improves bleeding within 2–3 days and serves to stabilize the endometrial lining prior to withdrawal bleeding. Patients treated with either of these methods should be counseled that they may experience moderately heavy bleeding within 1–2  days of stopping their medication and should start oral contraceptives on the Sunday following the withdrawal bleeding. A combination of oral and intramuscular medroxyprogesterone will result in a longer period of amenorrhea [68]. However, this intramuscular medroxyprogesterone should be avoided in women wishing to conceive in the near future because the median delay in conception after the last injection has been reported as approximately 9 months.

Progestin Endometrial Synchronization

Progestin therapy is the first-line approach to stop bleeding in hemodynamically stable patients. Progestins are also used for women with chronic irregular bleeding to synchronize the endometrium prior to the initiation of cyclic hormones. Synchronization can reduce breakthrough bleeding encountered with subsequent therapy. Approaches to synchronization use either an oral contraceptive taper or a potent progestin (. Table  8.2). For women with heavy vaginal bleeding, oral contraceptives starting  

8.10

Long-Term Management of Ovulatory Dysfunction

The most appropriate long-term management of chronic anovulation requires accurate diagnosis of any underlying pathology. For anovulatory women desiring conception, ovulation induction is usually the most appropriate treatment. For women not immediately desiring conception, this is followed by a combination of hormonal management and management of associated comorbidi-

..      Table 8.2  Effective acute outpatient therapies for anovulatory bleeding Medication

Routine

Dosage

Frequency and duration

Ethinyl estradiol plus Norethindrone (OCPs)

PO

35 μg 1 mg

TID × 1 week, then QD × 3 week

Medroxyprogesterone

PO

20 mg

TID × 1 week, then QD × 3 week

Medroxyprogesterone

IM Plus PO

150 mg 20 mg

Once TID × 3 days

Abbreviations: IM intramuscular injection, PO oral, QD once daily, TID three times daily, OCPs oral contraceptive pills

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S. Elguero et al.

ties including obesity, type 2 diabetes mellitus, and endometrial hyperplasia and cancer. 8.10.1

8

Ovulation Induction

Restoration of ovulation for women desiring conception is of paramount importance. Restoration of regular ovulatory cycles may necessitate treatment of any underlying condition responsible for anovulation. For example, in patients with hyperprolactinemia, using a dopamine agonist to normalize prolactin levels will often result in ovulation and subsequent pregnancy. In cases of PCOS, recent studies have demonstrated that insulin-­sensitizing agents, such as metformin, can promote ovulation (See 7 Chaps. 5 and 8). It is important to note, however, that utilization of these agents alone may not be sufficient for ovulation induction and conception. A recent randomized clinical trial did not demonstrate an improvement with live birth rates when adding metformin to clomiphene citrate [69]. While waiting for systemic therapies to result in resumption of ovulation and normal menses, monthly induction of withdrawal bleeding with an oral progestin should be considered to avoid ongoing AUB. In women not using combined oral contraception, the use of micronized progesterone (200–300  mg daily for 14  days) will result in reasonable withdrawal bleeding and will be safe should pregnancy occur. For patients who do not resume ovulation with systemic therapy, induction of ovulation using clomiphene citrate, aromatase inhibitors, or injectable gonadotropins should be considered (See 7 Chaps. 5 and 7).  

 

8.10.2

Hormonal Treatment of Anovulatory Bleeding

Women who do not desire pregnancy may initiate combined oral contraception or other hormonal therapies, such as cyclic progestins and a progestin-containing intrauterine device.

8.10.2.1

Oral Contraceptives

For decades, combined oral contraceptive pills have been the first-line therapy for managing AUB, and studies have repeatedly demonstrated their utility in decreasing the duration and amount of menstrual flow as well as dysmenorrhea [70]. In addition, extending the number of consecutive days of active pills and decreasing the annual number of menses may further minimize menstrual-­ related symptoms [70]. Extended cycle regimens increase the risk of spotting and breakthrough bleeding when compared with standard monthly cycle regimens, but the risk generally decreases over time [71]. 8.10.2.2

Progestins

Progestin therapy, cyclic or continuous, represents another option for long-term management of AUB.  The administration of progestins, such as 10 mg medroxyprogesterone or 300 mg micronized progesterone, daily, from day 15 to 26 of each cycle, will regulate menses in anovulatory patients. Cyclic progestin therapy represents a safe and effective approach to managing AUB and does not have the side effects or risks associated with oral estrogen. Additionally, cyclic progestin therapy provides endometrial protection against endometrial hyperplasia and cancer. Notable side effects of progestin therapy include mood changes or depression, nausea, breast tenderness, and bloating. Both progestin and continuous oral contraceptive therapy are equally efficacious in the treatment of AUB; however, progestin-only therapy has demonstrated superior patient satisfaction rates in direct comparison with combined oral contraceptives [67]. 8.10.2.3

Levonorgestrel-Releasing Intrauterine Devices

Levonorgestrel-releasing intrauterine devices (LNG-IUDs), originally developed for contraception, have been shown to be an effective treatment for dysmenorrhea, AUB-H, and endometrial hyperplasia. These IUDs release the potent progestin levonorgestrel (LNG) directly into the uterine cavity, suppressing endometrial proliferation and decreasing menstrual blood loss by as much as 97% [72].

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While many women will experience irregular or intermenstrual bleeding in the first 6 months of their use, at least 50% will have amenorrhea by 24 months [73]. LNG-IUDs have very few systemic side effects compared to oral and parenteral contraceptives containing progestins. However, extremely low amounts of LNG can be detected in the systemic circulation among LNGcontaining IUD users [74]. As a result, some users will experience hirsutism, acne, weight change, nausea, headache, mood changes, and/ or breast tenderness. The first LNG-IUDs contained 52 mg of LNG and released 20 μg every 24 hours from this polymer cylinder. LNG-IUDs are now available that contain and release less LNG: 13.5  mg/device and 19.5  mg/device. Initial LNG release rates are reduced by 50% after 5 years. Although the initial cost of an LNG-­ IUD is higher than other medical treatment options, long term they provide cost-effective therapy of AUB-H.

8.11

Treatment of AUB in Ovulatory Patients

In ovulatory women, AUB can be either between menses, often postcoital, or excessive bleeding (HMB) that occurs at normal, regular intervals. Intermenstrual bleeding can be related to cervical or endometrial infections or neoplasms, as discussed above. Chronic HMB is most often related to an anatomical cause, e.g., leiomyoma or adenomyosis, but can also be related to congenital or acquired bleeding disorders. Unfortunately, despite a thorough evaluation, approximately one-half of women with HMB have no discernible cause. These women must be treated with empiric hormonal or surgical therapies until a treatable cause can be ­identified or menopause occurs. 8.11.1

Medical Treatment

The majority of patients who present with AUB will be medically stable and thus good candidates for outpatient management.

8.11.1.1

Combination Oral Contraceptives

Estrogen-progestin oral contraceptives (OCPs) are often used for first-line management for AUB/HMB.  Significant advantages include reduction of menstrual flow, amelioration of dysmenorrhea, and providing contraception. Randomized trials have demonstrated the ability of OCPs to decrease menstrual blood loss in women with AUB from 35% to 69% [75]. Alternative routes of administration of estrogen-progestin include the transdermal contraceptive patch and vaginal contraceptive ring. The efficacy of these in treating AUB is likely similar to that of OCPs, and compliance may be improved. Furthermore, underscoring the impact of formulation on HMB, shorter duration of hormone free-­ intervals may be associated with less withdrawal bleeding than formulations with 7 hormone-free days per 28-day pill pack. Indeed, the only OC approved by the US Food and Drug Administration for treatment of AUB has a short hormone-free interval [76]. In a randomized trial, this OCP formulation significantly reduced menstrual blood loss compared with placebo (reduced by 64% versus 8%) [77]. Similarly to patients with anovulatory AUB, OCPs may be prescribed in a myriad of dosing regimens: a cyclic (with a monthly withdrawal bleed), extended (withdrawal bleeding every 3  months), or continuous (no withdrawal bleed) regimen. Although extended or continuous OCP use may be more efficacious in suppression of menstrual blood loss, breakthrough bleeding is a concern with this approach, limiting the utility of this strategy for some patients. 8.11.1.2

Progestins

Progestin-containing hormonal preparations are also effective in the treatment of HMB.  Highdose oral progestin formulations are generally reserved for patients who have contraindications, prefer to avoid estrogen, or who are trying to conceive a pregnancy. Examples of treatment regimens include norethindrone 5 mg one to three times a day or medroxyprogesterone 5–30  mg daily. Norethindrone is substantially more potent than medroxyprogesterone in the attenu-

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ation of menstrual flow [75]. Norethindrone is the most-studied progestin-only regimen for the treatment of AUB; however, other regimens including megestrol may be equally efficacious. Blood loss with progestin therapy use has demonstrated reductions by approximately 30% in some studies. High-dose progestin formulations, unfortunately, may instigate progestin-related side effects, including mood lability, bloating, and an increased appetite. Levonorgestrel-containing IUDs may be offered as a first-line treatment for patients with HMB wishing to defer conception in the near future. The 52  mg-containing IUD system (LNG 52) has been approved by the FDA for treatment of HMB due to its efficacy and compliance. Studies demonstrate superiority of LNG-containing IUDs in improving quality of life in patients with HMB by significant menstrual suppression, with the majority of patients experiencing amenorrhea or infrequent bleeding [73]. After 6  months, LNG 52 IUD treatment of women with HMB has been shown to increase their hemoglobin and ferritin levels by 7.5% and 68.8%, respectively. Further study is required to determine the efficacy of IUDs containing lower LNG dosages (e.g., 19.5 mg and 13.5 mg) for treatment of HMB. 8.11.1.3

Nonsteroidal Anti-inflammatory Drugs

Prostaglandins significantly impact endometrial hemostasis, and by inhibiting prostaglandin synthesis, NSAIDs serve to decrease menstrual blood loss. NSAIDs may reduce menstrual blood loss by 30–40% [78]. While naproxen has been the most extensively studied NSAID, no member of the drug class offers distinct advantages for AUB [79]. Additionally, NSAIDs provide an effective treatment for dysmenorrhea, which is often present in those with AUB. 8.11.1.4

Tranexamic Acid

Tranexamic acid, an antifibrinolytic agent, is a nonhormonal modality utilized in the treatment of AUB.  A Cochrane analysis has confirmed efficacy and patient tolerance of

tranexamic acid in the treatment of HMB, and in Europe this medication has become the preferred treatment for women with heavy menstrual bleeding [80]. The FDA has approved tranexamic acid for use in the treatment of HMB. This therapy is administered orally at a dose of 1300 mg three times daily for 5 days, initiated with onset of menses. Studies have demonstrated the superiority of this class of drugs in comparison with NSAIDs. Conversely, tranexamic acid is inferior to LNG 52 in the treatment of AUB [81] To date, studies have not demonstrated an increased risk of venous or arterial thromboembolism [82]. However, tranexamic acid should not be concomitantly administered with combined oral contraception or in women with an increased risk of thromboembolism. 8.11.2

Surgical Treatment of AUB

In the past, surgery was one of the most common treatments of AUB related to either structural or nonstructural abnormalities, primarily in the form of hysterectomy [5]. This was likely related to both an incomplete understanding of AUB and a paucity of effective medical treatments. Surgical treatments are now reserved for women with coexisting surgical indications in addition to AUB (e.g., pelvic organ prolapse, infertility, possible malignancy) or those who have completed childbearing and find medical treatment ineffective or unacceptable because of risks or side effects. Surgical approaches can be either conservative (e.g., myomectomy, polypectomy) or definitive (e.g., endometrial ablation, hysterectomy). The choice of surgical approach depends on the patient’s diagnosis, therapeutic goals, and desire for future fertility. For younger women whose fertility desires might change in the future, it should be kept in mind that hormonal management with a progestin-­ releasing IUD can often be as effective as a definitive surgery for controlling AUB [83]. The details of surgical approaches are provided in 7 Chaps. 20, 21, and 22.  

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8.11.2.1

Medical Pretreatment of Uterine Leiomyomas with GnRH Analogues

Medical pretreatment with GnRH agonists has been shown to be useful in some cases to decrease the size of leiomyoma by up to 47% prior to surgical intervention [84]. This approach has been shown to facilitate removal using minimally invasive approaches, decrease blood loss during open myomectomy, and facilitate specimen removal during hysterectomy. GnRH agonist injections result in an initial increase in pituitary and ovarian hormones (i.e., “flair”) followed by pituitary downregulation, hypoestrogenemia, and cessation of menses. The side effects of estrogen deprivation include hot flashes, mood alterations, and bone loss, which can be diminished by “addback” therapy with oral norethindrone. More recently, oral GnRH antagonists have become available to avoid the hormonal flare. However, their clinical utility remains to be determined for presurgical treatment of leiomyoma. 8.11.2.2

Myomectomy

Surgical removal of leiomyomas in symptomatic women is an effective treatment, although subsequent growth of addition leiomyomas often necessitates the need for additional surgery (see 7 Chap. 22). The best approach depends on the size and location of the fibroids in addition to the level of surgical expertise of the provider. Hysteroscopic resection is the ideal approach for all but the largest intracavitary and submucosal leiomyomas (FIGO stage 0, I, or II) because of the decreased morbidity and faster recovery. Myomectomy for larger fibroids (FIGO stage III or higher) can be performed laparoscopically, with or without robotic assistance, or using an abdominal approach. For patients desiring future childbearing, caution must be undertaken during repair of the endometrium to prevent intracavitary scarring in cases where the uterine cavity is entered.  

8.11.2.3

Endometrial Ablation

Endometrial ablation is a minimally invasive surgical procedure that, compared to hysterectomy, has less morbidity, shorter recovery,

and greater cost-effectiveness (see 7 Chap. 20). Ablation is not indicated for women who desire to maintain fertility, since pregnancies after ablation are at markedly increased risks of adverse pregnancy outcomes, including preterm premature rupture of membranes (PPROM) and abnormal placentation. Women undergoing this procedure should consider permanent sterilization since endometrial ablation does not provide reliable contraception [85].  

8.11.2.4

Hysterectomy

Hysterectomy remains the best option for some women with AUB who fail medical or surgical management or who have additional indications for hysterectomy. As many as 20% of women who initially undergo endometrial ablation will require hysterectomy within 5 years. Some studies have demonstrated a higher satisfaction rate in women who initially underwent hysterectomy rather than endometrial ablation [86].

8.12

Review Questions

?? 1. A 36-year-old woman is having frequent and heavy menses. After pregnancy was excluded, sonohysterogram revealed an intracavitary lesion consistent with a 3 cm intra cavitary (type 0) fibroid. What is the next best step? A. Do nothing. B. Place her on oral contraceptive pills. C. Order a hysterosalpingogram. D. Proceed with hysteroscopic myomectomy. ?? 2.  At 27-year-old woman presents with abnormal uterine bleeding. A careful history reveals new-onset acne, hirsutism, and deepening of the voice. Which test(s) would be most helpful at this point? A. Hysterosalpingogram B. CBC C. Serum testosterone and dehydroepiandrosterone D. Endometrial biopsy

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?? 3. A 33-year-old woman with a normalappearing uterus on transvaginal ultrasound has continued to bleed for 3 weeks despite treatment with high-dose oral contraceptives. What is the first adjuvant therapy would you consider? A. Sonohysterogram B. Oral antibiotics C. Endometrial biopsy D. Vaginal Hysterectomy

8

?? 4. A 23-year-old woman taking oral contraceptives presents with several months of postcoital spotting. Which test would be least helpful at this point? A. Pelvic examination with visualization of the cervix B. Papanicolaou smear C. Nucleic acid amplification tests for chlamydia and gonorrhea D. Endometrial biopsy

8.13

Answers

vv 1. D vv 2. C vv 3. B vv 4. D

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62. Kouides PA.  Menorrhagia from a haematologist’s point of view. Part I: initial evaluation. Haemophilia. 2002;8(3):330–8. 63. Valentine L.  Hysteroscopy for abnormal uter ine bleeding and fibroids. Clin Obstet Gynecol. 2017;60(2):231–44. 64. ACOG Committee on Practice Bulletins—Gynecology. Committee opinion number 557: management of acute abnormal uterine bleeding in non pregnant reproductive-aged women. Obstet Gynecol. 2013;120(1):891–6. Reaffirmed in 2020. 65. Schapiro L, Thorp JM. Management of leiomyoma causing myocardial infarction. Eur J Obstet Gynecol Reprod Biol. 1996;65(2):235–6. 66. Wu CC, Lee MH.  Transcatheter arterial embolotherapy: a therapeutic alternative in obstetrics and gynecologic emergencies. Semin Intervent Radiol. 2006;23(3):240–8. 67. Munro MG, Mainor N, Basu R, Brisinger M, Barreda L.  Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial. Obstet Gynecol. 2006;108(4):924–9. 68. Ammerman SR, Nelson AL.  A new progestogen-­ only medical therapy for outpatient management of acute, abnormal uterine bleeding: a pilot study. Am J Obstet Gynecol. 2013;208(6):499.e1–5. 69. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551–66. 70. Sulak PJ. The career woman and oral contraceptive use. Int J Fertil. 1991;36(Suppl 2):90–7. 71. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68:89–96. 72. Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivelä A, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia; randomized trial 5 year follow up. JAMA. 2004;291:1456–63. 73. Hidalgo M, Bahamondes L, Perrotti M, Diaz J, DantasMonteiro C, Petta C. Bleeding patterns and clinical performance of the levonorgestrel-­releasing intrauterine system (Mirena) up to two years. Contraception. 2002;65(2):129–32. 74. Nilsson CG, Lahteenmaki PL, Luukkainen T, Robertson DN.  Sustained intrauterine release of levonorgestrel over five years. Fertil Steril. 1986;45(6):805–7. 75. Hillard TC, Siddle NC, Whitehead MI, Fraser DI, Pryse-Davies J.  Continuous combined conjugated equine estrogen-progestogen therapy: effects of medroxyprogesterone acetate and norethindrone acetate on bleeding patterns and endometrial histologic diagnosis. Am J Obstet Gynecol. 1992;167(1):1–7. 76. Rafie S, Borgelt L, Koepf ER, Temple-Cooper ME, Lehman KJ.  Novel oral contraceptive for heavy

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menstrual bleeding: estradiol valerate and dienogest. Int J Women’s Health. 2013;5:313–21. 77. Wright KP, Johnson JV. Evaluation of extended and continuous use oral contraceptives. Ther Clin Risk Manag. 2008;4(5):905–11. 78. Livshits A, Seidman DS. Role of non-steroidal antiinflammatory drugs in gynecology. Pharmaceuticals (Basel). 2010;3(7):2082–9. 79. Lethaby A, Puscasiu L, Vollenhoven B.  Pre operative medical therapy before surgery for uterine fibroids. Cochrane Database Syst Rev. 2017;11(11):CD000547. 80. Cooke I, Lethaby A, Farquhar C. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev. 2000;2:CD000249. 81. Matteson KA, Rahn DD, Wheeler TL 2nd, Casiano E, Siddiqui NY, Harvie HS, Mamik MM, Balk EM, Sung VW, Society of Gynecologic Surgeons Systematic Review Group. Nonsurgical management of heavy menstrual bleeding: a systematic review. Obstet Gynecol. 2013;121(3):632–43.

82. Fraser IS, Porte RJ, Kouides PA, Lukes AS.  A benefit-­risk review of systemic haemostatic agents: part 2: in excessive or heavy menstrual bleeding. Drug Saf. 2008;31(4):275–82. 83. Kaunitz AM, Meredith S, Inki P, Kubba A, Sanchez-­Ramos L.  Levonorgestrel-releasing intrauterine system and endometrial ablation in heavy menstrual bleeding: a systematic review and meta-­ analysis. Obstet Gynecol. 2009;113(5):1104–16. 84. Lethaby A, Augood C, Duckitt K, Farquhar C. Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev. 2007;4:CD000400. 85. ACOG Committee on Practice Bulletins—Gynecology. ACOG practice bulletin no. 81: endometrial ablation. Obstet Gynecol. 2007;109:1233–48. 86. Lethaby A, Shepperd S, Cooke I, Farquhar C.  Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2000;2:CD000329.

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Menopause Tara K. Iyer and Holly L. Thacker Contents 9.1

Introduction – 203

9.2

Impact of Menopause – 204

9.3

Terminology – 204

9.4

Time to Natural Menopause – 205

9.5

The Physiology of Menopause – 205

9.5.1 9.5.2

 remenopause – 205 P The Menopause Transition – 206

9.6

Premature Ovarian Insufficiency – 207

9.7

Physiological Effects of Estrogen – 208

9.7.1 9.7.2 9.7.3 9.7.4 9.7.5 9.7.6 9.7.7 9.7.8 9.7.9 9.7.10 9.7.11 9.7.12 9.7.13 9.7.14

 reast Tissue – 208 B Central Nervous System – 208 Cardiovascular System – 208 Bone – 209 Adipose Tissue – 209 Liver – 209 Bowel – 210 Pulmonary System – 210 Skin – 210 Hair – 210 Eyes – 211 Vulvovaginal Tissue – 211 Pelvic Floor – 211 Urinary Tract – 211

9.8

Symptoms of Menopause – 211

9.8.1 9.8.2 9.8.3

 asomotor Symptoms (VMS) – 211 V Genitourinary Syndrome of Menopause (GSM) – 214 Other Peri- and Menopausal Symptoms – 214

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 T. Falcone, W. W. Hurd (eds.), Clinical Reproductive Medicine and Surgery, https://doi.org/10.1007/978-3-030-99596-6_9

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9.9

Evaluation – 214

9.9.1 9.9.2 9.9.3

 iagnosis – 214 D Clinical History – 215 Physical Exam – 215

9.10

Treatment – 217

9.10.1 9.10.2

 eneral Counseling and Recommendations – 217 G Hormone Therapy: Treatment of Vasomotor Symptoms and Systemic Menopausal Symptoms – 217 Clinical Data – 219 Unregulated Hormone Therapy – 224 Non-hormonal Therapy Options – 224 Neurokinin 3 Receptor (NK3R) Antagonists – 225 Treatment for Genitourinary Syndrome of Menopause – 225

9.10.3 9.10.4 9.10.5 9.10.6 9.10.7

9.11

Learning Assessment – 228

9.11.1 9.11.2

 eview Questions – 228 R Answers – 228

References – 229

203 Menopause

Key Points 55 Natural menopause, or the permanent cessation of menstruation in women due to the senescent loss of ovarian follicular activity, is typically clinically diagnosed retrospectively 12  months after the last menstrual period (LMP) has occurred, and often causes significant physical and mental health, social, and economic burdens. 55 The loss of estrogen that occurs with menopause has myriad physiologic consequences throughout the body. The most common clinical signs and symptoms of menopause include vasomotor symptoms (VMS), such as hot flashes and night sweats, and the genitourinary syndrome of menopause (GSM), encompassing vaginal dryness, dyspareunia, and urinary symptoms. 55 The gold standard of treatment for menopausal symptoms is hormone therapy (HT), which when initiated in low-risk women under the age of 60  years old or within 10  years of menopause is associated with improved cardiovascular, metabolic, neurological, and mortality outcomes. 55 Hormone replacement therapy (HRT) is the recommended standard of care in women who experience menopause younger than 45  years old to mitigate the consequences of early estrogen loss and should be continued at least until the median age of menopause (52 years old).

9.1

Introduction

The loss of endogenous ovarian hormone production that occurs at the menopause transition (MT) is perhaps the most consequential physiologic event experienced by women in midlife. While often overlooked as a risk factor for health consequences, menopause can have serious pathological, psychological,

social, and economic ramifications for women who live long enough to experience it. The average age of menopause ranges from 40 to 60  years old, with a median age of 52 years old [1]. As female life expectancy steadily increases, women may find themselves spending up to 40% of their lives in the postmenopausal phase. Given the significant morbidity that menopause and menopausal symptoms may cause for women, it is important for healthcare providers to adequately understand and counsel women about the associated health risks, appropriate preventive care, and available treatment options.

Case Vignette

A 48-year-old G3P2 white woman with an unremarkable past medical history presents to your clinic with concern about her menopausal symptoms of hot flashes and night sweats, vaginal dryness, and dyspareunia. She has not had any fractures after turning 40. She has a bone density scan done, which is normal. Obstetric history is remarkable for two spontaneous vaginal deliveries with no pregnancy complications. She had her menarche at age 13. She has a history of regular menses without a uterine bleeding disorder. She was on oral contraceptives for about 10 years and was well tolerated without developing venous thromboembolism or gallbladder problems. Her paternal grandmother was diagnosed with breast cancer in her 60s and a paternal aunt deceased in her 40s from breast cancer. She has no known genetic mutations. She has a personal history of abnormal mammograms remarkable for fibrocystic breast but never had breast biopsy. She had a recent normal mammogram. She has no history of hypertension, diabetes mellitus, stroke, or myocardial infarction. She is a nonsmoker. She has no personal or familial history of venous thromboembolism or prothrombotic mutations.

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Impact of Menopause

Menopause significantly impacts the prevalence of chronic disease and mortality among the female population. Several longitudinal studies have demonstrated that menopause leads to pronounced cardiometabolic changes, making it an independent risk factor for cardiovascular disease (CVD) and mortality [2–6]. The loss of estrogen that occurs with menopause has also been associated with increased risk of dementia [7]. Several population-­based studies have found that the use of estrogen therapy results in reduced prevalence and incidence of dementia and Alzheimer’s disease [7–10]. Additionally, menopause is a known risk factor for osteoporosis and has been associated with declining pulmonary function and worsening of chronic lung disease [11, 12]. Perhaps more consequential than the physiologic impact of menopause are the psychosocial ramifications, which are often overlooked. Several studies have demonstrated a negative association with menopause and quality of life (QOL) [13–15]. In addition to the health-related burden experienced by women, menopause may also significantly impact mental health, social life, relationships, and career. The US Bureau of Labor Statistics projects that the percentage of women in the workforce from 2014 to 2024 is expected to grow by 5.8%, with the largest increase ­occurring in postmenopausal women [16]. The number of women in the civilian labor force aged 65–74 and aged 75+ is expected to increase by 59.2% (~1,846,000) and 94.5% (~618,000), respectively [16]. Research has shown that menopausal symptoms negatively impact work performance and may increase absence from work [17, 18]. Hot flashes, mood swings, and “brain fog” (difficulties with memory and concentration) are all commonly reported symptoms in postmenopausal women that may interrupt work ability. Working may be correlated with improved selfesteem and decreased psychological stress in some women [19]. Menopause may also pose significant financial burdens to women and

families, as severe symptoms and subsequent poor work performance may make it difficult for women to advance in their careers or in some severe cases even remain employed at all. Many postmenopausal women also experience female sexual dysfunction (FSD) and changes in mood, which may have a negative impact on relationship satisfaction in both men and women [13]. The changes in appearance that occur due to estrogen loss may also provoke lower self-esteem and body image issues in women, leading to lower confidence levels. It is not uncommon for women and their spouses or partners to endorse relationship problems as a consequence of their menopausal symptoms.

9.3

Terminology

The stages of menopause have been classified and defined by a group of menopause experts in a model known as STRAW+10 (Stages of Reproductive Aging Workshop), which breaks down reproductive aging into seven stages throughout a woman’s life [20]. This is generally accepted as the gold standard for the characterization of reproductive aging in women. There are several different terms used both in STRAW+10 and, generally, to describe the different types and phases of menopause (see below): 55 Menarche: The first occurrence of menstruation. 55 Premenopause: The period of time in a woman’s life prior to menopause. 55 Premature menopause/premature ovarian insufficiency (POI): The permanent or transient cessation of ovarian function before age 40. Premature ovarian failure (POF) is to be avoided as it implies no chance of ovulation (which cannot be ruled out), so POI is a more helpful diagnostic construct. 55 Perimenopause: The highly symptomatic time frame that exists from the first occurrence of menopause-related symptoms to one full year after the final menstrual period (FMP).

205 Menopause

55 Menopause transition (MT): This term is often interchanged with perimenopause, though the MT by definition ends at the time of the FMP. 55 Climacteric: This term is the period of physiologic and psychologic changes that occurs during the menopausal transition. 55 Menopause: –– Natural menopause: The cessation of menstruation due to complete or near-­ complete follicular exhaustion, resulting in the end of ovarian hormone production. –– Early menopause: Menopause occurring before the age of 45. –– Late menopause: Menopause occurring after the age of 55. 55 Induced menopause: –– Surgical menopause: Cessation of ovarian function due to gynecologic surgical intervention. –– Iatrogenic menopause: Cessation of ovarian function due to an iatrogenic cause, such as chemotherapy or pelvic radiation. 55 Postmenopause: The period of time following menopause, starting 1  year after the final menstrual period and lasting through the end of life. Early postmenopause is typically a more symptomatic period than late postmenopause: –– Early postmenopause: Period of time when women are 5–10 years or less from FMP. –– Late postmenopause: Period of time when women are greater than 10 years from FMP.

9.4

Time to Natural Menopause

There are several factors that have been consistently identified as influencing the age at which natural menopause occurs (see . Table  9.1). Race/ethnicity, dietary habits, and physical activity have been inconsistently associated with influencing menopause onset [1].

..      Table 9.1  Factors associated with earlier or later onset of menopause [1] Factors associated with earlier onset of menopause

Factors associated with later onset of menopause

Active smoking

Increased body mass index (BMI)

Nulliparity/low parity

Multiparity

Medically treated depression/seizure disorder

Higher cognitive scores in childhood

Hereditary/familial influence

Hereditary/familial influence

Chemotherapy Pelvic radiation Gynecologic surgery Lower socioeconomic status No previous use of oral contraceptive pills

9.5

The Physiology of Menopause

Menopause occurs as a result of the progressive depletion of a woman’s ovarian reserve, leading to complete or near-complete follicular exhaustion, which is accompanied by a reduction in quality and capability of the aging oocytes. The subsequent disruption in ovarian steroid hormone production results in the cessation of ovulation and menstruation, as well as several physiologic consequences throughout the body that lead to increased risk of chronic disease and significant symptom burden in many women. 9.5.1

Premenopause

 

At 20 weeks of gestation, a female fetus possesses approximately 6–7 million eggs, the most ovarian follicles of its reproductive life

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[21]. In utero, a female fetus begins to lose follicles through granulosa cell-mediated apoptosis in a process known as follicular atresia. At birth a female has about 1–2 million oocytes, and follicular loss continues, but at a slower pace [21]. In reproductive-aged women, folliclestimulating hormone (FSH) stimulates ovarian folliculogenesis. Anti-Mullerian hormone (AMH) and inhibin B, peptide hormones primarily produced by granulosa cells in growing antral follicles, act in a negative feedback loop with FSH, functioning to restrain follicular growth. This negative feedback is necessary to moderate FSH and ensure only one dominant follicle reaches the preovulatory stage. As levels of inhibin B rise, negative feedback is provided to the pituitary gland to indicate the maturation of oocytes has started to occur, which signals the pituitary gland to stop producing FSH.  The FSH negative feedback loop is also influenced by the ovarian steroid hormone estradiol (E2) and corpus luteumsecreted progesterone. Developing follicles secrete E2, which acts on the hypothalamicpituitary-­ovarian (HPO) axis to suppress FSH secretion. Each time ovulation occurs, several antral follicles are recruited, though typically only one follicle undergoes ovulation, while the rest undergo apoptosis. E2 secretion from developing follicles also causes proliferation of the endometrium. Following ovulation, the corpus luteum secretes progesterone which, in combination with estradiol, causes the endometrial secretory changes necessary for implantation to occur. If fertilization does not occur, the corpus luteum regresses and progesterone secretion ceases, resulting in menstruation. Throughout a female’s reproductive life, she continues to experience a progressive loss of ovarian follicles through the natural ­processes of ovulation and follicular atresia. Ovarian reserve most sharply declines in the late reproductive period. As a woman ages, there is also a concurrent reduction in the quality and function of the remaining oocytes. In the late reproductive phase, menstrual cycles remain predominantly ovulatory. However, the follicular phase shortens due to hastened follicular growth, resulting in

increased time spent in the luteal phase of the menstrual cycle. Luteal phase progesterone levels also decline. This leads to increased menstrual frequency and subsequently more premenstrual symptoms. 9.5.2

The Menopause Transition

Follicular depletion continues into the early stages of the menopause transition, where there is a period of compensated failure of the HPO axis. The growing pool of oocytes decreases, leading to less granulosa cell production of inhibin B and AMH.  As inhibin B and AMH secretion declines, there is less restraint of ovarian negative feedback on FSH, resulting in increasing FSH levels [22, 23]. Elevated FSH levels prompt the recruitment and maturation of a new cohort of follicles at the beginning of each cycle, maintaining the drive necessary for continued ovulation. While there are more follicles available for recruitment, there is also accelerated follicular atresia [21]. Levels of estradiol and regular menstrual cyclicity typically remain preserved throughout this time [22, 23]. There are often fluctuating patterns of hormones as the menopausal transition continues. While FSH elevations accompanied by low inhibin B and estradiol levels are common, they may be followed by subsequent elevations in estradiol and declining FSH levels [22, 23]. A woman may experience elevated estrogen levels through increasing androgen aromatization incurred as a result of increasing age and body weight or by increased estradiol production by an enlarged oocyte cohort [22, 23]. These intermittently high levels of estradiol lead to endometrial proliferation with subsequent heavier periods. These expansive hormonal fluctuations account for why this period is so highly symptomatic. The significant loss in ovarian follicles that occurs in this period due to accelerated follicular atresia also leads to a decreased amount of receptors available to respond to FSH [21]. This decreased sensitivity to FSH can in turn lead to inhibition of the typical luteinizing hormone (LH) surge required for ovulation to occur [22, 23]. As a result, there is increased anovulation

207 Menopause

with subsequent menstrual irregularity and a reduction in estrogen secretion and circulation throughout the body. The decline in estrogen levels that occur lead to a disruption of HPO axis and a subsequent failure of endometrial development, causing further menstrual irregularities [22, 23]. Anovulation may occur due to LH surge failure secondary to HPO axis dysfunction or an absence of corpus luteum formation despite the occurrence of an LH surge [22, 23]. Decreased corpus luteum production due to anovulation leads to decreased progesterone secretion. Consequently, estrogen is often unopposed leading to endometrial proliferation and thus a possible increased risk for endometrial hyperplasia and endometrial cancer. The endometrium often outgrows its own blood supply in this case, provoking tissue necrosis and shedding, which contributes to irregular bleeding patterns [22, 23]. Oocyte quality and capability also decline during this time, leading to further increasing anovulatory cycles, decreased rates of conception, and increased risk of spontaneous abortion. The decreased oocyte quality and proficiency may be due to several mechanisms, including impaired dominant follicle recruitment and the age-dependent decrease in integrity and function of granulosa cells and meiotic spindles [24]. The late menopause transition is marked by increasing hormone fluctuation, decreasing frequency of ovulatory cycles, and an increasing number of days of consecutive amenorrhea. At this point in the MT, the persistently diminishing ovarian follicle quantity decreases to a level which can no longer be compensated for. When follicular growth and recruitment does occur, ovulation is more likely to fail. However, given the intermittent ovulatory cycles that may occur throughout the late menopause transition, it is important to note that women can experience pregnancy at any point up to their final menstrual period (FMP). Eventually, the follicular numbers reach a nadir at which folliculogenesis can no longer occur and E2 and progesterone production effectively cease, leading to persistent amenorrhea. This near-complete follicular exhaustion results in the characteristic hormone profile of postmenopausal women, consisting of high FSH, low E2, low inhibin B,

and low AMH [22, 23]. The menopausal ovary no longer produces sufficient E2. The resulting low level of endogenous estrogen is what causes menopausal symptoms, though severity varies between each individual woman. Some postmenopausal women may still produce small amounts of estrogen through the aromatization of adrenally secreted testosterone, which may lessen symptoms.

9.6

Premature Ovarian Insufficiency

Premature ovarian insufficiency (POI) occurs when there is a loss of ovarian function prior to the age of 40  years old. There are several possible etiologies of POI, the most common of which is idiopathic, which accounts for more than 90% of cases [25] (7 Box 9.1).  

Box 9.1  Etiologies of primary ovarian insufficiency (POI) [25, 115] Genetic Autoimmune Metabolic Iatrogenic 55 Surgery 55 Chemotherapy 55 Radiation Infectious Idiopathic

Surgical menopause has the most significant physiologic consequences among the causes of premature menopause. When the ovaries are removed, women experience a sudden loss of estrogen, testosterone, and progesterone, resulting in significant disruption of the HPO axis [26]. Subsequently, menopausal symptoms typically occur more acutely and more severely than with the gradual hormonal loss that occurs with natural menopause. Gynecologic malignancies, such as cervical cancer, endometrial cancer, ovarian cancer, and borderline ovarian tumors, may necessitate bilateral salpingo-oophorectomies (BSO). If there is a significant disruption in ovarian

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blood flow as a result of surgery, it is possible for early or premature menopause to occur in some women with a history of unilateral oophorectomy, or even hysterectomy alone. Nonmalignant gynecologic disorders, such as endometriosis, chronic pelvic pain, bilateral or recurrent ovarian cysts, tubo-ovarian abscesses, ovarian torsions, and prophylactic or risk-reducing salpingo-oophorectomy, are other possible causes of surgical menopause. There is an accelerated aging curve that occurs with premature and early menopause, whether from surgery or other causes, which leads to associated increases in coronary heart disease, early bone loss, dementia, Parkinson’s disease, mental health disorders, cancer admissions, cancer deaths, and all-cause mortality [27, 28].

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9.7

Physiological Effects of Estrogen

There are three naturally occurring estrogens in the human body, estrone (E1), 17β-estradiol or estradiol (E2), and estriol (E3). E2 is the strongest biologically active form of natural estrogen. E2 is predominantly produced by the dominant ovarian follicle and is the most potent and prevalent form of natural estrogen during a woman’s reproductive years [29]. E1 is primarily synthesized in the skin and adipose tissue through the peripheral conversion of androstenedione [29]. Following the cessation of ovarian steroid hormone production that occurs with menopause, estrone becomes the predominant form of endogenous estrogen in the postmenopausal woman [29]. In postmenopausal women, serum estradiol is formed by the extragonadal aromatization of testosterone. It is not uncommon for levels of estradiol in postmenopausal women to be less than 20 pg/mL, which is lower than a normal male level of estradiol (~40  pg/mL). Extragonadal estradiol synthesis may increase with age and an increasing amount of adipose tissue. Estrogens are cholesterol-derived steroid hormones that exert both genomic and non-­ genomic effects. They bind to estrogen receptors (ERs), ER-α and ER-β, throughout the body to perform myriad biochemical processes, such as the induction of nitric oxide,

the modulation of catecholamine release, and the regulation of intracellular calcium [30]. While it is widely known that estrogen plays an important role in the female reproductive system, estrogen is also responsible for several critical physiologic processes throughout the body. Both ER-α and ER-β are concentrated in the central nervous system (CNS) and cardiovascular (CV) system. ER-α predominates in the uterus, mammary glands, bone, vagina, cervix, liver, and adipose tissue [31–34]. ER-β is primarily located in the lung, skin, thyroid, spleen, thymus, bladder, and colon [31–34]. 9.7.1

Breast Tissue

Estrogens stimulate blood flow to breast tissue through vascular-mediated mechanisms [30]. They play a pivotal role in the growth of ductal epithelium and connective tissue within the breast [35]. Research has also demonstrated that estrogen can advance the production of breast cancer cells [36]. Later age to natural menopause, specifically greater than 55 years old, has been associated with increased risk of breast cancer. 9.7.2

Central Nervous System

Estrogen has myriad functions in the brain. It is known to play a role in the regulation of mood, memory, and cognition. It may also exert neuroprotective and neurotrophic effects [37, 38]. The loss of ovarian hormones that occurs during menopause is associated with mitochondrial dysfunction, oxidative stress, neuroinflammation, synaptic deficits, cognitive impairment, and an increased risk of age-­ related disorders, such as dementia [37, 38]. Postmenopausal women often experience new or worsening mood symptoms, cognition difficulties, and/or memory problems. 9.7.3

Cardiovascular System

Estrogen mediates a myriad of important regulatory functions in the cardiovascular system. The activation of estrogen receptors, ER-α and

209 Menopause

ER-β, throughout the CV system positively affects vascular function, insulin sensitivity, metabolic processes, lipid and lipoprotein levels, body fat distribution, inflammation, and cardiac myocyte structure and activity [39]. Estrogens exhibit vasoprotective effects. The estrogen-mediated vasodilation and inhibition of platelet activation through the synthesis of nitric oxide, as well as estrogen’s role in the suppression of inflammation and vasoconstrictive mechanisms, improve overall arterial function [30]. Estrogen plays an important role in the functional activity of cardiac myocytes through the regulation of ion channels. Through this mechanism, estrogen can influence cardiac contractility and modulate cardiac repolarization [40]. Estrogen may also play a part in delaying cardiac hypertrophy and creating more favorable myocardial remodeling, thus positively influencing the structure of cardiac myocytes [40]. Additionally, animal models have suggested that in  vivo estrogen delivery immediately prior to ischemia can reduce the size of myocardial infarct [40]. The loss of estrogen that occurs during the MT not only increases CV risk directly through the loss of estrogen’s cardioprotective mechanisms but indirectly as well. Hot flashes have been associated with a multitude of pathologic CV markers, including an increase in carotid intimal thickness, increased carotid and aortic calcifications, increased heart rate variability, increased sympathetic tone, endothelial dysfunction, and insulin resistance [41]. Furthermore, many women going through the MT experience novel or worsening mood symptoms, especially of depression and sleep disturbance, which have been associated with greater risk of CVD [42]. The American Heart Association (AHA) released a scientific statement in 2020 acknowledging menopause as an independent risk factor for cardiovascular disease [39]. This statement stands in agreement with the guidelines and recommendations of several other prominent specialist organizations, such as the North American Menopause Society (NAMS), the American College of Obstetricians and Gynecologists (ACOG), and the American Association of Clinical Endocrinologists (AACE).

9.7.4

Bone

Estrogen plays a critical role in the regulation of bone metabolism. Estrogen exhibits an antiresorptive effect through the inhibition of osteoclasts by suppressing the expression of receptor activator of NF-kB ligand (RANKL), a cytokine essential for osteoclast stimulation, differentiation, and longevity [43]. The bone loss that occurs after menopause due to the loss of estrogen may be most pronounced in the first 2 years after the FMP. 9.7.5

Adipose Tissue

The MT is associated with increases in both total and visceral adiposity. Estrogen regulates metabolism and deposition of adipose tissue in the female body [44]. Estrogens work directly on adipocytes to inhibit lipogenesis, and play a pivotal role in adipogenesis and adipocyte proliferation [44]. The accumulation of central body fat, a known risk factor for type 2 diabetes (T2DM), can be attenuated with the use of estrogen therapy in postmenopausal women [45]. Studies have shown that the early loss of estrogen in women who experience premature menopause is associated with a clear increased risk of T2DM [46]. Coinciding with these findings, large randomized controlled trials (RCTs) have suggested that the use of HT in postmenopausal women can reduce the risk of developing T2DM [46]. While the exact mechanisms are not completely clear, HT has been shown to decrease visceral adiposity and improve β-cell insulin secretion, insulin sensitivity, and glucose efficacy [46]. 9.7.6

Liver

Within the liver, estrogen inhibits fibrogenesis and cellular senescence, promotes innate immunity and antioxidant effects, and protects mitochondrial function [47]. Estrogen also increases hemostasis through the activation of gene transcription of clotting factors (VII, VIII, X, fibrinogen) and plasminogen, decreasing antithrombin III and protein S lev-

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els, and modifying activated protein C (APC) resistance [48]. Estrogen affects levels of circulating lipids. Estrogens lead to increased production of hepatic lipoprotein receptors leading to a decrease in serum LDL [49]. Premenopausal women have a more favorable lipid profile, with higher serum HDL levels and lower serum LDL levels, compared to agematched men and postmenopausal women [49]. Following the MT, plasma LDL levels increase, and HDL levels decrease [49]. Following menopause, there is also a reduction in liver volume, blood flow, function, and capacity for regeneration [47]. 9.7.7

9

Bowel

Estrogen is known to affect bowel motility. It also plays a protective role in cancer prevention in the colonic mucosa through the modulation of apoptotic signaling, tumor microenvironment, and immune mechanisms, and the inhibition of inflammatory markers [50]. 9.7.8

Pulmonary System

Estrogen plays a role in the development and maintenance of healthy lung tissue. It has been suggested that estrogen is involved in lung tissue elastic recoil and in the production of alveoli, extracellular matrix, and surfactant [51]. Menopause is associated with lower lung function and increasing respiratory symptoms in midlife women [52, 53]. This is an especially important consideration in women with pre-­ existing respiratory disease, such as asthma, COPD, or restrictive lung disease. 9.7.9

Skin

Estrogen also appears to play a significant role in the maintenance of skin elasticity and the prevention of skin aging. It regulates elastic fiber and collagen content in the skin, helping to maintain its thickness [54]. Estrogen also increases hyaluronic acid and other acid mucopolysaccharides in the skin, aiding in the

preservation of skin moisture [54]. Estrogen may also play a role in promoting cutaneous wound healing through the regulation of cellular growth factors and repair enzymes [55]. The loss of estrogen that occurs during the MT causes several significant changes in skin quality and function. The disruption of elastin, cellular growth factor, and repair enzyme production leads to decreased skin elasticity and increased skin fragility [55]. Changes in blood flow and cellular oxygenation effects on keratinocytes lead to epidermal thinning [55]. Women can experience impaired wound healing as a result of these changes. Many women find the changes to their skin distressing. It is not uncommon for women to complain of their appearance, often in vague terms. Accelerated lipoatrophy, fat distribution changes, and increased bone resorption can lead to facial hollowing, eyelid sagging, jowling, contour deformities, and shadow creation. The decreased fibroblast activity and glycosaminoglycan production cause decreased skin hydration, increasing skin dullness, and more pronounced appearance of lines and wrinkles [54]. Estrogen loss may also lead to a testosterone imbalance that can cause or worsen acne. 9.7.10

Hair

Many women in midlife experience hair thinning or loss on the scalp and eyebrows and/or increased growth of facial hair, and accurately associate these changes with menopause. Estrogen increases levels of sex hormone-­ binding globulin (SHBG), which is responsible for binding and carrying testosterone in its inactive state [56]. When estrogen levels drop during menopause, levels of SHBG also decrease, which increases the amount of free testosterone available in the circulation [56]. This increase in active testosterone may lead to symptoms such as hirsutism and female pattern hair loss in women. It is also important to note, however, that there are many other factors which may influence the thinning or loss of hair in midlife women, including genetic predisposition, stress, other hormones, medications, vitamin deficiencies, and chronic illness.

211 Menopause

9.7.11

Eyes

Estrogen may affect corneal elasticity, which in turn affects clarity of vision [57]. Estrogen also functions to reduce intraocular pressure [57]. Hormone therapy has been associated with decreased incidence of glaucoma, age-­related macular degeneration, and cataracts [58]. 9.7.12

Urinary Tract

9.7.14

Vulvovaginal Tissue

There are an abundance of estrogen receptors throughout the vagina and vulva [59]. Estrogen has several functions in the vulvovaginal tissue, including preserving adequate blood supply, maintaining the integrity and moisture of the tissue, and supporting the local microbiome [59–63]. Androgens have also been shown to help support nerve fibers and maintain moisture and tissue integrity [60]. Premenopausal women typically have well-­estrogenized, multilayered vaginal tissue with substantial blood supply and glycogen-rich superficial cell layers [62]. In contrast, p ­ ostmenopausal women typically have atrophic vulvovaginal tissue with marked epithelial thinning and reduced blood supply [59–61]. The tissue atrophy and reduction of tissue collagen can lead to narrowing of the vaginal canal and loss of elasticity, which may contribute to the dyspareunia experienced by some postmenopausal women [59–61]. Estrogen also functions to help maintain an acidic intraluminal vaginal pH by supporting the growth of lactic acid-secreting lactobacillus [64]. Glycogen acts as a substrate facilitating lactobacillus production of lactic acid [64]. The reduction in the glycogen content of the postmenopausal epithelium leads to decreased lactic acid production and resulting increased intraluminal vaginal pH [63, 64]. The change in local microbiome and more basic pH leads to unfavorable changes in the concentration of protective inflammatory cells, leaving the vulvovaginal tissue more vulnerable to infectious pathogens [63, 64] (. Fig. 9.1).  

9.7.13

sacral ligaments, pubocervical fascia, and pelvic floor musculature [65, 66]. Through the regulation of collagen metabolism, estrogen functions to support the strength of the pelvic floor [65, 66]. The loss of these supportive mechanisms in postmenopausal women may contribute to increasing the risk of pelvic organ prolapse [66].

Pelvic Floor

Estrogen receptors are located throughout the pelvic floor, and have been found in the utero-

Estrogen and androgen receptors in the urethra and the bladder contribute to numerous important functions, including protection against infection and aiding in the prevention of urogenital prolapse [60, 67]. Estrogen receptors located in the urethra and bladder also directly affect urethral smooth muscle, detrusor muscle contraction, and urethral pressure to help maintain urinary continence [67]. The loss of estrogen and androgen support in the urogenital tissue of postmenopausal women leads to reduced collagen and epithelial thinning with subsequent tissue atrophy (. Fig.  9.2). This atrophy increases the risk of urogenital prolapse [67]. Interestingly, despite the function of estrogen in these tissues, data has shown that there is no association between low serum estradiol levels and increased risk of urinary incontinence [68]. Menopause additionally puts women at risk for recurrent urinary tract infections (UTIs). The atrophy and shriveling of urogenital tissue also leaves the urethra more prominent and brings it closer to the introitus, leading to higher rates of UTIs. The change in vaginal microflora and decreased production of urogenital antimicrobial substances also increase the risk of urinary infections [69].  

9.8

Symptoms of Menopause

9.8.1

Vasomotor Symptoms (VMS)

Vasomotor symptoms (i.e., hot flashes and night sweats) are experienced by up to 80% of women during the menopause [70]. Hot flashes are typically described as a sudden intense feeling of warmth throughout

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9

..      Fig. 9.1  Normal vs. postmenopausal vaginal environments. From left to right, the left half of the figure demonstrates the ideal vaginal environment typically found in a healthy, premenopausal woman of reproductive age

[59–64]. The right half of the figure demonstrates the pathological changes that may occur in the vaginal environment of an untreated postmenopausal woman [59–64]

the upper body, typically most severe over the chest, neck, and face. If redness can be seen on the skin, these episodes are typically termed hot flushes. This feeling may be accompanied by several symptoms women find bothersome or even concerning, such as diaphoresis (this may range from mild to severe perspiration), flushing or reddening of the skin, chills, anxiety, and/or heart palpitations [71]. When a hot flash occurs during sleep, it is termed a night sweat. Night sweats can cause significant sleeping disruption for some women. A single hot flash episode typically lasts between 1 and 6  minutes [70–72]. The frequency and severity of hot flashes vary from woman to woman, though typical triggers that can provoke or worsen an episode include stress, heat, caffeine, alcohol, cigarette smoke, spicy foods, and tight clothing.

Estrogen is known to play an important role in the regulation of body temperature. Estrogen deficiency results in a disruption of the thermoregulatory center of the hypothalamus, triggering the occurrence of hot flashes [73]. During a hot flash, blood flows to the periphery leading to a decrease in core body temperature and cutaneous vasodilation with the associated sensation of extreme warmth [71]. Research has increasingly shown that hot flashes are not physiologically benign symptoms. Hot flashes have been associated with increased carotid intima thickness, increased carotid and aortic calcifications, increased endothelial dysfunction, decreased nitric oxide production, increased insulin resistance/ elevated blood glucose levels, increased sympathetic tone, increased heart rate variability, white matter hyperintensity, and increase in

213 Menopause

..      Fig. 9.2  Physiologic changes with menopause. The physiological changes of various organs and organ systems that occur due to the estrogen deficiency associated with menopause [30–69]. Abbreviations: GAG glucos-

aminoglycans, LDL-C low-density lipoprotein cholesterol, UTI urinary tract infection, RANKL receptor activator of NF-kB ligand, GI gastrointestinal, CVD cardiovascular disease

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N-telopeptide (NTx), which is a marker of bone turnover (increased bone loss) [74–84].

aches, palpitations, formications (tactile hallucinations), and hair thinning, for example, are often missed or misdiagnosed (. Table 9.2).  

9.8.2

9

Genitourinary Syndrome of Menopause (GSM)

Genitourinary syndrome of menopause describes the signs and symptoms resulting from estrogen deficiency of the female genitourinary system. There has been a change in vocabulary from the previous term vulvovaginal atrophy (VVA). This change was made to create more accurate and all-encompassing terminology, as vulvovaginal atrophy is only a component of GSM and does not encapsulate the entire syndrome. GSM symptoms will affect at least 50–70% of postmenopausal women at some point in their lives [85]. The most bothersome symptoms of GSM as recognized by the US Food and Drug Administration (FDA) are vaginal dryness, dyspareunia (painful intercourse), vulvovaginal irritation, vaginal soreness, dysuria, and bleeding associated with sexual activity [86]. Many women may also experience vulvovaginal burning and/ or abnormal vaginal discharge. These symptoms are chronic and progressive, and will not improve without treatment. Women with surgical menopause tend to have more severe symptoms than those who go through menopause naturally [87]. Many postmenopausal women are unaware of or embarrassed by the vulvar, vaginal, and urinary changes that result from estrogen loss. Additionally, symptoms do not always correlate to physical exam findings. As a result, GSM is typically underdiagnosed and/or treated with significant delay. The goals of GSM treatment are to relieve symptoms, reverse any anatomic changes that may have occurred, improve sexual dysfunction, and prevent infection. 9.8.3

 ther Peri- and Menopausal O Symptoms

There are myriad recognized symptoms of the menopause transition. While VMS, GSM, sleep disturbances, and mood changes are commonly thought of as menopausal, there are also many symptoms that are often overlooked. Joint

9.9

Evaluation

9.9.1

Diagnosis

Menopause is typically diagnosed retrospectively following 12  months of amenorrhea after the last menstrual period in a woman over the age of 45, though there remains a small possibility of continued cycles even after these characteristics are met. In women under 45 years old without any other known cause of early or premature menopause, an evaluation for underlying causes of secondary amenorrhea and premature ovarian insufficiency should be pursued. The European Society of Human Reproduction and Embryology (ESHRE) guidelines suggest that POI may be diagnosed in women with absence of menstruation for at least 4  months, and elevated FSH levels on two separate occasions, at least 4  weeks apart, in a women under the age of 40 years old [88]. While this guideline allows for diagnosis to be reached at 4 months after LMP, 12 months of amenorrhea is preferable for a more accurate diagnosis. While obtaining FSH levels is not necessary for diagnosis, they can be clinically useful in some patients. A clinician can be more confident in the diagnosis of menopause when it is supported by two elevated FSH levels (>30 mIU/mL) 12  months apart, especially in women with concurrent menopausal symptoms. In women with abnormal or absent menstrual cycles, such as women with PCOS, women with a hormonal levonorgestrel intrauterine system (IUS) in place or on continuous combined hormonal contraceptive (CHC) therapy, and women with a history of hysterectomy or endometrial ablation, the menstrual cycle criteria cannot accurately be applied. Endocrinological evaluation with FSH and 17β-estradiol levels can be especially helpful in the diagnosis of these patients. FSH should always be interpreted with a simultaneous serum estradiol level, as elevated estra-

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..      Table 9.2  Peri- and menopausal symptoms [91] Body system

Symptom

Genitourinary

Irregular periods/bleeding Vaginal dryness Changes in libido Urinary urgency and incontinence Recurrent UTIs

CNS

Headaches Paresthesias/electric shocks Difficulty with concentration Memory lapse Dizziness Formications (tactile hallucinations)

Gastrointestinal

Digestive issues (constipation, flatulence, cramps, abdominal bloating)

Psychological

Mood swings Sleeping difficulty New-onset or worsening anxiety/depression Panic disorder Formications

Breast

Breast tenderness or soreness Loss of breast fullness Breast sagging

Musculoskeletal

Joint aches and pains Muscle tightness/soreness Decreased skeletal muscle mass

Oral

Burning tongue Gum health issues

Integumentary

Dry, itchy skin Brittle nails Hair thinning or loss Change in body odor

Bone

Osteoporosis/bone loss

Cardiovascular

Hot flashes and hot flushes (redness seen) Night sweats Palpitations

Immunologic

Worsening allergies

General

Fatigue Weight gain Bloating/water retention

diol levels may suppress FSH, allowing for the momentary appearance of a normal FSH value. Of note, endocrine evaluation should not be completed until at least 3 months following hysterectomy or ablation, as FSH levels may be transiently elevated immediately after gynecologic surgery [89]. In 2018, the FDA approved an AMH enzyme-linked immunosorbent assay (ELISA) test, known as the pico AMH diagnostic ELISA test, for the determination of menopausal status. Research in the last few decades has shown that serum AMH levels may be the most accurate blood test reflecting ovarian follicular reserve [90]. Given that AMH is not affected by the menstrual cycle, it may be a more useful test than FSH and 17β-estradiol. However, given that this test remains expensive and is relatively new, it is not commonly used in practice to diagnose menopause (. Table 9.3).  

9.9.2

Clinical History

Full obstetric and gynecological history should be taken of all women who present with menopausal concerns. Women should also be assessed for full family history and past medical history, with special attention toward cancer history, neurological history, cardiovascular history, mental health history, and bone health history (. Table 9.4).  

9.9.3

Physical Exam

Clinical exam of the perimenopausal and menopausal patient should be focused on the possible physical changes that can occur during menopause. Vital signs should be taken at each office visit. Heart rate and cardiac exam should be recorded, as women undergoing hot flashes may experience tachycardia or palpitations. Weight, BMI, and blood pressure should also be trended, as these levels increase in the postmenopausal woman. While often overlooked, height is a valuable measurement

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..      Table 9.3  Hormone changes in menopause [21–24, 90]

9

Hormone

Source

Change in menopause

Notes

Estrogen

Ovaries, adrenal glands, peripheral conversion by adipose tissue

↓

E1 (estrone) is the dominant estrogen during menopause

Progesterone

Corpus luteum

↓

Often co-administered with estrogen for endometrial protection in the treatment of menopausal women with an intact uterus

Testosterone

Ovaries, adrenal glands, peripheral tissues

↓

White ethnicity, lower BMI, oral estrogen, and corticosteroid use are each associated with lower testosterone in women 65 and older Surgical menopause often results in lower testosterone than other types of menopause

Follicle-­ stimulating hormone (FSH)

Anterior pituitary gland

↑

FSH should be interpreted with estradiol because elevated estradiol can suppress FSH leading to “falsely” normal FSH levels Cycle day 3 FSH is commonly used as a test of ovarian reserve

Anti-Mullerian hormone (AMH)

Antral follicle granulosa cells

↓

AMH levels are reflective with ovarian follicular reserve

in postmenopausal women, as decreasing height may be indicative of osteoporotic vertebral fractures, especially more than or equal to 1.5 inches of height loss from maximum adult height in women (and 2 inches in men). Physical appearance may display increased visceral adiposity. Women should also be evaluated for signs of testosterone excess, such as hirsutism, hair thinning or sparseness, adult acne, and deepening of the voice (especially important to evaluate if changes are career significant for women, as with Opera singers). Mental status should be assessed for clinical signs of mental health issues and abnormalities in memory and cognition. A mini cognitive evaluation or mini-mental status exam (MMSE) may be appropriate in some patients. Pelvic examination should be completed to assess for signs of estrogen deficiency, such as vulvovaginal atrophy, vaginal dryness, pallor, lack of rugae, and narrowing of the vagi-

nal canal. Bimanual pelvic and rectal exam should also be performed to assess for adequate pelvic floor tonicity (7 Box 9.2).  

Box 9.2  Possible pelvic exam findings [85–87] Labial atrophy Vaginal dryness Introital stenosis Clitoral atrophy Phimosis of the prepuce Reduced mons pubis and labia majora bulk Reduced labia minora tissue and pigmentation Prominence and erythema of the urethral meatus Urethral caruncle Vaginal pallor Lack of vaginal rugae

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..      Table 9.4  Important history points in menopausal evaluation History

Specific questions

Gynecologic history

Age at menarche Menstrual history Last menstrual period Total number of years of oral contraceptive use

Obstetrics history

Gravidity and parity Breastfeeding history Age at first full-term pregnancy Pregnancy and postpartum-­ associated medical conditions

Breast history

Personal history of breast cancer Family history of breast cancer Personal history of breast biopsy or surgery

Menopausal history

Age at menopause onset Date of last menstrual period Menopausal symptom assessment   Vasomotor symptoms.   GSM symptoms   Sexual function

Cardiovascular history

Tobacco use history History of hypertension History of hyperlipidemia History of diabetes History of myocardial infarction History of:   Deep vein thrombosis (DVT)   Pulmonary embolism (PE)   Cerebrovascular accident (CVA) Family history of early CAD

Other medical history

History of gallbladder disease or surgery History of autoimmune disorder

Bone history

History of previous bone mineral density/DXA scan History of fractures over the age of 40 Family history of osteoporosis and/or hip fracture History of disorders that affect calcium absorption or regulation Vitamin D status

Patients should have annual vision and hearing screening after the age of 65. It should also be recommended that patients stay up to date with regular dental care, which is a reflection of bone status.

9.10

Treatment

9.10.1

General Counseling and Recommendations

Women should be educated about the health risks associated with menopause due to the deleterious effects of estrogen loss. Midlife women should be routinely counseled on lifestyle interventions aimed at reducing triglycerides, weight gain, blood pressure, insulin resistance, and atherosclerosis. There is also a need for individualized counseling on the indications and benefits of hormone therapy for treatment among menopausal women. When discussing treatment options, it is important to counsel that the beneficial effects of HT often supersede the risks when initiated within 10  years from LMP in symptomatic women under the age of 60 and that HT is the standard of care in women with menopause prior to age 45 and should be continued until at least 52  years old. There is no time limit to HT; rather, there should be yearly re-­ evaluation of the woman’s medical status, her preferences, and shared treatment goals. 9.10.2

9.10.2.1

Hormone Therapy: Treatment of Vasomotor Symptoms and Systemic Menopausal Symptoms Treatment of Perimenopause

Women in perimenopause often experience more severe symptoms than postmenopausal women, due to the extreme fluctuation in

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estrogen levels that can occur. Hormone therapy is the most effective medication currently available to treat menopausal symptoms. Combined hormonal contraceptives are often utilized to achieve symptom relief in women who are still ovulating, as these medications will relieve symptoms and are potent enough to prevent pregnancy. The greatest major health risk associated with the use of CHCs in midlife-aged women is the risk of blood clot/stroke. It is important to assess women for contraindications and other vascular risk factors prior to initiation of therapy. Another option for treatment of women in perimenopause is cycled or continuous progesterone, with or without concurrent estrogen therapy. Many women in perimenopause may experience periods of high levels of unopposed estrogen due to lack of corpus luteum formation and subsequent lack of progesterone production. Progesterone treatment can offset this balance and help to regulate bleeding patterns. Low-dose estradiol therapy can be added in women with continued symptoms of estrogen deficiency. Some women in perimenopause, especially if in late perimenopause, may achieve symptom relief with menopausal estrogen therapy, which contains a much lower dose of estrogen than found in CHCs. It is important to note that menopausal hormone therapy (MHT) is not potent enough to suppress ovulation and thus does not prevent ovulation or resultant pregnancy from a fertilized egg. Therefore, if using MHT in a perimenopausal woman who is still ovulating, it is of paramount importance that clinicians counsel patients on using some form of contraception if a pregnancy is not desired, as women can become pregnant up until the time of their final menstrual period. 9.10.2.2

Treatment of Menopause: Menopausal Hormone Therapy

Hormone therapy treatment for 5–10  years when used in appropriate candidates within

10  years of menopause and under the age of 60  years old can shift the aging curve of women and provide significant cardiovascular, neurological, and mortality benefits. This is the gold standard of therapy for treatment for vasomotor symptoms. Hormone replacement therapy (HRT) is also the gold standard of treatment for women who experience early or premature menopause and should be continued at least until the median age of menopause (52  years old) to mitigate the consequences of early estrogen loss. Estrogen monotherapy may be used in hysterectomized women. In women who possess an intact uterus, a progestogen (bioidentical or synthetic progesterone) must be co-administered with estrogen for endometrial protection. Co-­ administration of estrogen and progestogen may also be necessary in women who have a history of endometriosis, even when hysterectomized, if there is any concern for remnant endometrial tissue. Certain selective estrogen receptor modulators (SERMs), such as bazedoxifene, also offer sufficient endometrial protection when administered with estrogen. 9.10.2.3

Indications for Treatment with Hormone Therapy

Treatment of menopausal symptoms is indicated in any woman for symptom relief (VMS or GSM) and/or to improve or maintain quality of life. For patients who undergo premature or early menopause without contraindications (including surgical/radiation-­ induced menopausal patients and POI patients), HRT is the gold standard of treatment and should be continued at least until the age of natural menopause. Hormone therapy is also indicated and FDA-approved for the prevention of osteoporosis in postmenopausal women. While there are no absolute contraindications to hormone therapy use, there are several relative contraindications that necessitate further risk stratification. The decision to use HT for treatment should occur on an individualized basis, through shared decision-making between patient and

219 Menopause

medical provider after appropriate counseling has occurred (7 Box 9.3).  

Box 9.3  Relative contraindications to hormone therapy [91] Severe active liver disease History of endometrial cancer History of estrogen-sensitive malignancy Porphyria cutanea tarda History of deep vein thrombosis History of pulmonary embolism History of stroke Dementia Coronary heart disease Unexplained vaginal bleeding that has not been evaluated

Points to consider when prescribing hormone therapy: 55 Is she menopausal? Yes or no 55 Does she have a uterus? Yes or no 55 Does she have indications for HT? Yes or no (VMS, GU, bone, QOL) 55 Is she within 10 years of menopause and/ or under 65? Yes or no 55 What type of therapy is indicated: oral, transdermal, topical, or vaginal ring? If patients are postmenopausal and do not report systemic symptoms, providers must be sure to also assess for silent changes, such as bone loss and any genitourinary symptoms. 9.10.2.5

Estrogen (E) Therapy Formulations (. Tables 9.5, 9.6, and 9.7)  

Selecting a Route of Therapy

9.10.2.4

While conjugated and synthetic estrogen formulations are only available for oral administration, bioidentical estradiol can be administered orally, transdermally, or vaginally [92, 93]. Oral estrogens undergo first-­pass metabolism through the liver, a process which is avoided through transdermal or vaginal estrogen delivery [92, 93]. Subsequently, oral estrogens need to be given in higher dosages and have a more pronounced effect on liver protein production [93]. Oral estrogen therapy only has also been associated with increased triglycerides, slightly increased risk of VTE, gallbladder disease, and stroke [94]. Stroke risk with oral estrogen is increased 1 extra case per 1000 women in women over age 65, not under age 65 [94, 95]. These risks are not seen with transdermal or vaginal hormone therapy [91]. The advantages of oral HT include ease of use, and typically improved symptomatic control on skin, hair, and mood. Additionally, some women may have issues with skin adherence and skin irritability with the transdermal patch that can be avoided with oral therapy. Cost and insurance coverage, which may vary among treatment options between patients, are also considerations that clinicians must keep in mind when deciding between medication routes (. Fig. 9.3).  

9.10.2.6

Equivalencies of Estrogen Formulations

0.625 mg CEE/esterified estrogen = 5 ug ethinyl estradiol  =  1  mg 17β-estradiol  =  50 ug transdermal estradiol [93]. 9.10.2.7

Progestogen (P) Therapy (. Table 9.8)  

9.10.2.8

 strogen + Progestogen E (E+P) Therapy (. Tables 9.9, 9.10, and 9.11)  

9.10.3 9.10.3.1

Clinical Data Women’s Health Initiative

The confusion over the safety of hormone therapy first arose in July 2002, when the Women’s Health Initiative (WHI) published its initial results suggesting hormone therapy posed significant health risks to menopausal women while offering insufficient benefits [96]. The WHI was a National Institutes of Health (NIH)-sponsored multi-outcome study conducted in part to evaluate the risks and benefits of the use of HT for primary prevention of heart disease [96]. Postmenopausal women (average age 63  years old) were stratified to conjugated estrogen (CE) alone in hysterec-

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9

..      Fig. 9.3  Oral vs. transdermal hormone therapy. Distinctions in the pharmacology and result physiological effects of oral vs. transdermal hormone therapy administration [92, 93]

..      Table 9.5  Oral estrogens [93, 116, 117] Estrogen

Brand name

Dosage

Notes

17β-Estradiol (bioidentical)

Generic available Estrace

0.5 mg total daily 1 mg total daily 2 mg total daily

Total daily dose divided into two doses for BID (every 12 hours) dosing

Esterified estrogen

Generic available Menest

0.3 mg daily 0.625 mg daily 1.25 mg daily 2.5 mg daily

Conjugated equine estrogen (CEE)

Premarin

0.3 mg daily 0.45 mg daily 0.625 mg daily 0.9 mg daily 1.25 mg daily

Composed of ten different types of sulfated estrogens extracted from the urine of mares (female horses)

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..      Table 9.6  Transdermal estrogens [93, 116, 117] Generic

Route

Brand name

Dosages

Notes

17β-Estradiol (bioidentical)

Transdermal patch/film

Climara Menostar Alora Estraderm Minivelle Vivelle-Dot now generic available

0.025, 0.0375, 0.05, 0.06, 0.075 mg 1×/week 0.014 weekly only for bone protection 0.025, 0.05, 0.075, 0.1 mg 2×/week (every 84h) 0.05, 0.1 mg 2x/week 0.025, 0.0375, 0.05, 0.075, 0.1 mg 2x/week 0.025, 0.0375, 0.05, 0.075, 0.1 mg 2x/week 0.025, 0.0375, 0.05, 0.075, 0.1 mg 2x/week

Sufficient skin permeability required for adequate absorption Typically applied to buttocks, lower abdomen, lower back, or groin

Gel

Divigel EstroGel Elestrin

0.25, 0.5, 0.75, 1.0, 1.25 mg E/g gel 0.75 mg E in 1.25 g gel/ pump actuation 0.52 mg E in 0.87g gel/ pump actuation

Spray

Evamist

1.53 mg E/spray (1–3 sprays per day)

..      Table 9.7  Other formulations [93, 116, 117] Generic

Brand name

Dosage

Administration

Estradiol acetate

Femring

0.05 mg/d, 0.10 mg/d

Replace ring every 90 days

..      Table 9.8  Oral progestogens [93, 116, 117] Generic

Brand name

Dosage

Administration notes

Medroxyprogesterone acetate

Provera

2.5, 5, 10 mg/d

Cyclic administration 12–14 days/ month with 200 mg or 100 mg nightly

Micronized progesterone (bioidentical)

Prometrium

200 mg P or 100 mg P

Cyclic administration 12 days/month Use at night given relaxing properties Bioidentical

tomized women and conjugated estrogen plus medroxyprogesterone acetate (CE  +  MPA) in women with an intact uterus [96]. The CE + MPA arm was terminated after 5.6 years due to concern over increased risk of invasive breast cancer and no apparent coronary benefit [96]. Less than 2  years later, the CE-

alone arm was terminated due to concern over increased stroke risk [97]. Post hoc analysis of the data subsequently showed a reduction in CV risk in women using HT when initiated at or before the age of 60, or within 10 years of their last menstrual period (LMP) [97, 98]. Two subsequent landmark studies, the Kronos

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..      Table 9.9  Oral estrogen + progestogen therapy [93, 116, 117]

9

Generic

Brand name

Dosage

Conjugated estrogens + medroxyprogesterone acetate

Premphase

0.625 mg CE + 5.0 mg MPA (2 tablets: E daily and MPA days 15–28)

Conjugated estrogens + medroxyprogesterone acetate

Prempro

0.3, 0.45 mg CE + 1.5 mg MPA daily 0.625 mg CE + 2.5, 5 mg MPA daily

Ethinyl estradiol + norethindrone acetate

FemHRT Generic

0.025 mg EE + 0.5 mg NA daily 0.05 mg EE + 1 mg NA daily

17β-Estradiol + norethindrone acetate

Activella Mimvey Lo Mimvey (generic)

0.5 mg E + 0.1 mg NA daily 1 mg E + 0.5 mg NA daily

17β-Estradiol + drospirenone

Angelic

0.5 mg E + 0.25 mg DRSP daily 1 mg E + 0.5 mg DRSP daily In Europe 1 mg E/2 mg DRSP daily

17β-Estradiol + progesterone (bioidentical)

Bijuva

1 mg E + 100 mg P daily

..      Table 9.10  Transdermal estrogen + progestogen therapy [93, 116, 117] Generic

Brand name

Dosage

Administration

17β-Estradiol + norethindrone acetate

CombiPatch

0.05 mg E + 0.14 mg NA 0.05 mg + 0.25 mg NA

Replace patch every 84 h (2×/ week patch)

17β-estradiol + levonorgestrel

ClimaraPro

0.045 mg E + 0.015 mg L

Replace patch weekly

..      Table 9.11  Other formulations [93, 116, 117] Generic

Brand name

Dosage

Notes

Conjugated estrogens + bazedoxifene

Duavee

0.045 mg CE + 20 mg Bazedoxifene daily

Previously produced by Pfizer, currently post COVID not in production

Esterified estrogens + methyltestosterone

Previously Estratest Previously Covaryx

0.625 mg EE + 1.25 mg MT daily 1.25 mg EE + 2.5 mg MT daily

Early Estrogen Prevention Study (KEEPS) and the Early Versus Late Intervention Trial with Estradiol (ELITE), supported these findings in women who started HT less than

10  years after their LMP [99, 100]. Despite these critical trials and many others, the confusion around the safety of HT has remained prevalent throughout the medical community,

223 Menopause

resulting in a sharp decline in the number of HT prescriptions written since 2003 [101]. Presently, the FDA continues to mandate a package insert boxed warning indicating increased risk of endometrial cancer, breast cancer, CVD, and dementia to appear on all estrogen-containing MHT products. 9.10.3.2

Breast Cancer

Breast cancer risk associated with the use of hormone therapy has been a source of confusion for decades. The CE + MPA arm of the WHI initially demonstrated an increased risk of breast cancer diagnosis [96–98, 102]. Later review of the data, however, suggested that this increased risk was more likely due to the unexpectedly lower incidence of breast cancer in a subgroup of women with a history of HT use who were randomized to the comparative placebo arm, rather than a true increase in breast cancer risk [103]. The CE-alone arm of the WHI initially demonstrated a nonsignificant reduction in breast cancer risk, with the 18-year follow-up results showing a statistically significant decrease in breast cancer mortality compared to placebo [102]. Since the WHI, there have been several other studies examining the association between hormone therapy use and breast cancer. It is important to note that these studies are often plagued by confounders and biases and that they do not provide cause and effect conclusions. Several decades of observational studies suggest that HT does not increase breast cancer death. The data also appears to demonstrate that hormone therapy does not increase breast cancer risk in women with high risk of breast cancer (i.e., genetic mutations, family history, etc.). The Danish Osteoporosis Study (DOPS) was a prospective study that did not show any increase in breast cancer or mortality with prolonged HT treatment, rather a reduction in all-cause mortality [104]. 9.10.3.3

Venous Thromboembolism (VTE)

Several decades of research have shown an association between oral hormone therapy and rare increased risk of venous thromboembolism. Among specific oral estrogen for-

mulations, conjugated equine estrogen seems to have a higher risk of VTE than bioidentical 17β-estradiol. The WHI demonstrated a slightly increased risk of VTE with both CE and CE  +  MPA oral therapy compared to placebo [96–98]. A subsequent two-nested case-­control study that looked at the use of HT and VTE risk in the UK found that over 80,000 women aged 40–79 years old who had a primary diagnosis of VTE over the span of 19 years and who were matched by age, index date to almost 400,000 female controls, had a dose-dependent increased risk of VTE for all oral hormone therapy agents (E + P > E alone) [105]. Importantly, this study also found that transdermal hormone therapy was not associated with any increased risk of VTE [105]. 9.10.3.4

 lzheimer’s Disease (AD) or A Senile Dementia of the Alzheimer’s Type (SDAT)

There has been increasing research in the influence of hormone therapy on dementia outcomes. In one multi-institutional case control study, women aged 50–63 years old who used hormone therapy were found to have a reduced risk for AD (odds ratio [OR] 0.35, 95% CI 0.2– 0.7) [7]. In this study, no significant associations were found in women older than 63 using hormone therapy and Alzheimer’s risk [7]. There have been several other observational studies that support this notion that HT, when initiated in younger postmenopausal women, is associated with a reduced risk of AD [8–10]. When menopausal symptoms of VMS and sleep disturbance are treated, many women report resolution of their “brain fog.” The effects of endogenous hormones, menopause, and hormone therapy remain critical areas in need of further research, as there are still many unanswered questions. 9.10.3.5

Cardiovascular Disease

The ELITE trial showed less progression of atherosclerosis, as measured by carotid intima thickness levels, in women treated with oral estradiol within 6  years of menopause [100]. Oral estrogen therapy has been shown to reduce LDL levels, increase HDL levels, and increase VLDL levels in postmenopausal

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women [49]. HT has been shown to decrease serum levels of lipoprotein (a), which is considered an independent risk factor for developing cardiovascular disease due to its athero-thrombogenic properties [106]. Oral, not transdermal or vaginal, estrogen has been associated with 1 additional case of stroke per 1000 women over the age of 65 [94, 95]. However, after 10 years of randomized treatment, younger women on HT had a significantly reduced risk of heart failure, MI, VTE, and stroke, as well as reduced risk of mortality [107]. In women less than 10 years from menopause and under the age of 60 years old, the data consistently shows statistically significant reductions in cardiovascular mortality, coronary heart disease, and all-cause mortality, which strongly affects the risk benefit equation for younger and symptomatic menopausal women. 9.10.3.6

Mortality Data

A historical perspective shows that in the USA, female mortality rates from 1992 to 1996 vs. 2002 to 2006 increased in 42.8% of counties, while male mortality rates in comparison increased in only 3.4% of counties [108]. Menopause experts postulate one of the reasons for this dramatic change was the publication of the 2002 WHI study, which resulted in the decline of prescriptions for HT nationally [101]. A nationwide study in Finland examining mortality in postmenopausal women (average age 52.2  years old) showed a 12–38% reduction in the risk of all-cause mortality, an 18–54% reduction in cardiovascular mortality, and an 18–39% reduction in stroke mortality in HT users vs. age-matched controls [109]. Research has also shown that women who have undergone bilateral oophorectomy have an increased risk of cardiovascular mortality when not treated with E + P or estrogen-alone therapy [110].

9.10.4

Unregulated Hormone Therapy

Women should be counseled about the dangers of unregulated hormonal therapies,

such as testosterone pellets or unchecked compounded hormone regimens. If patients present on this type of therapy, detailed history of medication use and symptoms should be assessed. Serum hormone levels for 17β-estradiol, free and total testosterone, and dehydroepiandrosterone (DHEA) should be assessed if indicated. Progesterone levels are more accurately assessed through evaluation of the endometrial lining than through hormonal blood levels. If women have been on estrogen therapy with unregulated compounded progesterone creams, which may not absorb adequately enough to protect the uterus sufficiently, they may have been receiving unopposed estrogen which puts them at risk for endometrial cancer. If postmenopausal women have had any vaginal bleeding or spotting, they should undergo pelvic ultrasound to assess the endometrial stripe or thickness, which should be 4 mm or less, and ideally also undergo an endometrial biopsy. 9.10.5

Non-hormonal Therapy Options

Non-hormonal therapeutic options should be considered based on patient preference or if a woman has contraindications to hormone therapy. While lifestyle modification and non-­ hormonal medications exist for the treatment of vasomotor symptoms, women should be counseled that they are not as effective as hormone therapy. Non-pharmacologic treatment strategies should focus on patient education and lifestyle modification. Women should dress in layers, keep a lower temperature in the bedroom, and use fans/cooling devices, as needed. Women should be advised to avoid triggers and limit caffeine and alcohol intake. Smoking cessation should be encouraged in any tobacco users. Weight loss, meditation, deep breathing exercises, and yoga can be helpful in controlling symptoms. There is limited evidence that cognitive behavioral therapy (CBT), hypnosis, and acupuncture can also be helpful in the treatment of hot flashes.

225 Menopause

Non-hormonal Pharmacologic Therapy Options (. Table 9.12)

9.10.5.1

 

Herbal Remedies

9.10.5.2

There is insufficient evidence to support the use of any herbal remedies for the treatment of menopausal symptoms. Women should especially be counseled about the commonly used supplement black cohosh. There is not sufficient evidence that black cohosh improves menopausal symptoms and persistent use may lead to hepatotoxicity.

Fezolinetant, a novel neurokinin 3 receptor antagonist, is currently in phase 3 trials with promising results [112, 113]. Several clinical trials have demonstrated that use of NK3R antagonists is not only safe but associated with improved hot flash severity and frequency [112, 113]. This groundbreaking medication will likely become the treatment of choice for relief of vasomotor symptoms in women with contraindications to hormone therapy, who previously had very limited options for relief. 9.10.7

9.10.6

 eurokinin 3 Receptor N (NK3R) Antagonists

Emerging research regarding the physiology behind hot flashes has demonstrated that the thermoregulatory center in the brain is affected by several neuroendocrine influences, including the HPO axis and the hypothalamic expression of kisspeptin and neurokinin B (NKB) [111]. The loss of estrogen that occurs with menopause has been found to disrupt the thermoregulatory center in the hypothalamus through removal of negative feedback of neurokinin 3 receptor (NK3R) activation [111].

9.10.7.1

Treatment for Genitourinary Syndrome of Menopause Hormone Therapy for GSM Treatment

Treatment of GSM can be most effectively achieved through both systemic and local hormone therapies. Local hormone therapy can provide sufficient hormonal supplementation to relieve GSM with minimal systemic absorption. When systemic HT is needed, women may have resolution of GSM, though some may require additional low-dose vaginal hormone therapy to achieve adequate symptom relief (. Fig. 9.4).  

..      Table 9.12  Non-hormonal medication options [118] Generic

Brand names

Dosage

Notes

SSRI/SNRI Paroxetine Venlafaxine Desvenlafaxine Escitalopram Citalopram

Brisdelle Effexor Pristiq Lexapro Celexa

7.5 mg po daily 37.5, 75 mg po daily 50 mg po daily 5, 10 mg po daily 10, 20 mg po daily

Brisdelle is the only FDA-approved non-hormonal treatment for VMS Cannot use paroxetine in patients using tamoxifen because of cross-reaction between the drugs Lower dosages are more effective for hot flashes; higher doses may worsen VMS Fluoxetine and sertraline have not been shown to be as effective as the other SSRIs

Antihypertensive Clonidine

Catapres

0.1 mg daily po or patch

Can be useful in patients with high BP; however, use caution as these patients can get rebound HTN

Anticonvulsants Gabapentin Pregabalin

Neurontin Lyrica

300–900 mg total daily dose po 75–300 mg po daily

Can cause significant drowsiness in some women

Anticholinergic Oxybutynin

Ditropan

5 mg BID po

Can cause dry mouth, constipation, and worsening of acute angle glaucoma

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Is she menopausal?*

Is she permenopausal?

NO

YES Obtain DXA scan

Unknown

Counsel on non-hormonal treatment options

Bone health

- SERMs (I.e. raloxifene) - BIsphosphonates - Denosumab - Abaloparatice - Teriparatide - Romosozumab

NO

Stable or normal bones

Bone loss

Does she want HT?

Educate on Treatment options: hormonal and non-hormonal

VMS

YES

YES

Is she under 65 or within 10 years of menopause without contraindications to HT?

Evaluate and Treat: - CHCs - Cycled progesterone + -low dose E

NO

NO

Discuss na/a/se and non-hormonal options

Does she have a uterus?

YES

-SSRI/SNRIs - Clonidine - Gabapentin - Oxybutynin

Does she have systemic symptoms?

YES

Reassess annually or if symptoms change

YES

Does she have symptoms?

NO

What is her bone status?

NO

Start estrogen monotherapy**

Start estrogen + progestin therapy

Does she have persistent GSM symptoms?

NO

YES

Start vaginal HT: - Vaginal estrogen - Vaginal DHEA

9

..      Fig. 9.4  Treatment of menopause. CHCs combined hormonal contraceptives, DHEA dehydroepiandrosterone, DXA dual-energy X-ray absorptiometry, E estrogen, HT hormone therapy, GSM genitourinary syndrome of menopause, r/b/a/se risks, benefits, a­ lternatives, side effects, SERM selective estrogen receptor modulator,

SSRI selective serotonin reuptake inhibitor, SNRI serotonin-norepinephrine reuptake inhibitor. *Defined clinically as ≥12 months since LMP (see 10.9.1 Diagnosis for further details). **Consider estrogen+progestogen therapy in hysterectomized patient with a history of endometriosis if concerned for any remnant endometrial tissue

There are two main types of local hormone therapy currently available, vaginal estrogen and vaginal DHEA. Vaginal estrogen comes in several forms, including creams, rings, tablets, and inserts [87]. Vaginal DHEA comes in suppository form, though a ring formulation is currently in development. All of these FDA-approved products have proven efficacy in placebo-controlled trials to alleviate symptoms of vaginal dryness and dyspareunia [87]. Additionally, research has shown that with the use of both vaginal estrogen and vaginal DHEA, serum estradiol levels remain within postmenopausal range [87]. It is important for clinicians to know that the package insert boxed warning regard-

ing risk of endometrial cancer, breast cancer, CVD, and dementia that appears on systemic estrogen products is also seen in vaginal estrogen productions. Women must be educated about the differences between vaginal ET and systemic ET and should be informed about this box warning before they use the product so they are prepared (. Table 9.13).  

9.10.7.2

Non-hormonal Treatment for GSM

Non-hormonal options may be sufficient to relieve symptoms in some women, and would be an appropriate choice for those who do not wish to use local hormone therapy (. Table 9.14).  

227 Menopause

..      Table 9.13  Hormone therapy for the treatment of GSM [87, 116, 117] Generic

Brand name

Dosage

Notes

17β-Estradiol (bioidentical)

Estrace vaginal cream Generic

0.1 mg E/g 2–4 g/d × 1–2 weeks 1 g 1–3×/week

Conjugated equine estrogen

Premarin vaginal cream

0.625 mg CE/g 0.5–2 g/d for 2 weeks then then 0.5 g 2×/weekly

Estradiol hemihydrate

Vagifem vaginal tablet Generic Yuvafem vaginal tablet

0.01 mg Initial: 1 tablet/d × 2 weeks Maintenance: 1 tablet 2×/ week

Estradiol vaginal

Imvexxy vaginal insert

4mcg, 10 mcg Daily for 2 weeks then 2×/ week

FDA-approved

Vaginal DHEA (prasterone)

Intrarosa vaginal suppository

6.5 mg insert daily

Through intracrinological processes, genitourinary tissue takes up DHEA and processes it into androgens and estrogens, leading to improved dryness, urinary symptoms, and sexual function

Ospemifene (SERM)

Osphena

60 mg pill daily with food

FDA-approved for dyspareunia and dryness Not recommended for breast cancer survivors Can worsen VMS.

..      Table 9.14  Non-hormonal treatment options for GSM [87, 114] Type of therapy

Description

Mechanism of action

Duration of action

Notes

Moisturizers

Gel or cream Use regularly

Hydrophilic agents that coat the vagina and bring moisture to vaginal epithelial surface to maintain hydration and relieve dryness

Longer duration of action

Lubricants

Gel or cream (water vs. silicone vs. oil vs. hybrid) Use only prior to vaginal penetration

Moistens vaginal epithelium to improve dryness and alleviate dyspareunia prior to intercourse or medical examinations

Shorter duration of action

Silicone lubricants are more expensive, but typically last longer Water lubricants are easier to wash off Not all lubricants are condom compatible

MonaLisa Laser Therapy (experimental with FDA warnings issued)

Vaginal fractional carbon dioxide (CO2) laser

Produces new collagen and elastic fibers to remodel atrophic vaginal connective tissue

Longer duration of action

While women may experience improved symptoms with this treatment, there are no current well-powered studies that are sham procedure-controlled to confirm efficacy

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Conclusion

9

Menopause, whether premature, early, natural, or surgical, offers a key opportunity to clinicians and patients to chart the second half of female adult life with a focus on symptom control, risk assessment, and disease prevention. There are a multitude of hormonal and non-hormonal treatment options available. Women under age 65 and within 10  years of menopause are in the best situation to obtain both symptom control and increased longevity with the use of hormone therapy. However, regardless of time since menopause, vasomotor symptoms, bone tissue, and the genitourinary systems are responsive to HT. For maximal prevention and reduced risk, starting HT within 6–10 years of hormonal menopause is optimal, noting one cannot just rely on age and/or menstrual history to make the diagnosis of menopause.

9.11

Learning Assessment

9.11.1

Review Questions

?? 1.  Which of the following etiologies of POI causes the most significant physiological consequences and the most severe symptoms in women? A. Iatrogenic B. Infectious C. Surgical D. Autoimmune ?? 2. Estrogen has a multitude of functions in the body, including: A. Neuroprotective and neurotrophic effects on the brain B. Preserving blood supply, maintaining integrity, and supporting the microbiome of the vagina C. Bone protection through RANKLmediated antiresorptive effects D. All of the above ?? 3.  Which of the following statements about the diagnosis of menopause is not true?

A. Menopause is typically diagnosed retrospectively 12 months after the final menstrual period. B. There is a rare possibility of continued cycles even after a woman meets the criteria of the classic clinical definition of menopause. C. FSH and 17β-estradiol, which should always be interpreted together, can be helpful in confirming the diagnosis of menopause. D. The pico AMH diagnostic ELISA test is the most commonly used test to confirm the diagnosis of menopause. ?? 4.  Which of the following statements regarding systemic hormone therapy is not true? A. Women without a uterus can use estrogen therapy by itself. Women with an intact uterus must use E + P therapy. B. In accordance with the FDA-­ mandated black box warning, vaginal hormone therapy increases the risk of endometrial cancer, breast cancer, CVD, and dementia. C. There is only one FDA-approved SSRI for the treatment of vasomotor symptoms, Brisdelle (paroxetine 7.5 mg). D. NK3R antagonists will likely become the treatment of choice for relief of vasomotor symptoms in women with contraindications to hormone therapy.

9.11.2 vv 1. C vv 2. D vv 3. D vv 4. B

Answers

229 Menopause

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46. Mauvais-Jarvis F, Manson JE, Stevenson JC, Fonseca VA.  Menopausal hormone therapy and type 2 diabetes prevention: evidence, mechanisms, and clinical implications. Endocr Rev. 2017;38(3): 173–88. 47. Brady CW.  Liver disease in menopause. World J Gastroenterol. 2015;21(25):7613–20. 48. Tchaikovski SN, Rosing J.  Mechanisms of estrogen-­ induced venous thromboembolism. Thromb Res. 2010;126(1):5–11. 49. Guetta V, Cannon RO 3rd. Cardiovascular effects of estrogen and lipid-lowering therapies in postmenopausal women. Circulation. 1996;93(10):1928–37. 50. Caiazza F, Ryan EJ, Doherty G, Winter DC, Sheahan K.  Estrogen receptors and their implications in colorectal carcinogenesis. Front Oncol. 2015;5:19. 51. Hsu LH, Chu NM, Kao SH.  Estrogen, Estro gen Receptor and Lung Cancer. Int J Mol Sci. 2017;18(8):1713. 52. Real FG, Svanes C, Omenaas ER, Antò JM, Plana E, Jarvis D, Janson C, Neukirch F, Zemp E, Dratva J, Wjst M, Svanes K, Leynaert B, Sunyer J.  Lung function, respiratory symptoms, and the menopausal transition. J Allergy Clin Immunol. 2008;121(1):72–80.e3. 53. Campbell B, Davis SR, Abramson MJ, Mishra G, Handelsman DJ, Perret JL, Dharmage SC. Menopause, lung function and obstructive lung disease outcomes: a systematic review. Climacteric. 2018;21(1):3–12. 54. Shah MG, Maibach HI.  Estrogen and skin. An overview. Am J Clin Dermatol. 2001;2(3):143–50. 55. Wilkinson HN, Hardman MJ.  The role of estrogen in cutaneous ageing and repair. Maturitas. 2017;103:60–4. 56. Markopoulos MC, Kassi E, Alexandraki KI, Mastorakos G, Kaltsas G.  Hyperandrogenism after menopause. Eur J Endocrinol. 2015;172(2):R79–91. 57. Ogueta SB, Schwartz SD, Yamashita CK, Farber DB. Estrogen receptor in the human eye: influence of gender and age on gene expression. Invest Ophthalmol Vis Sci. 1999;40(9):1906–11. 58. Nuzzi R, Scalabrin S, Becco A, Panzica G. Gonadal hormones and retinal disorders: a review. Front Endocrinol (Lausanne). 2018;9:66. 59. Kelley C.  Estrogen and its effect on vaginal atrophy in post- menopausal women. Urol Nurs. 2007;27(1):40–5. 60. Labrie F, Martel C, Pelletier G.  Is vulvovaginal atrophy due to a lack of both estrogens and androgens? Menopause. 2017;24(4):452–61. 61. Lev-Sagie A. Vulvar and vaginal atrophy: physiology, clinical presentation, and treatment considerations. Clin Obstet Gynecol. 2015;58(3):476–91. 62. Shynlova O, Bortolini MA, Alarab M.  Genes responsible for vaginal extracellular matrix metabolism are modulated by women’s reproductive cycle and menopause. Int Braz J Urol. 2013;39(2): 257–67.

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63. Muhleisen AL, Herbst-Kralovetz MM.  Meno pause and the vaginal microbiome. Maturitas. 2016;91:42–50. 64. Chee WJY, Chew SY, Than LTL. Vaginal microbiota and the potential of lactobacillus derivatives in maintaining vaginal health. Microb Cell Factories. 2020;19(1):203. 65. Cardenas-Trowers O, Meyer I, Markland AD, Richter HE, Addis I.  A review of phytoestrogens and their association with pelvic floor conditions. Female Pelvic Med Reconstr Surg. 2018;24(3): 193–202. 66. Ismail SI, Bain C, Hagen S.  Oestrogens for treatment or prevention of pelvic organ prolapse in postmenopausal women. Cochrane Database Syst Rev. 2010;9:CD007063. 67. Blakeman PJ, Hilton P, Bulmer JN. Oestrogen and progesterone receptor expression in the female lower urinary tract, with reference to oestrogen status. BJU Int. 2000;86(1):32–8. 68. Waetjen LE, Johnson WO, Xing G, Feng WY, Greendale GA, Gold EB, Study of Women’s Health Across the Nation. Serum estradiol levels are not associated with urinary incontinence in midlife women transitioning through menopause. Menopause. 2011;18(12):1283–90. 69. Jung C, Brubaker L. The etiology and management of recurrent urinary tract infections in postmenopausal women. Climacteric. 2019;22(3):242–9. 70. Freeman EW, Sammel MD, Sanders RJ.  Risk of long-term hot flashes after natural menopause: evidence from the Penn ovarian aging study cohort. Menopause. 2014;21(9):924. 71. Low DA, Davis SL, Keller DM, Shibasaki M, Crandall CG.  Cutaneous and hemodynamic responses during hot flashes in symptomatic postmenopausal women. Menopause. 2008;15(2): 290–5. 72. Politi MC, Schleinitz MD, Col NF. Revisiting the duration of vasomotor symptoms of menopause: a meta-analysis. J Gen Intern Med. 2008;23(9): 1507–13. 73. Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol. 2013;34(3):211–27. 74. Thurston RC, Joffe H. Vasomotor symptoms and menopause: findings from the Study of Women’s Health Across the Nation. Obstet Gynecol Clin N Am. 2011;38(3):489–501. 75. Kravitz HM, Zhao X, Bromberger JT, et al. Sleep disturbance during the menopausal transition in a multi-ethnic community sample of women. Sleep. 2008;31(7):979–90. 76. Mishra GD, Chung HF, Pandeya N, et  al. The InterLACE study: design, data harmonization and characteristics across 20 studies on women’s health. Maturitas. 2016;92:176–85.

77. Chung HF, Pandeya N, Dobson AJ, et al. The role of sleep difficulties in the vasomotor menopausal symptoms and depressed mood relationships: an international pooled analysis of eight studies in the InterLACE consortium. Psychol Med. 2018;12:1–12. 78. Franco OH, Muka T, Colpani V, et  al. Vasomotor symptoms in women and cardiovascular risk markers: systematic review and meta- analysis. Maturitas. 2015;81(3):353–61. 79. Thurston RC, El Khoudary SR, Sutton-Tyrrell K, et al. Vasomotor symptoms and insulin resistance in the Study of Women’s Health Across the Nation. J Clin Endocrinol Metab. 2012;97(10):3487–94. 80. Thurston RC, El Khoudary SR, Sutton-Tyrrell K, et  al. Vasomotor symptoms and lipid profiles in women transitioning through menopause. Obstet Gynecol. 2012;119(4):753–61. 81. Jackson EA, El Khoudary SR, Crawford SL, et al. Hot flash frequency and blood pressure: data from the Study of Women’s Health Across the Nation. J Womens Health (Larchmt). 2016;25(12):1204–9. 82. Thurston RC, Chang Y, Barinas-Mitchell E, et  al. Menopausal hot flashes and carotid intima media thickness among midlife women. Stroke. 2016;47(12):2910–5. 83. Gast GC, Grobbee DE, Pop VJ, et al. Vasomotor symptoms are associated with a lower bone mineral density. Menopause. 2009;16(2):231–8. 84. Crandall CJ, Aragaki A, Cauley JA, et al. Associations of menopausal VMS with fracture incidence. J Clin Endocrinol Metab. 2015;100(2):524–34. 85. Moral E, Delgado JL, Carmona F, et al. Genitourinary syndrome of menopause. Prevalence and quality of life in Spanish postmenopausal women. The GENISSE study. Climacteric. 2018;21: 167–73. 86. US Food and Drug Administration. Guidance for industry: estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms: recommendations for clinical evaluation. 2003. http://www.­fda.­gov/ downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071643.­pdf. Accessed 9 Dec 2020. 87. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society. Menopause. 2020;27(9):976–92. 88. European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, Braat D, Cartwright B, Cifkova R, de Muinck Keizer-Schrama S, Hogervorst E, Janse F, Liao L, Vlaisavljevic V, Zillikens C, Vermeulen N. ESHRE guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31(5):926–37. 89. Qu X, Cheng Z, Yang W, Xu L, Dai H, Hu L. Controlled clinical trial assessing the effect of laparoscopic uterine arterial occlusion on ovarian reserve. J Minim Invasive Gynecol. 2010;17(1):47–52.

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90. Moolhuijsen LME, Visser JA.  Anti-Müllerian hormone and ovarian reserve: update on assessing ovarian function. J Clin Endocrinol Metab. 2020;105(11):3361–73. 91. The NAMS 2017 Hormone Therapy Posi tion Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24(7):728–53. 92. Mashchak CA, Lobo RA, Dozono-Takano R, et  al. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol. 1982;144(5):511–8. 93. Smith T, Sahni S, Thacker HL.  Postmeno pausal hormone therapy-local and systemic: a pharmacologic perspective. J Clin Pharmacol. 2020;60(Suppl 2):S74–85. 94. Gartlehner G, Patel SV, Feltner C, Weber RP, Long R, Mullican K, Boland E, Lux L, Viswanathan M. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2017;318(22):2234–49. 95. Henderson VW, Lobo RA.  Hormone therapy and the risk of stroke: perspectives 10 years after the Women's Health Initiative trials. Climacteric. 2012;15(3):229–34. 96. Rossouw JE, Anderson GL, Prentice RL, et  al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–33. 97. Manson JE, Chlebowski RT, Stefanick ML, et  al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310(13): 1353–68. 98. Manson JE, Aragaki AK, Rossouw JE, et  al. Menopausal hormone therapy and Long-term all-cause and cause-specific mortality: the women’s health initiative randomized trials. JAMA. 2017;318(10):927–38. 99. Santoro N, Allshouse A, Neal-Perry G, et  al. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause. 2017;24(3):238–46. 100. Hodis HN, Mack WJ, Henderson VW, ELITE Research Group, et  al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221–31. 101. Crawford SL, Crandall CJ, Derby CA, El Khoudary SR, Waetjen LE, Fischer M, Joffe H.  Menopausal hormone therapy trends before versus after 2002: impact of the Women’s Health Initiative Study Results. Menopause. 2018;26(6):588–97.

102. Manson JE, Aragaki AK, Rossouw JE, et  al. Menopausal hormone therapy and long-term all-­ cause and cause-specific mortality. Obstet Gynecol Surv. 2018;73(1):22–4. 103. Hodis HN, Sarrel PM.  Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials? Climacteric. 2018;21(6):521–8. 104. Mosekilde L, Hermann AP, Beck-Nielsen H, Charles P, Nielsen SP, Sørensen OH. The Danish Osteoporosis Prevention Study (DOPS): project design and inclusion of 2000 normal perimenopausal women. Maturitas. 1999;31(3):207–19. 105. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810. 106. Anagnostis P, Galanis P, Chatzistergiou V, et al. The effect of hormone replacement therapy and tibolone on lipoprotein concentrations in postmenopausal women: a systematic review and meta-analysis. Maturitas. 2017;99:27–36. 107. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012;345:e6409. 108. Sarrel PM, Njike VY, Vinante V, Katz DL.  The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59 years. Am J Public Health. 2013;103(9):1583–8. 109. Mikkola TS, Tuomikoski P, Lyytinen H, et  al. Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality. Menopause. 2015;22(9):976–83. 110. Rivera CM, Grossardt BR, Rhodes DJ, et  al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause. 2009;16(1): 15–23. 111. Modi M, Dhillo WS.  Neurokinin 3 receptor antagonism: a novel treatment for menopausal hot flushes. Neuroendocrinology. 2019;109(3):242–8. 112. Fraser GL, Lederman S, Waldbaum A, Kroll R, Santoro N, Lee M, Skillern L, Ramael S.  A phase 2b, randomized, placebo-controlled, ­double-­blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause. Menopause. 2020;27(4):382–92. 113. Santoro N, Waldbaum A, Lederman S, Kroll R, Fraser GL, Lademacher C, Skillern L, Young J, Ramael S.  Effect of the neurokinin 3 receptor antagonist fezolinetant on patient-reported outcomes in postmenopausal women with vasomotor symptoms: results of a randomized, placebo-controlled, double-blind, dose-ranging study (VESTA). Menopause. 2020;27(12):1350–6. 114. Cruff J, Khandwala S.  A double-blind randomized sham-controlled trial to evaluate the efficacy

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of fractional carbon dioxide laser therapy on genitourinary syndrome of menopause. J Sex Med. 2021;18(4):761–9. 115. Torrealday S, Pal L. Premature menopause. Endocrinol Metab Clin North Am. 2015;44(3):543–57. https://doi.org/10.1016/j.ecl.2015.05.004. Epub 2015 Jun 22. 116. U.S. Food and Drug Administration. Orange Book: approved drug products with therapeutic equivalence evaluations. https://www.accessdata.

fda.gov/scripts/cder/ob/search_product.cfm. Accessed 29 Apr 2021. 117. Pinkerton JA, Estrogen therapy and estrogen progestogen therapy. In: The North American Menopause Society. Menopause practice: a clinician’s guide. 6th edn. Pepper Pike: The North American Menopause Society; 2019. p. 284–303. 118. Carrol D. Nonhormonal therapies for hot flashes in menopause. Am Fam Physician. 2006;73(3):457–64.

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Osteoporosis Tiffany M. Cochran and Holly L. Thacker Contents 10.1

Definition and History of Osteoporosis – 237

10.2

Epidemiology – 238

10.3

Pathophysiology – 239

10.4

 enopause Transition and Its Effect M on Bone – 240

10.5

Premenopausal and Bone Health – 241

10.5.1 10.5.2

 ypothalamic Amenorrhea and Bone Health – 241 H Female Athlete Triad and Bone Health – 242

10.6

Classification of Osteoporosis – 243

10.6.1 10.6.2

 rimary Osteoporosis – 243 P Secondary Osteoporosis – 243

10.7

Clinical Symptoms of Osteoporosis – 244

10.8

Diagnostic Criteria for Osteoporosis – 246

10.9

Osteoporosis Treatment – 249

10.9.1

 onpharmacologic Modalities for Osteoporosis N Prevention – 249 Pharmacologic Therapies for Treatment and Prevention of Osteoporosis – 250 Antiresorptive Therapies – 250 Anabolic Therapies – 255

10.9.2 10.9.3 10.9.4

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 T. Falcone, W. W. Hurd (eds.), Clinical Reproductive Medicine and Surgery, https://doi.org/10.1007/978-3-030-99596-6_10

10

10.10 Combination Therapy – 256 10.11 Monitoring Bone Health – 256 10.12 When to Consider a Drug Holiday – 257 10.13 Barriers to Effective OP Medications – 257 10.14 When to Refer to Osteoporosis Specialist – 258 10.15 Review Questions – 258 10.16 Answers – 260 References – 260

237 Osteoporosis

Key Points 55 Osteoporosis is a global pandemic and a growing public health concern, significantly affecting women as one in three women will have at least one fragility fracture. 55 Often, women with established osteoporosis are underdiagnosed and undertreated. 55 The diagnosis of osteoporosis can be made by history of fragility fracture, based on fracture risk prediction tools, or BMD testing in the appropriate setting. 55 Women who are being evaluated and treated for osteoporosis should have a thorough evaluation of relevant risk factors or other secondary causes of low bone mass. Then, appropriately monitor and follow to ensure optimal treatment. 55 Fragility fracture should raise suspicion for osteoporosis and warrants optimal therapeutic intervention. 55 There are many effective treatment options, including hormonal therapy, which is the only therapy shown to reduce vertebral, hip, and non-vertebral fractures as a preventive treatment. 55 Nonadherence is a significant barrier to effective treatments, and evidence shows good counseling and patient education can improve the continuation of therapy. 55 Consider referring to an osteoporosis specialist for women with unusual features or difficult-to-treat disease for appropriate evaluation.

Case Vignette

A 48-year-old G3P2 white woman with unremarkable past medical history presents to your clinic concern about her bone health. She has not had any fractures after turning 40. Her mother has osteoporosis treated previously with ibandronate. She

has two sisters with osteopenia. Given her family history of osteoporosis, she has a bone density scan done, which is normal. She experiences mild, tolerable hot flashes occasionally during the day, one to two times weekly. She is amenorrheic with Mirena IUD.  Obstetric history is remarkable for two spontaneous vaginal deliveries with no pregnancy complications. She had her menarche at age 13. She has a history of regular menses without a uterine bleeding disorder. She was on oral contraceptives for about 10 years and was well-tolerated without developing venous thromboembolism or gallbladder problems. Her paternal grandmother was diagnosed with breast cancer in her 60s and a paternal aunt deceased in her 40s from breast cancer. She has no known genetic mutations. She has a personal history of abnormal mammograms remarkable for fibrocystic breast but never had breast biopsy. She had a recent normal mammogram. She has no history of hypertension, diabetes mellitus, stroke, or myocardial infarction. She is a nonsmoker. She has no personal or familial history of venous thromboembolism or prothrombotic mutations.

10.1

Definition and History of Osteoporosis

Osteoporosis is the most frequent chronic disease of the skeleton, characterized by a reduction in the quantity and quality of bone, and altered microarchitecture, resulting in decreased bone strength and increased risk of fracture [1–4]. These fractures, often occurring with little or no trauma, are diagnostic of skeletal fragility, which in conjunction with classification by the bone mineral density (BMD) criteria form the basis for this diagnosis in clinical practice. The burden of illness associated with fragility fractures for children, men, and women worldwide is enormous, growing, and similar or greater to other noncommunicable diseases such as cardiovascular disease and cancer [1–8]. The remainder of

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this chapter will focus primarily on this illness in women. In 1833, German-born French pathologist and surgeon Dr. Jean Lobstein coined the term osteoporosis following his description of pathologic diseased bones with holes in the bone microarchitectural structure causing increased bone weakness [9]. As far back as the 1880s, women were noted to have a greater tendency for osteoporosis than men, possibly due to greater longevity and earlier onset [9]. At that time, the link to the postmenopausal state was unknown. In the 1940s, American endocrinologist Dr. Fuller Albright’s observations linked estrogen’s role in regulating bone metabolism for both women and men [9]. Dr. Albright treated these women that had hypocalcemia and bone disease with estrogen, demonstrating significant improved calcium metabolism and bone health [9]. Osteoporosis existence in antiquity has been established using analyses of archaeological skeletal remains. These remains show similar age-­ matched femoral neck bone mineral density (BMD), rates of decline in bone strength indices, and differential BMD values between those with and without fractures to modern populations [10].

10.2

Epidemiology

Osteoporosis is a global pandemic, representing an enormous growing public health concern worldwide. This disease affects people across race, gender, and regions, in part due to the aging of the world’s population [2, 11]. Affected people remain asymptomatic until a fracture happens [2, 3, 11]. Although most fractures occur in postmenopausal women, males and females of all ages may suffer a broken bone. Today, one in three women and one in six men will sustain at least one fragility fracture before they die [4]. Although the entire skeleton is at risk, the vertebrae represent the most frequently injured site [12]. This disease results in more than two million people with a fragility fracture requiring hospitalization per year at a cost of $70 billion

US [13, 14]. In Europe, approximately four million major osteoporotic fractures occur each year at a cost of almost €60 billion [1, 4]. All clinical fractures result in some burden of illness, can be life-threatening and costly, and represent a leading cause of pain, disability, and loss of independence [1–4, 15–18]. Clinical vertebral and hip fractures are among the most devastating, whose impact on patients’ quality of life and independence may persist long after the fracture [11, 15, 18]. The impact of radial and other major fractures is less dramatic and associated with a greater recovery [19]. These fractures are sentinel events, multifactorial in origin and associated with a severalfold risk of subsequent fracture in the next few years [20–22]. Fractures are associated with increased mortality, though the attributable portion may be small and varies between people and fracture location [16–17, 23–27]. Hip and clinical vertebral fractures have the worst prognosis [26], with up to one in three individuals dying in the year following these events in population studies [17, 23, 24]. Clinical trial populations are younger, with fewer comorbidities, and have much lower rates [27]. Despite the immense advances in osteoporosis treatment, a treatment gap exists for patients at high risk for osteoporosis [11]. Osteoporosis affects postmenopausal women more than the diagnosis of stroke, myocardial infarction, or breast cancer combined [28]. An estimated one in two postmenopausal women will experience a fragility osteoporosis-related fracture during their lifetime [13]. Limited opportunity is given for patients to discuss the risk of fracture or bone health. Even now, for postmenopausal women, osteoporotic fractures are underdiagnosed and undertreated despite multiple known and efficacious therapies and treatment strategies for osteoporosis treatment [28]. Clinicians need to identify and treat patients at high risk for fracture for effective utilization of these treatments, thus emphasizing the need for continued education for clinicians to become competent in identifying, managing, and monitoring osteoporosis.

239 Osteoporosis

Pathophysiology

than premenopausal women, and this production decreased with estrogen therapy [32]. Specialized cells and a mineralized matrix of Whether through direct or indirect effects, salts form skeletal bone. Cortical bone makes estrogen deficiency increases RANKL proup about 80% of the skeleton, including long duction, and thus fuel increased bone resorpbones such as femur, tibia, vertebral shell, and tion. Denosumab, one of the treatments for flat bones’ surfaces. Trabecular bone makes osteoporosis, acts at this level by acting as an up the axial skeleton and has a distinct honey-­ antibody to RANKL and will be discussed later in this chapter. combed appearance. The Wnt/B catenin signaling pathway is Skeletal bone is continually being turnover now known to have a prominent role in reguwith bone destruction by osteoclast and forlating bone formation and a possible mediator mation of new bone by osteoblast. This highly of skeletal remodeling. Sclerostin, an dynamic process occurs throughout life at difosteocyte-­ s pecific protein, decreases bone forferent skeletal sites in response to changes in mation by blocking Wnt signaling [33]. The systemic signaling. Osteoblast, osteoclast, drug romosozumab acts by blocking sclerosand osteocytes assemble into anatomic structin, leading to increased bone mass, and is distures called basic multicellular units (BMUs). cussed later in this chapter. Osteoclasts migrate to various sites in the Estrogen and androgens influence skeletal skeleton from the circulation and erode into development, maturation, and maintenance the bone surface, creating deep cavities named for both females and males. Androgen pro“resorption pits.” This process happens over duction for women happens primarily via several weeks. Following the formation of conversion in peripheral tissues with smaller resorption pits, osteoblasts replace osteoclasts amounts from the ovaries and adrenal to build new bone to restore the eroded bone glands [32]. Skeletal differences between men surface over a few months steadily. Naturally, and women are related to differences in estrothis bone remodeling process occurs synchrogen and testosterone serum levels and tissue nously to sustain a healthy, intact skeleton. response to these hormones. Testosterone is Various factors (such as regulatory genes, known to act directly on osteoclast progeniseveral cytokines, and hormones including estrogen, testosterone, vitamin D, and para- tors and mature osteoclasts to decrease osteothyroid) can influence the systemic signaling, clast production along with bolstering possibly uncoupling this remodeling process osteoclast apoptosis [32]. Testosterone also [29, 30]. It is unknown the exact sequence of stimulates osteoblast proliferation. Studies in events caused by estrogen deficiency. However, mice with androgen receptor deletion resulted various studies established that estrogen medi- in decreased trabecular bone mass without ates the production of specific cytokines affecting cortical bone mass, with a milder blocking the action of tumor necrosis factor-­ effect in female mice [32]. Overall, androgens alpha (TNFa) and, to a lesser extent, interleu- increase bone formation and less bone resorpkin-­ 1 beta (IL-1B). This effect leads to tion through less known mechanisms, even increased osteoprotegerin (OPG), resulting in though it plays a minimal role compared to less bone resorption and reduced osteoclast estrogen. Furthermore, peak bone mass (PBM) differentiation. 1,25-Hydroxyvitamin D determines bone mineral density (BMD) and potentiates the action of OPG [31]. The recepstrongly correlates with fracturing risk at any tor activator of nuclear factor kappa beta given age. Bone mass is the total bone gained (RANK) binds to the RANK ligand. Thus, during childhood and adolescence minus TNFa, OPG, RANK, and RANKL all influbone loss with advanced aging. Maximal bone ence skeletal remodeling [29, 32]. Khosla and mass accrual is considered reached by age Monroe designed a study showing RANKL 18  in many or young adulthood, with rapid production increased by two- to threefold in bone mass obtained during puberty [34, 35]. It estrogen-deficient postmenopausal women 10.3

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is suggested that about 94% of BMD is gained at age 16 [30]. PBM is deemed as being achieved during the second and third decades of life [35]. However, timing is controversial as it is gender- and site-dependent, one study suggesting PBM occurs in the hip for women between ages 16 and 19 [35, 36]. Various factors can influence PBM attained, including genetics and race, endocrine disorders, nutrition (calcium and vitamin D), physical activity, exposure to risk factors (e.g., smoking and alcohol intake while rare), specific medical diseases, and medications [35, 36]. Conditions affecting bone growth and mineralization during childhood, puberty, or adolescence will result in less PBM than expected for an individual. Hence, a 6.4% loss of bone mass during childhood has an associated twofold fracture risk in adulthood [35]. Osteoporosis is delayed by 13 years with a ten percent gain in bone mass [35]. Women with low PBM possibly failed to reach peak genetic potential bone mass by the mid-30s due to processes causing bone loss at an earlier age than usually seen [36]. For that reason, puberty and adolescence are crucial periods for attaining optimal PBM.  Any interruption of normal physiology by illness or other factors may result in lower PBM reached, affecting future bone strength and risk for osteoporosis. Optimal PBM achievement is usually a multifactorial process. Heredity greatly influences acquired PBM, accounting for most BMD variability and the most influential determinant of PBM in adulthood. Various genetic polymorphisms and syndromes have been identified to play an essential role in the variance of PBM. A genome-wide association study (GWAS) identified several genes and variants in children and young adults. For example, the CPED1-WNT16-FAM3C gene locus is linked to wrist BMD, bone strength, cortical thickness, and forearm fracture risk in adults, and PBM in premenopausal women, and accrued bone mass and fracture risk in elderly patients in Europe [30]. Genetic variances can influence BMD throughout a person’s entire lifetime. PBM differs among ethnic groups. Compared to white women, black women have the highest areal BMD, decreased corti-

cal porosity, increased trabecular thickness, higher cortical thickness, and appreciable bone strength [37]. For that reason, black women have lower hip fractures after adjusting for BMI and DXA BMD [37]. Lower BMD was observed in Chinese and Malaysian women compared to Indian women [37]. Intriguingly enough, Asian women still had lower hip fracture rates compared to white women. BMD variation results from genetic differences among racial groups, local environmental factors, individual body weight, skeletal size, and microarchitecture [37]. 10.4

Menopause Transition and Its Effect on Bone

Estrogen maintains bone mass by decreasing bone turnover and sustaining the coupling of bone remodeling through stimulation of osteoclast apoptosis. After menopause and with aging, the bone remodeling process favors more bone resorption causing more bone loss. This decrease in BMD happens at an expeditious rate in women with a higher prevalence in older, inactive women. There is about a 2% bone loss annually, starting 1–3 years preceding menopause and continuing for 5–10  years [38]. Nearly 20% of bone loss occurs during the menopause transition, with an average loss of BMD of 10%–12% in the spine and hip across the menopause transition [38, 39]. Higher rates of bone loss happen in postmenopausal women who are thin weight compared to overweight. Following this period of accelerated bone loss, the rate plateaus to an annual 0.5% loss in bone density and continues even into advanced age. Women aged 80 years have lost roughly 30% of their peak bone mass consequence of this remodeling imbalance [3]. The Study of Women’s Health Across the Nation (SWAN) is one of the largest racially and ethnically diverse cohorts, following more than 2000 women over 20 years across 5 clinical centers in the United States and observed changes in women’s bone health throughout menopause transition [34]. The SWAN study showed increased bone resorption 2 years before the final menstrual period (FMP),

241 Osteoporosis

peaking at about 1.5 years after the FMP, followed by a plateau of bone loss [34]. Simultaneously, there is an acceleration of bone loss occurring 3 years before FMP [34]. A gradual decline in bone loss occurs around 2 years following FMP [34]. During the 3 years of rapid bone loss occurring in the early part of the menopause transition, the BMD decline rate occurred in white women at an estimated annual rate of 2.5% in the lumbar spine and 1.8% in the femoral neck [34]. Chinese women and Japanese women had a substantially increased bone loss at the femoral neck at about an annual rate of 2.2% and 2.1%, respectively [34]. After adjusting for body mass index (BMI), black women had a small-­ scale BMD loss at both spine (2.2% per year) and femoral neck (1.4% per year) [34]. As expected, changes in estrogen and testosterone serum levels drive these changes in bone mass. In the SWAN study, every doubling of FSH during menopause transition equated to an additional 0.3% decline in BMD at both femoral neck and lumbar spine  [34]. Women with vasomotor symptoms (such as hot flashes and night sweats) had lower BMD correlating with a steeper decline in estrogen.

10.5

Premenopausal and Bone Health

Pregnancy may cause three to five percent loss of bone mass [40]. Pregnancy-induced osteoporosis happens very infrequently, causing substantial trabecular bone loss and fragility fractures, particularly of the spine. It usually spares the cortical bone. Advanced maternal age heightens the risk for osteoporosis with pregnancy. Rare observational studies suggested physiological changes related to ­ pregnancy alter serum calcium and phosphate levels, leading to increased calcium metabolism [41, 42]. The placenta, lactating mammary glands, and fetal parathyroid gland produce parathyroid hormone-related protein (PTHrP), which mobilizes calcium from the skeleton through resorption activity by osteoclasts [41, 42]. This mechanism allows the body to maintain calcium levels despite

increased demands from the fetus and later from lactation. The mainstay treatment is calcium and vitamin D supplementation. The safety of certain anti-osteoporotic drugs during pregnancy is not fully known. Bisphosphonates can impact fetal bone formation based on a few studies observing mothers receiving various bisphosphonates for secondary osteoporosis before or throughout pregnancy without witnessing adverse effects [41]. Bisphosphonate use in pregnancy has to be balanced against risks. Raloxifene is not recommended in premenopausal women. Denosumab can cause fetal harm, so it is important to avoid use in pregnancy [41]. Teriparatide cannot be used during pregnancy as it can affect open epiphyseal bone formation [41]. Primary hyperparathyroidism during pregnancy is managed conservatively by observing unless significantly elevated calcium. Then, surgery is preferably done in the second trimester [41]. Lactation may cause temporary bone loss and elevated bone turnover markers, especially during the exclusive breastfeeding stage. It occurs within the first few weeks of lactation with longitudinal studies demonstrating decrease in the femoral neck and lumbar spine bone mass of two to six percent within the first months of lactations [43, 44]. It is suggested that the elevation of prolactin prolonged suppression of the hypothalamic-pituitary-ovarian axis results in amenorrhea due to a generated hypoestrogenic state [43]. The lactating mammary glands also secrete PTHrP, decreasing the efficiency of intestinal calcium absorption. 10.5.1

Hypothalamic Amenorrhea and Bone Health

Hypothalamic amenorrhea impacts bone health due to estrogen deficiency, causing a cascade of hormonal signaling resulting in an upsurge in bone resorption. Hypothalamic amenorrhea frequently causes amenorrhea in young women besides pregnancy. Multiple factors can contribute to hypothalamic amenorrhea, such as ovarian dysfunction, pituitary

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T. M. Cochran and H. L. Thacker

disorders, hypothalamic disorders, polycystic ovarian syndrome, and endocrine disorders [45]. Iatrogenic causes stem from a created hypoestrogenic state seen with depot medroxyprogesterone acetate (DMPA) and gonadotropin-­ releasing hormone (GnRH) agonist. Exogenous use of androgens can also lead to hypothalamic amenorrhea. The next following sections will delve into these factors mentioned earlier. Hormonal contraception that suppresses normal ovulatory cycles potentially has a negative bone effect as it creates a hypoestrogenic state, a clinical risk factor for bone loss or osteoporotic fracture. A recent Cochrane review highlighted certain hormonal contraceptives which posed a higher risk of negatively impacting bone health, particularly depot medroxyprogesterone acetate (DMPA) and etonogestrel implant [46]. Its effect appears reversibly primarily with discontinuation. A retrospective cohort study found higher fracture risk associated with recent use of DMPA for less than 2 years or exceeding 2 years of cumulative use [47]. There was no increased fracture risk in women with past DMPA usage [47]. There is a lower fracture risk using combined oral contraceptive pills [47]. If choosing a hormonal contraceptive, select an option that will allow for some ovulatory activity if possible. For combined oral contraceptive pills, better to choose an estrogen dose between 30 and 35 mcg as it is less likely to result in a hypoestrogenic state [46, 47]. There is a boxed warning on DMPA that, if administered for over 2 years, a baseline evaluation of BMD should be obtained. If the BMD test is low for age-matched peers, then a secondary evaluation should be done with add-back estradiol, and repeat BMD in 2 years if the woman continues on that mode of contraception [47]. 10.5.2

 emale Athlete Triad F and Bone Health

The female athlete triad (Triad) was first coined by the American College of Sports Medicine in 1992 [48]. It is a disorder with three compo-

nents: amenorrhea, low energy availability, and osteoporosis. Women participants of esthetic and weight-dependent sports (e.g., ice skating, weight lifting, gymnastics, and endurance running) were thought to be the most often affected [48]. Over time, this Triad became more of a spectrum as athletes do not always present with all three clinical features. Excessive exercise generates an energy deficit limiting fuel availability. Then, energy is shunted from bodily growth and reproduction to metabolic processes for survival and homeostasis for energy conservation [48, 49]. Consequently, there is a decrease in the metabolic rate of total triiodothyronine (TT3), insulin-like growth factor 1 (IGF-1), leptin, and insulin [49]. This process leads to a hypoestrogenic state inducing amenorrhea. As discussed earlier, estrogen deficiency brings about more bone resorption due to the indirect effect on hormonal signaling and influencing bone remodeling. Eating disorders are suggested as another plausible explanation for low energy availability [48, 49]. Athletes have a higher prevalence of eating disorders than the general population, especially sports preferring lean body image such as figure skating and gymnastics or ballerina dancers [48]. The eating disorder behaviors may not limit to just restrictive or purging eating patterns. It is imperative to identify at-risk individuals for eating disorder behaviors as the outcome results in decreased energy availability affecting the hypothalamic-­ pituitary-­ gonadal axis and ultimately bone health [48]. Experimental studies conducted by Dr. Loucks, Dr. Bullen, and Dr. Williams showed evidence of menstrual disruption caused by changes in energy availability. The random controlled trials of Bullen et al. and Williams et al. observed a mild to a modest reduction in energy availability equated to markedly suppression of metabolic hormones, suppressive luteinizing hormone (LH) pulse frequency, and the onset of abnormal menstrual cycles [49]. Early studies performed by Dr. Loucks showed significant hormonal dysfunction if energy availability was less than 30 kcal/kg/fat-free

243 Osteoporosis

mass (FFM), with minimal dysfunction seen at 45  kcal/kg/FFM [48, 49]. The minimum energy availability needed is 30  kcal/kg/ FFM, with 45 kcal/kg/FFM being ideal [48]. In fact, it varies per individual based on their energy needs and availability. With the considerable rise in female participation in sports, clinicians must be aware of the Triad due to short-term and long-term health consequences. One associated short-­ term consequence is stress-related fractures due to weakening bone [48, 50, 51]. A long-­ term aftereffect is the higher risk for osteoporosis due to decreased bone mass related to delayed menarche with recommended hormonal therapy to mitigate this risk [51, 52]. The goal is to have an athlete with optimal bone health, optimal energy availability, and regular menstrual cycles with menarche at an appropriate time [48].

10

..      Table 10.1  Summary of clinical risk factors for osteoporosis Non-modifiable risks

Modifiable risks

Age

Tobacco use

Gender

Excessive alcohol use (>2 drinks per day for women)

Race/Ethnicity

Caffeine intake (>3 cups coffee per day)

Family history of osteo­ porosis

Glucocorticoid use (>5 mg prednisone daily or equivalent ≥ 3 months)

Lower peak bone mass

Vitamin D deficiency

Lower body mass index

Low body weight (BMI 5 mg prednisone daily or equivalent ≥ 3 months)

Cortisone, prednisone, and methylprednisolone

Thyroid supplementation

Levothyroxine (Synthroid)

Pain medications

Opioids (oxycodone and hydrocodone) Nonsteroidal anti-­inflammatory (NSAIDs)

Refs. [51, 52] an exhaustive list of medications bLow molecular weight heparin (LMWH) aNot

Obtain at minimal a complete comprehensive metabolic panel, total blood count, thyroid-­stimulating hormone (TSH), 24-hour calcium urine collection for calcium excretion, and a 25-hydroxyvitamin D level in all patients (54–55). Whether radiographic imaging or other laboratory studies, such as serum and urine protein electrophoresis, parathyroid hormone, or cortisol levels, should be undertaken is a decision that needs to be taken by the individual physician, as ancillary

testing should be based upon the clinical impression.

10.7

Clinical Symptoms of Osteoporosis

Individuals with osteoporosis routinely present first with fracture as it is most often a symptom-free and painless condition. Over

10

245 Osteoporosis

..      Table 10.3  Common causes of secondary osteoporosis Laboratory evaluation Drug-­ induced

For example, aromatase inhibitors, anticonvulsants, and chronic steroids

Medication reconciliation – revisit . Table 10.1

Nutritional disorders

Anorexia Malnutrition

Comprehensive metabolic panel 25-Hydroxyvitamin D serum level 24-hour calcium urine

Genetic

Turner’s syndrome Gaucher’s disease Cystic fibrosis Muscular dystrophy Marfan syndrome Osteogenesis imperfecta Ehlers-Danlos syndrome

Appropriate genetic testing

Endocrine/ Hormonal

Hyperparathyroidism Hypophosphatemia Vitamin D deficiency Hypothalamic dysfunctions Hypercortisolism (Cushing’s syndrome) Hypogonadism Type 1 and 2 Diabetes Mellitus Pregnancy Lactation Amenorrhea Hypercalciuria Hypothyroidism

Parathyroid hormone, phosphorus serum level, 25-hydroxyvitamin D serum level, FSHa, estradiol level, prolactin, anti-Müllerian hormone, 24-hour urinary free cortisol, dexamethasone suppression test, Hgb A1c, fasting glucose, glucose intolerance test, 24-hour calcium urine, TSH, free T4, total T3

Gastrointestinal

Malabsorption Inflammatory bowel disease (Crohn’s disease and Ulcerative colitis) Celiac disease

Endomysial IgA antibody, anti-tissue transglutaminase, anti-­deamidated gliadin peptide IgG antibodies, serum total iron binding capacity, transferrin, serum ferritin level, comprehensive metabolic panel, 25-hydroxyvitamin D serum level, 24-hour calcium urine, sweat chloride testing or genetic testing

Hematologic disorders

Hemochromatosis Thalassemia major Multiple myeloma

Serum total iron binding capacity, transferrin, serum ferritin level, comprehensive metabolic panel, hemoglobin electrophoresis, protein electrophoresis, serum electrophoresis

Inflammatory disorders

SLEb Rheumatoid arthritis Chronic obstructive lung disease

Antinuclear antibodies, anti-double-stranded DNA, anti-Smith antigens, anti-cyclic citrullinated antibodies, rheumatoid factor

Connective Tissue disorders

Marfan syndrome Osteoporosis imperfecta Ehlers-Danlos Syndrome

 

Organ transplant Renal disease

Chronic renal failure

Renal function test (continued)

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T. M. Cochran and H. L. Thacker

..      Table 10.3 (continued) Laboratory evaluation Immobility

Multiple sclerosis Muscular dystrophy Bedbound individuals Stroke Quadriplegia Space Flight

Refs. [51, 52] aFollicle-stimulating bSystemic

10

hormone (FSH) lupus erythematosus (SLE)

two-thirds of vertebral fractures are clinically silent and incidentally detected on imaging, not once capturing medical attention [55, 56]. Often sites for fractures involve the spine, hip, distal forearm, or proximal humerus. A clinician may palpate a collapsed vertebrae on physical exam, discern a stooped posture (kyphosis or dowager’s hump), notice a bluish tint to sclerae (hallmark for osteogenesis imperfecta), the clinical manifestation of adrenal insufficiency (e.g., abdomen with striae, buffalo hump of posterior neck, moon facies), or conclude an unremarkable physical exam. Women with osteoporosis frequently lose a significant amount of height, deemed as height loss greater than 4 cm or more than 1.5 inches. Clinicians should ask about back pain, height loss, dietary calcium intake, dental health, age of menarche and age of menopause, history of eating disorder, menstrual cycle history, smoking history, alcohol consumption, and caffeine intake and screen for medications. It is also practical to screen for fracture risk such as poor vision, history of falls, or complete fall risk assessment. 10.8

Diagnostic Criteria for Osteoporosis

A thorough history and physical exam are invaluable in diagnosing osteoporosis. Assess for risk factors for bone loss (see . Table 10.1), including female gender, small body frame or low body mass index (BMI), prior fragility  

fracture, and family history of osteoporosis, and inspect for medications predisposing for bone loss. Obtain an accurate weight and height to calculate BMI and analyze for drastic weight or height loss. The gold standard for diagnosing osteoporosis is the standard measuring of BMD with a central dual-energy X-ray absorptiometry (DXA) of the spine and hip as noninvasive and quickly performed. The forearm is only useable when the spine or hip is unmeasurable or BMD data uninterpretable. DXA calculates T- and Z-scores, expressions of BMD in standard deviations to a distributed reference population compared to a population matched by age, gender, and race. T-score compares BMD to young, healthy Caucasian women at peak bone mass. Z-score compares persons to age, gender, and racially matched control populations. Specific BMD and T-score criteria by the World Health Organization (WHO) for diagnosis of osteopenia and osteoporosis are outlined in . Table  10.4 [57, 58]. DXA studies have shown a substantial correlation to biomechanical bone strength through finite element analysis and a clinical predictor of fracture risk, all with low-­ radiation exposure [59]. DXA and clinical risk tools used conjointly can remarkably identify persons at high fracture risk. Nevertheless, DXA is limited in assessing bone microarchitecture. Although not commonly obtained in clinical practice, other modalities are obtainable to evaluate bone quality, such as high-­resolution quantitative computed tomography (QCT), high 

247 Osteoporosis

resolution magnetic resonance imaging (MRI), or double tetracycline-labeled transiliac bone biopsy histomorphometry [59–61]. Trabecular bone score (TBS) and vertebral fracture assessment (VFA) are possible tools used conjunctly with DXA to provide data on bone quality. TBS is an analytical tool calculator that uses lumbar spine images from DXA to estimate bone microarchitecture, expressed as a score quantifying variation among pixels and not an exact dimensional measurement [59, 62]. VFA utilizes DXA to detect vertebral fractures owning to persons not meeting criteria for osteoporosis based on BMD alone [59, 63]. This additional data from TBS and VFA can influence an individual’s decision on starting and adhering to treatment. Various organizations (such as the International Society for Clinical Densitometry

(ISCD) and the American Association of Clinical Endocrinology (AACE)) recommend BMD evaluation for the following individuals [64–66]: 55 All women 65 and older 55 Younger postmenopausal women with risk factors for osteoporosis (e.g., smoker, fragility fracture, family history of osteoporosis or hip fracture, BMI 21 or 20 ng/mL per the ISCD.  A Korean study found that a daily dose of 1000–2000 international units of vitamin D is needed to maintain a serum level  >  50  ng/mL [71]. Further, vitamin D3 is better absorbed compared to ergo-­ cholecalciferol, vitamin D2. The best recommendation is a daily vitamin D3 supplementation to maintain serum level  > 30  ng/mL, which would be for the majority about 2000 international units daily of vitamin D3. Exercise plays an influential role in the bone remodeling process by stimulating osteoblast production, pivoting toward bone formation. Progressive resistance training (weight lifting or resistance bands) is an extensively researched exercise technique in preserving BMD.  One Australian prospective study showed improved BMD in the femoral neck (2.8%) and lumbar spine (3.3%) [72]. Other studies have shown similar results with increased BMD with progressive resistance training [72]. Weight-bearing exercise (activity moving against gravity) is the physical activity

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also known to impact bone health and reduce fall risk. Such exercises include walking, running, jogging, dancing, golf, tennis, high-­ impact aerobics, and stairs. A study found a positive association with walking steps daily and improved hip BMD, with a 25% increase in walking steps associated with a 1.4% increase in hip BMD [73]. Evidential data shows that high-impact exercise (exercise bands, weight lifting, tai chi, yoga, or Pilates) positively impacts BMD without increasing musculoskeletal injury risk [74]. If warranted, physical therapy and balance training are promising modalities for bone health and fall risk prevention.

Pharmacologic Therapies for Treatment and Prevention of Osteoporosis

10.9.2

10

Pharmacologic therapies are usually necessary for a patient at high risk for fracture. A crucial goal for treating clinicians is to identify persons with established osteoporosis for appropriate treatment to improve bone health and, more importantly, prevent future osteoporotic fractures. Individuals with osteoporosis need periodic evaluation with initiation of optimal treatment and adjustments as warranted. Choosing the ideal osteoporotic treatment calls for a thorough assessment of modifiable and non-modifiable risk factors (see . Table  10.1) and risk stratifying for available osteoporotic therapies and then followed by ensuring that the treatment is affordable and convenient for patients’ adherence. Several proven effective pharmacologic therapies are available and grouped based on being antiresorptive or osteoanabolic agents, listed in . Table 10.5. Pharmacologic treatment is highly advised for the following patients [65]: 55 Have osteopenia and a history of fragility fracture. 55 Have a T-score of −2.5 or less in the spine, femoral neck, total hip, or 1/3 radius. 55 Have a very low T-score (for instance, T-score   65  IU/L and estradiol 15 million sperm/ mL. Men with semen concentrations between 5 and 15 million/mL are labeled as oligospermic, and men with   50% decrease in most semen parameters [24]. These changes appear to be directly correlated with the duration of hemodialysis. Most of these parameters will improve following renal transplantation, though a significant proportion of men will remain azoospermic [25]. Klinefelter Syndrome  Klinefelter

syndrome (47, XXY) is a common genetic syndrome affecting roughly 1 in 1000 life male births and commonly presents in adulthood with primary infertility. Physical examination may reveal gynecomastia, mild cognitive dysfunction, sparse body and facial hair, and decreased lean muscle mass. Genital exam will universally

demonstrate prepubertal-­ sized firm testicles usually associated with primary testicular failure and hypogonadism. Proper identification and management of men with Klinefelter syndrome is important for avoiding the untoward effects of hypogonadism and simultaneously maximizing fertility capacity using assisted reproduction technology (ART). Even with aggressive management and early surgical sperm retrieval, however, only 50% of men will be found to have sperm. Infertility and Cystic Fibrosis  While the link

between mortality and infertility remains poorly understood, the link between infertility and other comorbidities is quite strong. Approximately 1 in 1000 men have congenital bilateral absence of the vas deferens (CBAVD), and this population accounts for roughly 1% of all men presenting for infertility workup [26]. Mutations in the cystic fibrosis transmembrane region (CFTR) family of genes are found in roughly 90% of men with CBAVD [27]. When suspected by an experienced urologist during physical examination, these men should undergo kidney ultrasound to rule out a solitary kidney, CFTR gene testing, and referral to pulmonology for further management. In addition, the partner of these men should be screened, and couples should be counseled on the genetic implications of their condition should they choose to proceed with assisted reproductive technology. In contrast, congenital unilateral absence of the vas deferens (CUAVD) is less commonly associated with CFTR mutations but should still be evaluated using a similar algorithm. 11.7

Obtaining a History of the Infertile Male

Obtaining a thorough history is a vital step to identifying potential causal factors in men with infertility. First, age is an important factor to consider as fertility diminishes over time. Despite this, however, roughly 80% of men in their fifth to seventh decades of life maintain normal semen parameters [28]. Assessment of prior pregnancies or children with a current

11

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or prior partner will distinguish men with primary from secondary infertility. Men should be queried for the length of unprotected intercourse and the use of conception strategies (e.g., ovulation kits, calendar-­based approaches, basal body temperature, etc.). While seemingly superfluous, it is also important to confirm with couples that they are participating in penetrative intercourse and that ejaculation occurs. Ideally, the female partner will be present at the consultation to provide an accurate partner history and encourage a coordinated workup and treatment discussion. This should include assessment of menstrual pattern, prior pregnancies with this or another partner, and consent to coordinate care with the reproductive endocrinology team when appropriate. Partner age is a critical component to assess, as this can directly dictates the intensity of therapy for men whose partners are nearing menopause. A developmental history including assessment for cryptorchidism, hypospadias, posterior urethral valves, or other congenital genitourinary anomalies will identify key risk factors for poor testicular function. Assessment of the age of puberty is also important. Delayed puberty can be seen in men with Kallmann syndrome, Turner syndrome, hypogonadism, and men with pituitary masses and hyperprolactinemia. Aside from these diagnoses, men with subjectively delayed puberty appear to have worse semen parameters and a 25% decrease in semen concentration [29]. Infectious etiologies are a common cause of infertility and account for up to 15% of cases [30]. Recent illness is also an important factor to discuss, as a single febrile illness reduces sperm concentration by one third [31]. A discussion of sexually transmitted disease history is also indicated, as prior gonorrhea or chlamydia infection can result in obstruction of the epididymis and obstructive azoospermia [32]. Next, providers should strive to capture a thorough genitourinary surgical history including prior scrotal surgery, urethral instrumentation to assess for possible strictures, and history of retroperitoneal surgery

as a risk factor for retrograde ejaculation. As many as 27% of infertile men who underwent inguinal hernia repair as a child will go on to develop vasal obstruction [33]. Thus, particular focus should be given to assessing for a history of hernia repair including age of intervention and type of repair (e.g., with or without mesh). A minority of men will report an oncologic history, most commonly testicular cancer and some hematologic malignancies. Thorough documentation of malignancy type and treatments (including specific chemotherapeutic or radiation treatments) can elucidate important gonadotoxic exposures. Numerous agents are detrimental to spermatogenesis including alkylating agents (e.g., cyclophosphamide), cisplatin, and dactinomycin [34]. Environmental exposures can cause significant decreases in sperm counts and are primarily centered around exposure to gonadotoxic agents such as pesticides [35] . Heat is also a significant environmental exposure risk factor and can be applied by hot tubs [36] or laptops [37]. Smoking is a significant risk factor for subfertility and appears to decrease sperm concentration, total motile count, and oxidative stress [38]. Scrotal trauma is an often-forgotten cause of infertility. Men with a history of high-­ impact sport activities such as football can develop hypogonadism and erectile dysfunction [39]. Repetitive low-impact activities such as cycling may also have a detrimental effect [40], though the literature in this area remains mixed [41]. Finally, countless medications have been implicated in male infertility. For a full list, the reader is referred to . Table 11.1 and to several recent reviews on the topic [42, 43].  

11.8

Physical Examination of the Infertile Male

The physical exam remains a critical aspect in the evaluation of the infertile or subfertile male. Assessment of body habitus, presence of secondary sex characteristics, and gynecomastia should be performed. Abdominal exam may reveal surgical incisions from prior

11

271 Male Infertility

..      Table 11.1  List of medications suspected or proven to cause male infertility Category

Subcategory

Drugs

Pattern

Strength of evidence

Tamsulosin, Silodosin

Retrograde ejaculation or anejaculation

Strong

Oxycodone

Decreased libido, ED, concentration

Strong

Methadone

Hypogonadism, decreased motility

Strong

Tramadol

Decreased count, motility

Strong

H2 blockers

Cimetidine, famotidine, ranitidine

Decreased sperm counts for cimetidine only

Weak

Proton pump inhibitors

Lansoprazole, Omeprazole, Pantoprazole

Modestly decreased sperm counts

Weak

Nitrofurantoin

Macrobid, macrodantin

Decreased motility

Weak

Tetracycline

Doxycycline, Minocycline, tigecycline

Decreased viability and motility

Weak

ACE Inhibitors

Captopril, enalapril, lisinopril

Decreased motility

Weak

Beta-Blockers

Atenolol, Carvedilol, Metoprolol

Decreased motility

Weak

Calcium channel Blockers

Amlodipine, nifedipine, Verapamil

Decreased motility and capacitation

Weak

Diuretics

Spironolactone

Decreased motility

Weak

Colchicine

Decreased concentration

Weak

Sulfasalazine

Decreased concentration, motility, morphology

Weak

Alkylating Agents

Cyclophosphamide, chlorambucil

Cytotoxic to spermatogonia

Strong

Mitotic Inhibitors

Vinblastine

Cytotoxic to spermatogonia

Strong

Androgens

Testosterone

Azoospermia

Strong

Antiandrogens

Bicalutamide, flutamide

Erectile dysfunction, decreased libido

Strong

5-ARIs

Dutasteride, Finasteride

Decreased concentration, semen volume

Strong

GnRH analogs

Leuprolide, goserelin

Erectile dysfunction, decreased libido

Strong

Alpha-­ blockers Analgesics

Antacids

Antibiotics

Antihypertensives

Opioids

Anti-­ inflammatory drugs Chemotherapeutics

Hormonal Therapies

(continued)

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..      Table 11.1 (continued) Category

Subcategory

Drugs

Pattern

Strength of evidence

Immunosuppression

Antimetabolites

Azathioprine, Mycophenolate

Decreased motility, teratogenic

Weak

mTOR inhibitors

Everolimus, sirolimus

Decreased concentration, motility, teratogenic

Weak

Steroids

Prednisone

Minimal effect on sperm

Strong

Phenothiazines

Chlorpromazine

Increased prolactin, decreased motility

Weak

SSRIs

Fluoxetine, Paroxetine

Decreased counts and motility

Weak

Lithium

Decreased motility

Weak

Spermatogonia toxicity

Strong

Psychiatric medications

Radiation (pelvic)

11

inguinal hernia repair raising suspicion of vasal obstruction in the appropriate clinical context. Close attention is then paid to the genital exam which is often best performed in the standing position. Evaluation of testicular size can be performed with the use of an orchidometer or by subjective assessment by an experienced provider. The consistency of the testis is important to assess, as men with testicular failure may have soft testes, whereas a testicular mass will be firm and irregular. The epididymis should be palpated for tenderness, which may suggest epididymitis, or masses such as epididymal cysts (spermatoceles). Epididymal fullness can be appreciated on obstructed men. The presence or absence of the vas deferens is critical to identify men with vasal agenesis. The presence and grade of varicocele should then be noted, again with the patient in the standing position and with a Valsalva maneuver. Varicoceles are graded on physical exam as follows: Grade 1 varicocele is palpable only with Valsalva maneuver, Grade 2 varicocele is palpable without Valsalva, and Grade 3 is visible. Evaluation of meatal location, Tanner stage, and penis size may be important particularly in men with history of hypospadias and congenital hypogonadotropic hypogonadism, respectively. If the patient is of appropriate age, a rectal exam

should be performed to assess for prostate masses.

11.9

Semen Analysis

Basic Semen Analysis  The cornerstone of male

fertility workup is the basic semen analysis. According to WHO guidelines [16], men are instructed to abstain from ejaculation for between 2 but not more than 7  days prior to providing a specimen. Specimens should be collected in a clean fashion without the use of saliva or most commercially available lubricants, both of which can negatively impact semen parameters [44]. Men should be educated on the importance of a complete collection, as a “split collection” where the initial or terminal portion of the specimen is lost can underestimate the true semen concentration significantly. Following collection, the semen sample should be processed in a consistent manner by experienced technicians. While semen has a remarkable ability to buffer pH, a value of less than 7.0 is often associated with obstruction due to the loss of fructose-rich alkaline fluid from the seminal vesicles. Volume should typically exceed 1.5 mL in a normal specimen, and volumes lower than this should raise

273 Male Infertility

c­ oncern for obstruction or retrograde ejaculation. It is important to note that vasal obstruction does not cause decreased ejaculate volume, as the testicular contribution to the ejaculate volume is only a fraction of the total ejaculated volume. Semen concentration is perhaps the most versatile basic semen analysis parameter, as this provides a key measure of fertilizing ability. When combined with percentage of motile sperm and total volume, the total motile sperm count (TMSC) can be calculated. In subfertile men, TMSC of >5 million per mL is sufficient for intrauterine insemination (IUI), whereas values less than this are typically best managed with IVF or ICSI. Many labs now perform computer-aided semen analysis (CASA) in addition to or in some cases in place of manual counts. These platforms use high-throughput digital imaging and analysis software to determine semen concentration, motility, and several other parameters including linearity and velocity. While these systems provide relatively consistent data, most literature suggests equivocal results to manual analysis [45, 46], and there is little evidence suggesting that these expanded parameters provide additional clinical utility. Leukocytospermia Assessment  Semen should

be examined for the presence of round cells, which can represent either immature sperm precursor cells or white blood cells. If positive, samples are typically assessed using the myeloperoxidase test. Men with positive leukocytospermia testing should be further assessed for underlying etiologies including smoking and the presence of occult infection, which can be empirically treated using doxycycline [47]. DNA Fragmentation  The fidelity of sperm

DNA is critical to the successful generation and propagation of a human embryo, and as such the field of male infertility has spent considerable effort into studying assays to assess DNA fragmentation. Numerous assays have been developed including TUNEL, sperm chromatin structure, and sperm chromatin dispersion assays [48]. Despite its theoretical importance, clinical implementation of the

data from these assays has proved to be difficult and is limited to specific clinical scenarios such as recurrent pregnancy loss or unexplained infertility. Furthermore, treatment of elevated DNA fragmentation primarily relies on antioxidant therapy or  – in the setting of ART  – collection of testicular sperm, which may relieve some of the accumulated DNA damage from elevated oxidative stress exposure in ejaculated sperm. Oxidative Stress  It is thought that the root cause of DNA damage in sperm is the presence of elevated oxidative stress. Measurement of oxidative stress can be accomplished via numerous assays including reactive oxygen species measurement using luminol chemiluminescence [49], total antioxidant capacity [49], and direct measurement of the oxidation reduction potential [50]. Viability Testing  In cases of severely compro-

mised motility and oligospermia or cryptospermia, sperm viability testing provides an attractive tool to confirm that sperm are alive and can be used successfully for intracytoplasmic sperm injection (ICSI). Some of the most common tests used for this purpose include the eosin-nigrosin stain [51], the hypoosmotic swelling test [52], and the laser-assisted detection tests [53]. Antisperm Antibodies  Some semen specimens demonstrate significant sperm agglutination, which can be due to the presence of antisperm antibodies (ASA) from prior trauma or scrotal surgery [54]. These can be measured using the IgG-mixed antiglobulin reaction (MAR) test [55]. If identified, men with ASA can be treated with a host of approaches including immunosuppression, sperm washes, and sperm purification, and/or ICSI can be utilized depending on the clinical scenario [56]. Capacitation Assays  The need for sperm to be able to penetrate the zona pellucida and enter the egg, as is necessary in traditional in  vitro fertilization, has largely been supplanted by advances in ICSI. As such, the role for capacitation assays has been largely diminished, and these tests are now rarely performed.

11

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11.10

S. Lundy and S. C. Vij

Laboratory Workup

Bloodwork  A typical laboratory workup performed in conjunction with semen analysis includes assessment of the HPG axis via measurement of follicle-stimulating hormone and testosterone, both of which are mandatory in men with impaired libido, erectile dysfunction, oligozoospermia or azoospermia, atrophic testis, or abnormal physical exam findings such as testicular atrophy [17]. If hypogonadism is identified, prolactin and luteinizing hormone should also be checked to assess for primary or secondary hypogonadism [18]. Genetics  Genetic evaluation for the infertile

11

male is typically reserved for men with severe oligospermia or azoospermia, recurrent pregnancy loss, or men with consanguinity or known syndrome or other high-risk populations. This involves a karyotype to assess for additional chromosomes or macroscopic insertions/deletions. Y-chromosome microdeletion (YCMD) is a special case whereby small deletions within the long arm of chromosome Y in one of three azoospermic factor (AZF) regions (AZFa, AZFb, or AZFc). While men with AZFa and AZFb have not been shown to have sperm on surgical interrogation, up to 75% of men with isolated AZFc mutations will have foci of spermatogenesis and thus should undergo surgical sperm retrieval [57]. While hundreds of single nucleotide polymorphisms have been identified and reported in the literature [58], the clinical utility in routinely assessing for these remains unproven. Finally, CFTR mutation testing is indicated in men with suspected CBAVD or CUAVD.  If positive, the female partners should also be tested. All patients with a genetic abnormality on testing should be offered genetics counseling.

11.11

Imaging

Imaging can be a useful adjunctive tool in the diagnostic workup of the infertile male. Physical exam along with laboratory testing and semen testing can often provide sufficient diagnostic information; however in certain

circumstances, imaging may be useful. Scrotal ultrasonography is the most commonly utilized imaging modality in this context. Ultrasonography can assess testicular volume, testicular echogenicity, presence or absence of varicocele in the setting of difficult physical exam as well as testicular mass, and epididymal anatomy. Clinicians might order scrotal ultrasonography if the physical exam is challenging or further anatomic information about the scrotal contents is desired. Transrectal ultrasonography can be a useful tool in the setting of obstructive azoospermia to evaluate for dilated seminal vesicles and ejaculatory ducts as well as prostatic utricle or Wolffian duct cysts. In patients with elevated prolactin, cranial MRI is indicated. Lastly, vasography can be performed intra-­operatively to evaluate for distal genital tract obstruction in anticipation of operative repair.

11.12

Management

Medical Management of Male Infertility  In many cases of oligozoospermia, medical interventions are sufficient to improve sperm parameters and cause a pregnancy. Men who are smoking should be counseled on the importance of cessation, particularly if associated with leukocytospermia. The importance of a healthy diet and healthy body composition also cannot be overstated. Antioxidants and vitamins are also often r­ecommended to decrease oxidative stress, but the evidence for this approach is weak at best. Nevertheless, the risk to this approach appears to be quite low, and for oligozoospermic men with limited options for intervention, this can be considered. HPG Axis Manipulation for Hypogonadism  There are several indications

for the treatment of infertile men with medications designed to modulate the HPG axis. Men with hypogonadism but with relatively normal pituitary hormone levels may benefit from treatment, but prescribing these men traditional testosterone replacement therapy is strictly contraindicated due to its suppression of spermatogenesis. Instead, selective estrogen

275 Male Infertility

receptor modulators (SERMs), aromatase inhibitors, or human chorionic gonadotropin (hCG) can be prescribed. SERMs such as clomiphene citrate are mixed agonist/antagonists of the estrogen receptor which exert their effects by increasing GnRH pulse frequency and thus increasing FSH and LH levels. Aromatase inhibitors such as anastrozole work by limiting the conversion of androgens to estrogen. This class of medications is particularly helpful in obese men with elevated estradiol levels. Finally, recombinant hCG can also provide a safe way to increase testosterone in men desiring fertility. HPG Axis Manipulation for Hypogonadotropic Hypogonadism  In cases of hypogonadotropic

hypogonadism (e.g., Kallmann syndrome), men desiring fertility should be referred to endocrinologists or male infertility specialists. The most common regimen used in these men consists of initial treatment with hCG and recombinant FSH to restore testicular function. HPG Axis Manipulation for Idiopathic Subfertility  The role for hormonal manipula-

tion in the subfertile man with normal testosterone levels remains controversial. Many providers will consider a trial of off-label clomiphene in these men with the intention of optimizing sperm parameters for natural conception. Similarly, there is evidence supporting medical management in patients with nonobstructive azoospermia (NOA) prior to sperm retrieval to optimize sperm yeilds [59].

11.13

Surgical Management of Male Infertility

TURED  For

men with ejaculatory duct obstruction, transurethral resection of the ejaculatory ducts (TURED) can restore normal ejaculation volumes and thereby improve fertility. In this procedure, a transrectal ultrasound is performed and the dilated seminal vesicles aspirated for sperm preservation purposes. Many providers then inject methylene blue to provide visual feedback for the subsequent resection [60]. The cystoscope with working

element of choice (cold knife, hot knife, hot loop, button, etc.) is then inserted and used to resect the verumontanum until blue efflux is noted. Outcomes are modest but favorable, with 83% of men experienced increased semen volume and 63% of men demonstrating increased semen concentration [61]. Varicocelectomy  For men with a clinical vari-

cocele and subfertility or varicocele-related pain, surgical varicocelectomy can be offered. For a detailed review on the management options for varicocele, the reader is referred to a recent systematic review [62] and Cochrane review [63] on the subject. Briefly, varicocelectomy can be accomplished with either surgical or endovascular intervention. Surgical approaches include laparoscopic, retroperitoneal, inguinal, and subinguinal approaches. Regardless of the approach used, success rates are high and range from 75% to 90%. Complications include hydrocele and varicocele recurrence. Testicular loss is exceedingly rare and should be mentioned as a complication. Despite its well-described role and high prevalence in infertile men, outcomes for fertility purposes remain contentious. On the one hand, Abdel-Meguid [64] conducted a randomized controlled trial and found an odds ratio for pregnancy of 3.0 for varicocelectomy compared to observation. This corresponds to a number needed to treat of 5.3. A Cochrane review subsequently confirmed the benefit of varicocelectomy, but the number needed to treat for this analysis was much higher at 17. Diagnostic Testicular Biopsy  Outside of con-

cern for malignancy or carcinoma in situ, the role for diagnostic testicular biopsy in the infertile male is limited [65]. Most men with azoospermia can usually be correctly categorized as obstructive or non-­obstructive based upon a thorough history, semen analysis, and laboratory workup. In cases where the diagnosis for obstruction is equivocal, diagnostic testicular biopsy can be considered to ensure whether spermatogenesis is present prior to a moreinvolved reconstruction operation. Another viable option for these patients is testicular

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sperm extraction with cryopreservation for both diagnostic and therapeutic purposes.

11

Surgical Sperm Retrieval  For men with little to no sperm in their ejaculate, surgical sperm retrieval offers the ability to retrieve sperm directly from the epididymis or the testicle. The specific procedure indicated is dependent upon numerous factors including the etiology of azoospermia (obstructive or non-obstructive), patient anatomy, procedure setting, and management goals. For men with prior vasectomy who wish to father a child and would prefer IVF over surgical reconstruction, percutaneous epididymal sperm aspiration (PESA) using a narrow-gauge needle passed repeatedly into the dilated epididymis offers a minimally invasive approach with good success rates. The use of the operating microscope to target individual tubules is termed a microsurgical epididymal sperm aspiration (MESA) [66]. This procedure can increase yield but requires surgical delivery of the testicle and microsurgical expertise and is less commonly performed. A percutaneous testicular sperm aspiration (TESA) is another for men with obstructive azoospermia, but success rate is typically lower [67]. Non-obstructive azoospermic men are typically managed using surgical testicular sperm extraction (TESE) or microdissection testicular sperm extraction (microTESE or mTESE). This procedure requires surgical delivery of the testicle followed by incision of the tunica albuginea and sharp removal of a portion of the testicular parenchyma and tubules. The use of an operating microscope provides the ability to identify islands of tubules that visually appear to contain spermatogenesis without necessitating large quantities of parenchymal excision, which may lead to hypogonadism. The overall success rates for mTESE are reasonably good for men with NOA and typically hover around 50–60% [68]. Unfortunately, the only factor consistently shown to predict success rates is surgical pathology, which is typically not available preoperatively. Vasectomy Reversal While the surgical nuances of vasectomy reversal are beyond the scope of this chapter, it is important for clinicians to recognize that vasectomy reversal is an

operation commonly performed by urologists with specialty training in male infertility and offers excellent (>90%) technical success rates in most situations. Men with short interval between vasectomy and reversal ( 4 mIU/L) during pregnancy is associated with higher rates of miscarriage; however, a meta-­ analysis of levothyroxine (LT4) supplementation in infertile women with SCH found no significant association between LT4 supplementation and rates of clinical pregnancy, live birth, or preterm birth rates [14]. Given a lack of a single standard of care, alongside the low cost and safety of replacement, many practitioners will obtain patients’ consent to offer treatment to achieve a TSH of 10 IU/L, success with therapies including IVF is diminished [43]. Estradiol levels should be drawn with all basal FSH levels to demonstrate that a low FSH level is not falsely suppressed secondary to a prematurely elevated estradiol level (defined as greater than 60–80  pg/mL). Although a day 3 FSH was required historically, FSH and estradiol levels can be drawn on either cycle day 2 or 3 to facilitate the process for the patient [44]. zz Anti-Müllerian Hormone (AMH)

Anti-Müllerian hormone, also known as Müllerian inhibiting substance (MIS), is produced by the granulosa cells of ovarian follicles and reflects the primordial follicle reserve. Unlike other ovarian reserve tests, AMH can be measured at any point during the menstrual cycle. Levels less than 1.0  ng/mL are considered abnormal and are associated with poor ovarian response to gonadotropin stimulation [45, 46]. zz Antral Follicle Count (AFC)

The AFC is determined using transvaginal ultrasound in the early follicular phase to quantify the number of follicles between 2 and 10 mm in diameter. These antral follicles may be thought of as eggs in the “pipeline” reflecting overall ovarian reserve and can be used as a predictive measure of overall future production. An AFC of less than 10 has been shown to correlate with poor ovarian response to gonadotropin stimulation [47]. High antral follicle counts are often associated with PCOS. zz Clomiphene Citrate Challenge Test (CCCT)

Clomiphene citrate is a selective estrogen receptor modulator (SERM) that has an antagonist effect on the hypothalamus, therefore blocking the inhibitory feedback of estrogen. This in turn leads to an increase in GnRH and therefore FSH at the level of the pituitary. The CCCT is a provocative examination designed to “unmask” those patients with a normal day 3 FSH level. With this test, a basal FSH level and estradiol are measured on cycle day 3. The patient is given clomiphene citrate 100  mg daily on cycle days 5 through 9 and the FSH level is again measured on cycle day

293 Female Infertility

10. The test is considered abnormal if the day 3 FSH, day 3 estradiol, or day 10 FSH levels are elevated [48]. Given the utility of tests for AMH and AFC, and the fact that the CCCT requires exogenous medication (clomiphene citrate) and a second blood draw on day 10, this test is obtained infrequently. 12.4.4 12.4.4.1

Imaging Studies Ultrasonography

Transvaginal ultrasonography is the first-line imaging study for identifying structural abnormalities in the pelvis, particularly of the uterus and ovaries [49]. It should be considered if a structural lesion is suspected on physical examination. In addition, the ultrasound probe can be used to push on structures to localize symptoms (such as pain in an endometrioma) as well as to assess sliding of the ovary or uterus alongside bowel to assess for adhesions. However, some conditions may be undetectable, especially if the exam is limited by patient discomfort, body habitus, or if any abnormalities are located above the field of view. Transvaginal ultrasound may be considered in all infertile women, especially if the plan is to obtain an AFC. 12.4.4.2

Sonohysterography

Sonohysterography (also known as saline infusion sonography or SIS) is an imaging test that utilizes transvaginal ultrasonography in which a fluid medium, typically saline, is instilled through the cervix to distend the uterine cavity in the early follicular phase after the conclusion of menses. More accurate than transvaginal ultrasound alone, this increases the provider’s ability to identify endometrial or intracavitary lesions such as polyps or fibroids and intrauterine adhesions (synechia). When used with specialized contrast media (saline with bubbles infused), sonohysterography may also be used to attempt to assess tubal patency. If combined with 3D ultrasound, SIS provides significant information about the uterus including possible differentiation of uterine anomalies such as a bicornuate from a septate uterus.

12.4.4.3

Hysterosalpingography

Hysterosalpingography (HSG) is a radiographic evaluation of the uterine cavity and fallopian tubes. Contrast dye is injected through the cervix into the uterine cavity with spillage of the dye into the abdominal cavity if the fallopian tube(s) are patent. This test is used to diagnose synechia and other intracavitary defects such as polyps and fibroids as well as Müllerian anomalies such as a septate or bicornuate uterus. Furthermore, hysterosalpingography can not only assess tubal patency but also potentially identify the site of obstruction if the fallopian tubes are blocked. Of note, although the primary purpose of this study is not therapeutic, oil-based media have been shown to increase subsequent pregnancy rates [50]. The HSG is not as sensitive as the SIS for evaluating the cavity; however, because it provides greater details about the tubes, it is often the first-line test in an infertility evaluation. 12.4.5

Surgery

Hysteroscopy involves introducing a small diameter telescope with a light source through the cervix into the uterine cavity. Similar to sonohysterography, saline is typically used to distend the cavity. Hysteroscopy is often considered the gold standard for visualizing the cavity and can be used for both diagnostic and therapeutic purposes. Diagnostic hysteroscopy can often be performed in the office when there is suspicion for an intracavitary lesion based on the patient’s history such as abnormal uterine bleeding or specific findings noted on prior imaging. Hysteroscopy in the office provides the advantage of potentially being able to immediately treat any findings found (i.e., “see and treat”) if the lesions are small. For more substantial findings (i.e., fibroids), anesthesia is typically required; hence, the study is more commonly performed in the operating room. Laparoscopy can be useful for some infertile women since it is the only definitive method of accurately diagnosing anatomic lesions such as endometriosis and intraperitoneal adhesions and the only modality to treat

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structural findings. However, as fertility treatments have evolved, fewer laparoscopies are done for infertility alone, as IVF provides higher pregnancy rates with a lower risk of ectopic pregnancy in women with pelvic pathology. Furthermore, laparoscopic treatment of low-stage endometriosis results in only a small absolute increase in pregnancy rates, requiring many women to undergo a laparoscopy to achieve a pregnancy [51]. Nevertheless, in situations where higher stage endometriosis or pelvic pathology is suspected, the patient has significant pelvic pain which she desires to be addressed surgically, or IVF is not able to be performed, then laparoscopy may be an excellent option for both diagnostic and therapeutic purposes.

12.5

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Treatment

There are many options for infertility treatment. Specific therapies should be selected based on the results of the patient’s evaluation as described above. As many of these therapies can be extremely expensive and are not necessarily covered by medical insurance, it is always ideal to begin with the least invasive and least expensive option. However, there has been greater movement to move immediately to IVF if pregnancy has not been achieved with lesser treatment [52]. Furthermore, some conditions such as tubal blockage and severe male factor dictate moving directly to IVF. 12.5.1

Oral Medications

Clomiphene citrate is a selective estrogen receptor modulator (SERM) that inhibits the negative feedback effect of estrogen on the hypothalamus and, therefore, upregulates the hypothalamic–pituitary–gonadal axis to increase the likelihood of ovulation in anovulatory women or the release of more than one egg in women who are already ovulatory. Letrozole functions as an aromatase inhibitor, decreasing the peripheral enzymatic conversion of androgens to estrogens. This overall decreases the body’s estrogen level and provides feedback to

the hypothalamic–pituitary–gonadal axis to similarly increase FSH production. When using these medications, it is important to distinguish patients who have ovulatory infertility from those with unexplained and ovulatory infertility. In women who are anovulatory, the goal is to achieve mono-­ follicular development. Letrozole has emerged as a superior choice over clomiphene in this population [53]. In women who are ovulatory and not conceiving despite releasing an egg each month, the goal is to increase their ovulatory function using a more aggressive protocol. Clomiphene citrate remains the protocol of choice over letrozole [53]. As opposed to the traditional 50 mg during cycle days 5–9, the standard dosing regimen for clomiphene, when used for ovulation induction, is 100 mg orally during cycle days 3–7. Furthermore, to optimize pregnancy rates, this should be combined with intrauterine insemination (IUI) as ovulatory women who take clomiphene and utilize timed intercourse do not have an increased pregnancy rate compared to non-medicated cycles [54]. 12.5.2

Ovarian Stimulation (Injectable Gonadotropins)

Controlled ovarian stimulation with gonadotropins (i.e., follicle stimulating hormone) is used to stimulate the ovaries to produce one egg in anovulatory women refractory to oral medications and more than one mature follicle per cycle in women who are infertile and not conceiving. Multiple follicular development increases both the chances of any one egg fertilizing (and therefore overall pregnancy rates) and also more than one egg fertilizing (increasing the risk of multiple gestations). Gonadotropin therapy is more effective than clomiphene or letrozole for ovulatory women with infertility [55]. Side effects of these medications include ovarian hyperstimulation syndrome (OHSS) and ovarian damage or torsion. Multiple gestations typically only occur in 1–2% of naturally occurring pregnancies. With injectable gonadotropins, 20–30% of

295 Female Infertility

these pregnancies are associated with multiple implantations. Multiple pregnancies are associated with an increased risk of miscarriage, preterm delivery, pregnancy-induced hypertension, postpartum hemorrhage, and other maternal complications. Given the accepted goal of avoiding multiple gestations, especially high-order multiple gestations, many providers avoid using gonadotropins other than with IVF, especially as the literature supports a faster time to pregnancy by moving directly from clomiphene to IVF [52]. 12.5.3

Intrauterine Insemination

Intrauterine insemination (IUI) is a procedure performed in the ambulatory setting in which prepared sperm is placed directly into the woman’s uterus through a catheter. When treating ovulatory infertile women, IUIs are typically included routinely in the treatment regimen to maximize pregnancy rates. There are several indications for IUI alone including the use of donor sperm, male factor infertility such as low motility [56], coital dysfunction, cervical factor such as no mucous production, or stenosis due to a surgical ­procedure such as a loop electrosurgical excision procedure (LEEP) or cone biopsy. IUIs will not be effective in patients with tubal blockage, severe endometriosis, or intraabdominal adhesions since they still require the oocyte to travel from the ovary to the uterine cavity. IUI alone is not indicated for ovulatory women with unexplained infertility or in medicated cycles in anovulatory women. 12.5.4

Assisted Reproductive Technology

Assisted reproductive technology (ART) consists of technologies in which eggs or embryos are handled which narrows the definition to IVF. If only the sperm is handled (e.g., intrauterine insemination), this is not considered ART by the CDC [57]. IVF is the most successful fertility intervention in any one treat-

ment cycle for the majority of women. It involves ovarian stimulation with injectable gonadotropins typically with the use of a gonadotropin-releasing hormone (GnRH) agonist or a GnRH antagonist to suppress the LH surge and premature ovulation. Human chorionic gonadotropin (hCG) is typically given to mature the eggs, triggering ovulation. The oocytes are then retrieved through needle aspiration transvaginally under ultrasound guidance. In some cycles, all oocytes and/or embryos may be frozen, for example, when the indication is fertility preservation or when genetic testing (e.g., preimplantation genetic testing) is done. Alternatively, the oocytes can be fertilized with a prepared sperm sample and incubated. The embryos are graded using quality assessment criteria such as cell regularity, degree of fragmentation, and other microscopic characteristics [58]. Those of highest quality are selected for transfer, which is performed transcervically through a small catheter under ultrasound guidance. Supplemental progesterone is used to support the luteal phase since no ovulation takes place in IVF, and there may be inadequate endogenous progesterone production. The live birth rate using IVF varies widely depending on many factors including, but not limited to, the woman’s age, BMI, duration of infertility, and presence of hydrosalpinges. Importantly, of these, the woman’s age is perhaps the most important and the factor used when quoting pregnancy rates. The goal of IVF is to achieve a singleton pregnancy, given the risks associated with twins or higher order multiple gestations. The Society for Assisted Reproductive Technology has an excellent website with information about IVF and pregnancy rates [59], as well as a calculator to help predict pregnancy rates [60].

12.5.5

Donor Gametes

Donor gametes (sperm or eggs) or donor embryos should be discussed with appropriate patients. Care should be taken to anticipate and prepare for the period of grieving or anger associated with these routes in patients

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who have not anticipated this need. Patients should be given time and resources to address the psychological aspects of the situation prior to pursuing either of these options and psychological counseling is recommended [61]. Of note, although specific recommendations are made for counseling when donor gametes are used, psychological support should be available for all patients presenting with infertility given the associated stress. 12.5.6

Adoption, Fostering, and Childfree Living

While advances in female infertility evaluation and treatment have greatly improved the rate of successful pregnancies, a percentage of couples will fail all interventions and/or be 12.6

12

unwilling or unable to continue treatment. If these couples are unwilling to consider adoption, the clinician should be prepared to discuss childfree living, a concept that may be difficult for infertile couples to accept. It is important to recognize that couples may perceive childfree living as their personal failure and are prone to develop depressive symptoms or even marital conflict as a result [62]. Fortunately, there is evidence to suggest that cognitive-behavioral therapy focused on ­validating emotion, educating on the psychological effects of infertility and treatment, and providing tools to manage emotions can significantly reduce couples’ rejection of the childfree lifestyle [63]. During this grieving period, clinicians may refer patients for support to reduce couples’ psychological and relational burdens.

Comparison of International Protocols for Evaluation of Female Infertility

Country of Origin

United States

Canada

United Kingdom

Germany, Switzerland, and Austria

Publishing Body

American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice

Canadian Fertility and Andrology Society

National Institute for Health and Care Excellence (UK)

German Society of Gynecology and Obstetrics; Swiss Society of Gynecology and Obstetrics; Austrian Society of Gynecology and Obstetrics

Last Updated

2019

2002

2017

2020

Definition of Infertility

Failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse

Inability to conceive after 1 year of unprotected intercourse

The period of time people have been trying to conceive without success after which formal investigation is justified and possible treatment implemented

Failure to achieve a successful pregnancy after 12 months or more of appropriate, timed, unprotected intercourse

297 Female Infertility

Country of Origin

United States

Canada

United Kingdom

Germany, Switzerland, and Austria

Recommendations on Etiology Testing

Serum TSH: Perform for women with ovulatory dysfunction, infertility, or evidence of thyroid disease Serum Prolactin: Perform in women with irregular menses or signs of hyperprolactinemia Tubal Patency: Evaluate using hysterosalpingography and/or hysterosalpingo-contrast sonography Sexually Transmitted Infections: Obtain exposure information during initial medical interview Endometrial Biopsy: Perform only when endometrial pathology (e.g., neoplasia, chronic endometriosis) is strongly suspected

Serum TSH: Do not measure in the absence of irregular cycles Serum Prolactin: Do not measure in the absence of irregular cycles Tubal Patency: Evaluate using hysterosalpingogram Sexually Transmitted Infections: Perform endocervical culture to rule out asymptomatic disease prior to performing uterine instrumentation Endometrial Biopsy: Do not perform

Serum TSH: Offer only to women with symptoms of thyroid disease Serum Prolactin: Offer only to women who have an ovulatory disorder, galactorrhea, or a pituitary tumor Tubal Patency: Offer hysterosalpingogram to women with no known uterine comorbidities to rule out tubal occlusion Sexually Transmitted Infections: Offer screening for CChlamydia trachomatis prior to performing uterine instrumentation Endometrial Biopsy: Do not offer to evaluate the luteal phase

Serum TSH: Perform for all women; if greater than 2.5 mU/L, measure anti-thyroid antibody level Serum Prolactin: Perform at time of diagnostic workup Tubal Patency: Evaluate using laparoscopy with chromopertubation or hysterosalpingocontrast sonography (HyCoSy) Sexually Transmitted Infections: Not stated Endometrial Biopsy: Do not perform if menstrual cycle length is unremarkable and regular

Evaluation of Ovarian Reserve

Antral Follicle Count: Perform for evaluation of etiology of infertility

Antral Follicle Count: Not stated

Antral Follicle Count: Perform as an initial predictor of success through natural conception or with IVF

Antral Follicle Count: Perform during diagnostic workup for hormonal disorders

Recommendations on Lifestyle Factors

Obesity: Obtain BMI during initial physical examination Low Body Weight: Obtain BMI during initial physical examination Smoking: Obtain history during initial medical interview

Obesity: Recommend a supervised weight-loss program regardless of ovulatory status Low Body Weight: Not stated Smoking: Advise to give-up smoking

Obesity: Advise women with a BMI ≥ 30 to lose bodyweight Low Body Weight: Advise women with a BMI  30 to lose weight Low Body Weight: Advise women with a BMI 45 Gy during adulthood would be at very high risk of infertility. It has been demonstrated in women treated with total body irradiation that sex steroid replacement in physiological doses significantly increases uterine volume and endometrial thickness, as well as reestablishes uterine blood flow. However, it is not known whether standard regimens of estrogen replacement therapy are sufficient to facilitate uterine growth in adolescent women treated with total body irradiation in childhood. 13.14  Pregnancy After Radiation

Therapy

Pregnancies achieved by survivors of childhood cancer who have received pelvic irradiation must be considered high risk [34  – 36]. Radiation damage to the uterine musculature and vasculature can adversely affect pregnancy outcomes in these women. Even if the uterus is able to respond to exogenous sex steroid stimulation, and appropriate ART’s are available, pregnancy prognosis remains guarded. Common obstetric problems reported in these patients include early pregnancy loss, premature labor, and lowbirth-­weight infants [37, 38]. 13.15  Fertility Preservation

Strategies

A wide variety of strategies are available in an effort to preserve ovarian function and fertility in women undergoing chemotherapy and/ or radiotherapy. Fertility-sparing procedures, pharmacologic options, and ARTs will be discussed (. Table 13.2).  

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..      Table 13.2  Fertility preservation strategies Technique

Pros

Cons

Experimental vs. Established

Fertility-preserving surgery (including trachelectomy)

May be able to conceive and carry future pregnancy Less aggressive Usually covered by insurance

May leave residual disease Requires close follow-up May still require ART

Established

Ovarian transposition

Reduces ovarian exposure to radiation

Requires surgery May still be affected by radiation (Scatter/ fall into field) Can cause pain

Established

Pharmacologic

GnRH agonists

Minimal delay in treatment

Not proven Side effects similar to menopause

Experimental

Assisted reproductive technology

Embryo cryopreservation

Commonly performed, good success rates

Elevated hormone levels Time-consuming (14 days) Requires a sperm source May not be covered by insurance

Established

Oocyte cryopreservation (by vitrification)

Good success rates, no longer experimental Does not require a sperm source

Elevated hormone levels Time-consuming (14 days) May not be covered by insurance

Established

Ovarian tissue cryopreservation

No delay in treatment Does not require a sperm source Option for prepubertal females

Requires surgery Ovarian tissue ischemia Possible re-exposure to cancer cells May not be covered by insurance

Established

In vitro maturation

Minimal delay in treatment Does not require a sperm source May be combined with Ovarian tissue cryopreservation

Limited experience with this procedure

Experimental

Surgical

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311 Fertility Preservation

13.16  Surgical Techniques

13.19  Endometrial Cancer

In general, the conventional therapy for a gynecologic malignancy consists of removal of the uterus, tubes, and ovaries. However, there are specific circumstances that may allow a more conservative surgical approach.

Both complex endometrial hyperplasia with atypia and early-stage endometrial adenocarcinoma (Stage IA1) can be treated conservatively. A hysteroscopy with dilatation and curettage, followed by high-dose progesterone therapy, is the standard treatment for those women who desire fertility preservation. Unfortunately, recurrence is common, and close periodic evaluation is required to avoid progression. It is also important to stress to these patients that they should pursue child-­ rearing sooner rather than later and then have a complete hysterectomy and bilateral salpingo-­oophorectomy to ensure a disease-­ free survival. In the event hysterectomy is strongly considered before pregnancy, a patient can still preserve oocytes or embryos but then requires a gestational carrier for future parenthood.

13.17  Cervical Cancer

Cervical cancer is typically treated with surgery or radiation therapy, depending on the stage at presentation. Those with early-stage disease, Stage IA1, may be treated with cervical conization and close follow-up. Women who desire future fertility and are diagnosed with Stage IA2 and Stage IB disease may opt for a radical trachelectomy, which involves removal of the cervix, surrounding tissues, and lymph node dissection [39]. Patients treated with trachelectomy may require ART to achieve a future pregnancy and cerclage and should be aware that they are at increased risk of second-trimester loss and preterm birth after this procedure [40]. Successful fertility preservation and spontaneous pregnancies have been reported after robotic trachelectomy [41]. 13.18  Ovarian Cancer

Ovarian tumors classified as low malignant potential, germ cell, sex cord stromal, or early epithelial malignancies have the potential to be treated with conservative surgery. Most ovarian cancers diagnosed in the reproductive years tend to be unilateral and are less likely to have metastasized. The surgical option most likely to succeed in removing the cancerous tissue, as well as preserve fertility potential, is unilateral oophorectomy with conservation of the remaining normal ovary and the uterus. These women should still undergo complete staging and be monitored closely by a gynecologic oncologist for possible recurrence [42].

13.20  Ovarian Transposition

Transposition of the ovaries out of the field of radiation appears to help maintain ovarian function in patients scheduled to undergo pelvic gonadotoxic radiation therapy. This technique can be utilized for gynecologic (cervix and uterus), colon, rectal, and anal cancers. Transposition of the ovaries has been reported to reduce the radiation dose to each ovary by approximately 90–95% compared to ovaries left in their original location [38]. There are two techniques available, lateral and medial transpositions. Lateral transposition appears to be more effective than medial transposition. A compilation of ten case reports and a small series showed an ovarian failure rate of 14% after lateral transposition compared to 50% after medial transposition [43]. Ovarian transposition can be performed by either laparotomy or laparoscopy. When surgery is required for the treatment of cervi-

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cal cancer or during staging and treatment of ovarian cancer, lateral ovarian transposition can be performed simultaneously. However, if a surgical procedure is not required for treatment, the transposition can easily be performed as an outpatient procedure. The ovaries have a tendency to migrate back to their original position, so it is recommended to complete the procedure immediately prior to the initiation of radiation therapy [33, 44, 45]. Most ovaries will maintain function if they are transposed at least 3  cm from the upper edge of the field [46]. It has been shown that approximately 80% of women undergoing laparoscopic ovarian transposition will maintain ovarian function after radiation therapy for various indications [47]. Ovarian failure following transposition can occur because of several different mechanisms. Ovarian failure may result if the ovaries are not moved far enough out of the radiation field. Another reason for failure would be ovarian migration back to their original position. Ovarian failure following transposition may also be due to compromised ovarian blood flow from surgical technique or radiation injury to the vascular pedicle [48]. Pregnancies have been reported after ovarian transposition. Some have occurred spontaneously, but others required reversal of the procedure or ART, which may include abdominal oocyte retrieval if the ovaries are still kept outside the pelvic cavity. 13.21  Pharmacologic Protection 13.21.1

Gonadotropin-Releasing Hormone Agonists

An ideal approach to decrease or eliminate the risk of gonadal damage from chemotherapy would be pharmacologic. The patient can take a medication and proceed with her cancer treatment without undergoing an invasive procedure. The critical step in the development of such a drug is an understanding on how chemotherapy actually causes ovarian follicle destruction. The impact, as stated earlier, depends not only on the type of che-

motherapeutic agents but also on age, ovarian reserve, dose, and duration of treatment. The unique feature of chemotherapy-induced irreversible gonadal damage is the destruction of the primordial follicle, which consists of non-­growing cells. Growing follicles are immediately impacted by chemotherapy, resulting in amenorrhea. Chemotherapeutic agents can directly cause apoptosis of follicles, with the dividing granulosa cells being particularly susceptible to damage [49–51]. This latter phenomenon leads to the theory of “follicle burnout” [49]. Since growing follicles have a direct effect in dampening the initiation of primordial follicle growth, the immediate and complete loss of growing follicles causes an accelerated recruitment of the “resting” primordial follicles and therefore a decrease in the total ovarian follicular reserve. In addition to these effects, chemotherapy can cause stromal fibrosis and damage to intraovarian vessels. The ideal drug would impede these effects. Drugs that act on apoptotic pathways such as sphingosine-1-phosphate or drugs that impede follicle activation pathways such as AMH would be ideal. Most are still in preclinical trials and not available clinically. While testing these drugs, it also is important not to interfere with the efficacy of the cancer treatment. The only drug clinically available for use in patients undergoing gonadotoxic treatment belongs to the class of gonadotropin-­releasing hormone agonists (GnRHa). Protection of gonadal function is more than just preservation of fertility. Many aspects of quality of life are related to gonadal function. Hypogonadal symptoms such as hot flashes, insomnia, vaginal dryness, dyspareunia, and impaired sexual function are equally important. Ovarian failure is associated with osteoporosis, cardiovascular disease, and neurocognitive decline. Therefore drugs that prevent chemotherapeutic damage can be efficacious in maintaining an estrogenic environment and quality of life without necessarily protecting fertility. It is unclear how GnRHa can shield the ovaries from the gonadotoxic effects of chemotherapy. Its effect on suppressing the pituitary gonadotropin secretion is well described.

313 Fertility Preservation

This aspect of the drug cannot be solely responsible for its observed effects as primordial follicle activation is independent of gonadotropins. It may be acting on avoiding follicle recruitment by different mechanisms [49]. GnRHa are thought to decrease vascularity at the level of the ovary, thereby reducing the concentration of chemotherapy acting directly on the ovary [49]. The use of GnRHa during chemotherapy is, therefore, still controversial and considered experimental. In some circumstances such as preventing the severe menstrual bleeding associated with some chemotherapeutic drugs, it is quite effective. GnRHa can be useful for preservation of gonadal function when used in conjunction with chemotherapy in some patients with breast cancer showing more benefit than for lymphoma patients [52–54]. This may be due to the temporal relationship of the diagnosis and initiation of treatment. Breast cancer patients are often delayed to start chemotherapy until after surgery as compared with lymphoma patients who often start immediately. A review of 14 previously published meta-analyses evaluating RCTs on this subject showed mixed results [55]. The majority showed a favorable impact on gonadal protection, but others did not. This is most probably the result of the heterogeneous population of patients with different cancers and different chemotherapy protocols. Additionally, GnRHa are often beneficial as adjuvant treatment in combination with chemotherapy for a subset of patients. Breast cancer patients, including those with estrogen receptor-positive tumors, who received GnRHa co-treatment had increased or no impact on disease-free survival and overall survival compared to chemotherapy alone [52, 53]. In the Prevention of Early Menopause Study [52], a trend toward a higher rate of disease-free survival in those individuals treated with GnRHa was observed, as well as a statistically significant higher rate of overall survival in this group compared to those treated with chemotherapy alone [52]. Similarly, in the Lambertini et  al. study, a trend toward improved 5-year disease-free survival was observed in the GnRHa group versus controls [53].

The impact of GnRHa on improving fertility potential is less clear. It is especially difficult to ascertain because spontaneous pregnancy rates in women after breast cancer treatment are high enough to make clinical studies difficult to interpret. The American Society for Reproductive Medicine (ASRM) recommends the use of GnRHa in concert with other fertility preservation methods for patients who desire future pregnancies [56]. The use of GnRHa does not impede the use of other strategies for fertility preservation [55]. Additionally, the National Comprehensive Cancer Network and the St. Gallen International Expert Consensus panel guidelines support the use of GnRHa for the prevention of ovarian failure secondary to gonadotoxic chemotherapy [42]. For individuals who have completed childbearing but are still far from menopause, GnRHa can be considered with the goal of preserving of ovarian endocrine function.

13.22  Assisted Reproductive

Technology

The utilization of ARTs for patients interested in fertility preservation depends on multiple factors, such as the type of cancer, treatment planned, time until treatment will start, and presence of a partner. There are multiple options available, and today the great majority of these strategies are considered established practices and no longer experimental techniques. The overall goal is to preserve embryos, oocytes, or ovarian tissue for these women prior to treatment, so they may have options to reproduce in the future.

13.23  Embryo Cryopreservation

For postpubertal patients who have a committed male partner, embryo cryopreservation is an established, successful procedure for fertility preservation [56]. The age of the patient and number, stage, and quality of the frozen embryos mainly determine the future likelihood of successful live birth when choosing

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embryo cryopreservation. The chances of a live birth from a cryopreserved (by vitrification) embryo in a woman under the age of 40  years old are 28.5–38.7%. In general, the rewarming survival rate of embryos is very high, around 95%, and across most ages, the clinical pregnancy rate is between 37.5 and 62.5% [57]. A typical IVF cycle for fertility preservation can be done in a couple of weeks from start to finish. In the past, the time constraint was dependent on where the patient was in her menstrual cycle, but today this has been completely removed thanks to the so-called random-­ start ovarian stimulation protocols described below. Some centers have offered natural cycle IVF for breast cancer patients. During this process, a single oocyte is aspirated during a woman’s spontaneous menstrual cycle. Unfortunately, cancellation rates are high, and the pregnancy rates are very low for this protocol (7.2% per cycle and 15.8% per embryo transfer) [58, 59]. Most centers will use mild ovarian stimulation with a GnRH antagonist to prevent ovulation [60], and particularly for breast cancer, the aromatase inhibitor letrozole is an important part of the ovarian stimulation protocol. In patients who present in the luteal phase of the menstrual cycle, gonadotropins can be started immediately (random start) and GnRH antagonists used as needed, thereby reducing the time to retrieval to no more than 2  weeks. Reports in the literature have identified similar dosage requirements, numbers of oocytes retrieved, and fertilization rates in women who started in the luteal phase compared to those who started in the follicular phase of their menstrual cycle [60, 61]. 13.24  Oocyte Cryopreservation

Postpubertal female patients who do not have a male partner or do not wish to fertilize their oocytes and create embryos can cryopreserve their oocytes for future use [62]. Freezing oocytes, rather than embryos, also avoid ethical and legal considerations of embryo storage and disposal, which is of concern for some

patients. The greatest concern about utilizing oocyte cryopreservation is that the success rate in the past was significantly lower than with embryo cryopreservation. Early studies reported a low survival, fertilization, and pregnancy rate with thawed oocytes, mostly due to a technique of cryopreservation called slow freezing, which has been now completely supplanted by a new one called vitrification [63]. The structural complexity of the oocyte is most likely responsible for the reduced success rate in oocyte cryopreservation. Unlike fertilized embryos, the surface-area-to-volume ratio is unfavorable in the oocytes, making water exchange more difficult during the dehydration phase of vitrification and hence more prone to thermal injury [64, 65]. Improvements in the cryopreservation technique have led to significant improvements in the overall outcome of oocyte cryopreservation. The advent of vitrification for cryopreservation, rather than the slow-­ freeze protocol, has reduced the damage caused from ice crystal formation and subsequent cellular damage [66]. Recent reports have seen survival rates after a thaw of 75–90%, fertilization rates of 77%, and live birth rates of 38% [67]. In those pregnancies that have resulted from oocyte cryopreservation, there appears to be no increase in chromosomal abnormalities, birth defects, or developmental deficits [68]. How many oocytes should be cryopreserved to have a good chance for future reproductive success? A survey of the literature on oocyte vitrification reported about 5% live birth rate per vitrified oocyte in women under the age of 36 years, meaning that on average, one live birth should be expected for about 20 vitrified oocytes [69]. Other reports suggest live births with as little as 8–10 frozen-thawed oocytes [70]. 13.25  Tamoxifen and Letrozole

There has been some concern that the high estrogen levels obtained during ovarian stimulation may decrease long-term survival for breast cancer patients. In those women with hormone-sensitive tumors, stimulation with

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cannot delay oncological treatments or cannot undergo ovarian stimulation necessary to create embryos or oocytes for cryopreservation [78]. It is also the only option currently available to prepubertal females. It involves removal of strips of ovarian cortical tissue and freezing it as an avascular graft, in an effort to save thousands of primordial follicles for future use. When the patient is in remission, the frozen-thawed ovarian tissue can then be transplanted back onto the non-­functioning ovary or to a peritoneal site (orthotopic transplants) or to the patient’s subcutaneous tissue (heterotopic transplants). When ovarian cortex is transplanted onto a remaining ovary or on nearby peritoneum, there is not always need for follicular aspiration and ARTs, as the fallopian tube can pick up and transport the 13.25.1 Unconventional spontaneously ovulated oocyte. However, if Stimulation Protocols the ovarian cortex is transplanted heterotopiStudies on ovarian follicle development of cally, then follicular aspiration and in  vitro large domestic species such as sheep and cattle fertilization are required. It is also possible demonstrated how follicular growth proceeds that one day the primordial follicles can be in waves [73]. Likewise in humans, some inves- matured in vitro. One of the concerns about regrafting tistigators have documented the growth of non-­ sue back to the patient is the theoretical risk atretic follicles during the luteal phase [74, of reintroducing cancer cells. This concern 75]. This observation paved the way to a new may limit its use in malignancies that have a stimulation protocol called “duo-stim,” aimed high chance of involving the ovaries, includat collecting oocytes during both the follicuing leukemia and potentially advanced stages lar and luteal phases [76]. Recently, Ubaldi of breast cancers. and collaborators demonstrated the non-­ An additional limitation to the procedure inferiority of collecting oocytes during the is the loss of a large fraction of follicles durluteal as compared to follicular phase in terms ing the initial ischemia that occurs after transof maturity, chances for fertilization, developplantation [79–81]. Previous work indicated ment, and euploidy rate [77]. Therefore, the that while loss due to freezing is relatively possibility to harvest oocytes during both small, up to two-thirds of follicles are lost phases of the cycle is a suitable tool for fertilsubsequent to transplantation. ity preservation patients as it allows to maxiThe return of ovarian function (after mize the number of gametes cryopreserved about 4  months from the transplant) and without having to wait for a new menstrual the occurrence of many pregnancies (>150 cycle to repeat stimulation cycles and conselive births), both spontaneous and after IVF quently delay cancer therapies. have been documented in patients after orthotopic transplantation [82–85]. It is however difficult to estimate the true pregnancy rate 13.26  Cryopreservation of Ovarian after ovarian transplantation because there is Tissue not an official registry that can keep track of the number of cases performed, and there is Ovarian tissue cryopreservation is no longer lacking of proper follow-up for many of the considered an experimental procedure and is women who received the regrafting. However, indicated to preserve fertility in women who a pregnancy rate of about 25–30% has been tamoxifen, a nonsteroidal antiestrogen, or letrozole, an aromatase inhibitor, may be beneficial. In a manner similar to clomiphene citrate, tamoxifen (40–60  mg) is started on day 2 or 3 of the cycle and given daily for 5–12  days. Letrozole has more recently been utilized as an ovulation induction agent as well. Adding letrozole at doses of 2.5 mg or 5 mg during a standard gonadotropin stimulation protocol has been shown to lower total serum estradiol levels [71]. To date, ovarian stimulation for fertility preservation has not been associated with an increase in breast cancer recurrence rates [71, 72].

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reported by the groups with the largest experience [86]. In some patients, this does not exclude the possibility that ovarian function resumed from areas in the ovary that had not been removed and reimplanted. Of note, another advantage of ovarian cortical freezing and retransplant is the preservation of the endocrine function.

strips is not yet possible. Contrary to in vitro maturation of oocytes from antral follicles, which requires days to mature, in  vitro ­maturation of oocytes derived from primordial follicles would require months [88–90]. 13.28  Whole Ovary

Cryopreservation

13.27  In Vitro Maturation

13

In vitro maturation is another potential modality for obtaining oocytes with little or no ovarian stimulation. In the context of fertility preservation for cancer patients, this approach appears most effective in patients who undergo ovarian tissue freezing, where oocytes can be harvested from visible follicles on the ovarian strips and allowed to mature in vitro. In these instances, a patient will benefit from cryopreservation of both ovarian tissue and in vitro matured oocytes (87, 88). In addition, IVM can be attractive for patients who have multiple follicles (e.g., polycystic ovaries), some of which will inevitably provide immature oocytes at the time of retrieval. Patients with a clear contraindication to ovarian stimulation can also benefit from IVM. In these instances, an ultrasound is performed on days 6–8 of the cycle, and human chorionic gonadotropin (hCG) is given to help increase oocyte maturity at the time of retrieval. Oocyte retrieval is scheduled 36 h later and immature oocytes are obtained and incubated in special culture media. If the oocytes mature in 24 h, as determined by extrusion of the first polar body, either the oocytes or embryos (if fertilization is attempted) can be cryopreserved. This procedure is significantly less successful than those mentioned earlier. To date, over 300 live births have resulted from this procedure; however, significantly fewer embryos will be obtained per cycle, and the chance of implantation, pregnancy, and live birth is lower than conventional IVF [89]. In vitro maturation of primordial follicles obtained from frozen-thawed ovarian cortical

One of the major limitations of ovarian tissue freezing is the result of ischemia-induced damage to the tissue, which consequently impacts the viability of the primordial follicles within the cortex. Freezing an intact whole ovary instead of ovarian cortex could be used as an option for fertility preservation [91]. By harvesting the ovary and maintaining its vascular anastomosis, there are higher chances of follicle pool survival. Moreover, the entire follicular pool will be transplanted as opposed to a portion of it. Clearly, there are still several obstacles to this procedure, such as the complex microsurgery needed for transplantation and the technical limitations of the cryopreservation procedures [91]. If from one side the surgical limitations have been overcome by some, resulting in successful pregnancies in animals and in humans [92–96], cryopreservation of an entire organ still represents a major challenge. Technically, it requires the penetration of an adequate amount of cryoprotectant into a rather complex tissue such as the ovary. Although no attempts of frozen-thawed human whole ovary transplantation have been performed to date, promising results have been reported for experimental models with large animals such as ewes and sheep [96, 97]. An alternative, new method of fertility preservation is based on an ex  vivo perfusion platform of whole ovaries using a bioreactor. Preliminary results using ewe ovaries are very promising in being able to maintain the whole organ in culture for 7 days and stimulating in vitro folliculogenesis. This method could be beneficial for prepubertal girls and for cases of cancer with ovarian metastasis [98].

317 Fertility Preservation

13.29  Review Questions ?? 1. Which of the following fertility preservation options is still considered experimental research? A. Oocyte freezing B. Ovarian tissue cryopreservation C. Ovarian transposition D. In vitro follicular maturation ?? 2.  Which of the following is an appropriate means to evaluate the ovarian reserve of women planning to undergo fertility preservation? A. Antral follicle count (AFC), FSH, progesterone, and estradiol B. Antral follicle count (AFC), FSH, estradiol, and AMH C. Antral follicle count (AFC), LH, FSH, and inhibin B D. AMH, FSH, LH, and progesterone ?? 3. The return of ovarian function after the retransplant of ovarian tissue occurs: A. At about 2 months from the transplant B. At about 1  month from the transplant C. At about 4 months from the transplant D. At about 6 months from the transplant

13.30  Answers

3.

4.

5.

6.

7.

8.

9.

10.

11.

vv 1. D vv 2. B

12.

vv 3. C

References 1.

2.

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13

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treated with chemotherapy: final long-term report of a prospective randomized trial. J Clin Oncol. 2016;34:2568–74. 55. Hickman LC, Valentine LN, Falcone T. Preservation of gonadal function in women undergoing chemotherapy: a review of the potential role for gonadotropin-releasing hormone agonists. Am J Obstet Gynecol. 2016;215(4):415–22. 56. Practice Committee of American Society for Reproductive Medicine. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril. 2013;100:1214–23. 57. Kolibianakis EM, Venetis CA, Tarlatzis BC. Cryopreservation of human embryos by vitrification or slow freezing: which one is better? Curr Opin Obstet Gynecol. 2009;21:270–4. 58. Oktay K, Buyuk E, Davis O, Yermakova I, Veeck L, Rosenwaks Z.  Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod. 2003;18:90–5. 59. Pelinck MJ, Hoek A, Simons AH, Heineman MJ. Efficacy of natural cycle IVF: a review of the literature. Hum Reprod Update. 2002;8:129–39. 60. Noyes N, Knopman JM, Melzer K, Fino ME, Friedman B, Westphal LM. Oocyte cryopreservation as a fertility preservation measure for cancer patients. Reprod Biomed Online. 2011;23:323–33. 61. von Wolff M, Thaler CJ, Frambach T, Zeeb C, Lawrenz B, Popovici RM, Strowitzki T.  Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase. Fertil Steril. 2009;92:1360–5. 62. Practice Committees of American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. Mature oocyte cryopreservation: a guideline. Fertil Steril. 2013;99: 37–43. 63. Oktay K, Kan MT, Rosenwaks Z.  Recent progress in oocyte and ovarian tissue cryopreservation and transplantation. Curr Opin Obstet Gynecol. 2001;13:263–8. 64. Magistrini M, Szollosi D.  Effects of cold and of isopropyl-N-phenylcarbamate on the second meiotic spindle of mouse oocytes. Eur J Cell Biol. 1980;22:699–707. 65. Stachecki JJ, Cohen J, Willadsen S.  Detrimental effects of sodium during mouse oocyte cryopreservation. Biol Reprod. 1998;59:395–400. 66. Shaw JM, Jones GM. Terminology associated with vitrification and other cryopreservation procedures for oocytes and embryos. Hum Reprod Update. 2003;9:583–605. 67. Doyle JO, Richter KS, Lim J, Stillman RJ, Graham JR, Tucker MJ. Successful elective and medically indicated oocyte vitrification and warming for autologous in vitro fertilization, with predicted birth probabilities for fertility preservation according to number of cryopreserved oocytes and age at retrieval. Fertil Steril. 2016;105:459–66.. e2

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68. Noyes N, Porcu E, Borini A. Over 900 oocyte cryopreservation babies born with no apparent increase in congenital anomalies. Reprod Biomed Online. 2009;18:769–76. 69. ESHRE Task Force on Ethics and Law, Dondorp W, de Wert G, Pennings G, Shenfield F, Devroey P, Tarlatzis B, Barri P, Diedrich K. Oocyte cryopreservation for age-related fertility loss. Hum Reprod. 2012;27:1231–7. 70. Cobo A, Garcia-Velasco JA, Coello A, Domingo J, Pellicer A, Remohi J. Oocyte vitrification as an efficient option for elective fertility preservation. Fertil Steril. 2016;105:755–64.. e8 71. Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z.  Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol. 2005;23:4347–53. 72. Azim AA, Costantini-Ferrando M, Oktay K. Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study. J Clin Oncol. 2008;26:2630–5. 73. Evans AC. Characteristics of ovarian follicle development in domestic animals. Reprod Domest Anim. 2003;38:240–6. 74. Baerwald AR, Adams GP, Pierson RA. A new model for ovarian follicular development during the human menstrual cycle. Fertil Steril. 2003;80:116–22. 75. McNatty KP, Hillier SG, van den Boogaard AM, Trimbos-Kemper TC, Reichert LE Jr, van Hall EV. Follicular development during the luteal phase of the human menstrual cycle. J Clin Endocrinol Metab. 1983;56:1022–31. 76. Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, Shoham Z. Double stimulations during the follicular and luteal phases of poor responders in IVF/ ICSI programmes (Shanghai protocol). Reprod Biomed Online. 2014;29:684–91. 77. Ubaldi FM, Capalbo A, Vaiarelli A, Cimadomo D, Colamaria S, Alviggi C, Trabucco E, Venturella R, Vajta G, Rienzi L. Follicular versus luteal phase ovarian stimulation during the same menstrual cycle (DuoStim) in a reduced ovarian reserve population results in a similar euploid blastocyst formation rate: new insight in ovarian reserve exploitation. Fertil Steril. 2016;105:1488–95.. e1 78. Oktay K, Buyuk E. The potential of ovarian tissue transplant to preserve fertility. Expert Opin Biol Ther. 2002;2:361–70. 79. Aubard Y. Ovarian tissue graft: from animal experiment to practice in the human. Eur J Obstet Gynecol Reprod Biol. 1999;86:1–3. 80. Baird DT, Webb R, Campbell BK, Harkness LM, Gosden RG.  Long-term ovarian function in sheep after ovariectomy and transplantation of autografts stored at −196 ° C. Endocrinology. 1999;140:462–71. 81. Oktay K, Nugent D, Newton H, Salha O, Chatterjee P, Gosden RG.  Isolation and characterization

82.

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of primordial follicles from fresh and cryopreserved human ovarian tissue. Fertil Steril. 1997;67: 481–6. Donnez J, Dolmans MM, Demylle D, Jadoul P, Pirard C, Squifflet J, Martinez-Madrid B, van Langendonckt A. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;364:1405–10. Silber S, Pineda J, Lenahan K, DeRosa M, Melnick J. Fresh and cryopreserved ovary transplantation and resting follicle recruitment. RBMO. 2015;30:643–50. Meirow D, Levron J, Eldar-Geva T, Hardan I, Fridman E, Zalel Y, Schiff E, Dor J.  Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med. 2005;353:318–21. Oktay K, Buyuk E, Veeck L, Zaninovic N, Xu K, Takeuchi T, Opsahl M, Rosenwaks Z. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;363:837–40. Andersen CY.  Success and challenges in fertility preservation after ovarian tissue grafting. Lancet. 2015;385:1947–8. Nikiforov D, Junping C, Cadenas J, Shukla V, Blanshard R, Pors SE, Kristensen SG, Macklon KT, Colmorn L, Ernst E, Bay-Bjørn AM, Ghezelayagh Z, Wakimoto Y, Grøndahl ML, Hoffmann E, Andersen CY.  Improving the maturation rate of human oocytes collected ex  vivo during the cryopreservation of ovarian tissue. J Assist Reprod Genet. 2020;37(4):891–904. Silber S.Goldsmith S, Castleman L, Hurlbut K, Fan Y, Melnick J, Hayashi K.  In vitro maturation and transplantation of cryopreserved ovarian tissue: understanding ovarian longevity. RBMO. 2022 (in press). Smitz JE, Thompson JG, Gilchrist RB. The promise of in  vitro maturation in assisted reproduction and fertility preservation. Semin Reprod Med. 2011;29:24–37. McLaughlin M, Albertini DF, Wallace WHB, Anderson R, Telfer E.  Metaphase II oocytes from human unilaminar follicles grown in a multi-step culture system. Mol Hum Reprod. 2018;24:135– 14291. Wallin A, Ghahremani M, Dahm-Kahler P, Brannstrom M. viability and function of the cryopreserved whole ovary: in vitro studies in the sheep. Hum Reprod 2009;24:1684–94. Brännström M, Milenkovic M. Whole ovary cryopreservation with vascular transplantation  – a future development in female oncofertility. Middle East Fertil Soc J. 2010;15:125–38. Racho El-Akouri R, Kurlberg G, Dindelegan G, Molne J, Wallin A, Brannstrom M.  Heterotopic uterine transplantation by vascular anastomosis in the mouse. J Endocrinol. 2002;174:157–66. Silber SJ, Grudzinskas G, Gosden RG.  Successful pregnancy after microsurgical transplantation of an intact ovary. N Engl J Med. 2008;359:2617–8.

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94. Wranning CA, Akhi SN, Kurlberg G, Brannstrom M. Uterus transplantation in the rat: model development, surgical learning and morphological evaluation of healing. Acta Obstet Gynecol Scand. 2008;87:1239–47. 95. Wranning CA, El-Akouri RR, Lundmark C, Dahm-Kahler P, Molne J, Enskog A, Brannstrom M.  Auto-transplantation of the uterus in the domestic pig (Sus scrofa): surgical technique and early reperfusion events. J Obstet Gynaecol Res. 2006;32:358–67. 96. Imhof M, Bergmeister H, Lipovac M, Rudas M, Hofstetter G, Huber J.  Orthotopic microvascular reanastomosis of whole cryopreserved ovine ovaries resulting in pregnancy and live birth. Fertil Steril. 2006;85(Suppl 1):1208–15.

97. Torre A, Vertu-Ciolino D, Mazoyer C, Selva J, Lornage J, Salle B.  Safeguarding fertility with whole ovary cryopreservation and microvascular transplantation: higher follicular survival with vitrification than with slow freezing in a ewe model. Transplantation. 2016;100(9):1889–97. 98. Tsiartas P, Mateoiu C, Deshmukh M, Banerjee D, Arvind M, Padma AM, Milenkovic M, Gandolfi F, Hellström M, Patrizio P, Akouri R. Seven days ex vivo perfusion of whole ewe ovaries with follicular maturation and oocyte retrieval: towards the development of an alternative fertility preservation method. Reprod Fertil Dev. (epub 1/28/2022). https://doi.org/10.1071/RD21197.

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Ovarian Reserve Testing Paula Amato Contents 14.1

Introduction – 324

14.2

Basic Principles of Screening Tests – 326

14.3

A Shortened Menstrual Cycle – 326

14.4

Biochemical Markers of Ovarian Response – 327

14.4.1

Basal Follicle Stimulating Hormone – 327

14.5

Basal Estradiol – 327

14.6

Anti-Müllerian Hormone – 328

14.7

Inhibin B – 328

14.8

Clomiphene Citrate Challenge Test – 329

14.9

Home Fertility Tests – 329

14.10 Ultrasound Evaluation of Ovarian Reserve – 329 14.10.1 Antral Follicle Count – 329

14.11 Ovarian Volume – 330 14.12 Combined Ovarian Reserve Tests – 330 14.13 Repetitive Testing – 330 14.14 Review Questions – 332 14.15 Answers – 332 References – 332

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 T. Falcone, W. W. Hurd (eds.), Clinical Reproductive Medicine and Surgery, https://doi.org/10.1007/978-3-030-99596-6_14

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Key Points 55 Currently, AMH and antral follicle count (AFC) are the most sensitive and reliable markers of ovarian reserve. 55 Markers of ovarian reserve do not predict reproductive potential, independent of age, in women with unproven fertility. 55 Markers of ovarian reserve predict ovarian response and oocyte yield during controlled ovarian stimulation in the context of IVF.

reproductive potential [1, 2]. Ovarian reserve testing should be performed in women older than 35  years who have not conceived after 6 months of attempting pregnancy (or women less than 35 who have not conceived after 1  year) and women at higher risk of diminished ovarian reserve, such as those with a history of cancer or other medical conditions treated with gonadotoxic therapy and/or pelvic irradiation, or women who have had ovarian surgery for endometriomas. Available tests for ovarian reserve include biochemical markers, i.e., FSH, estradiol, AMH, and inhibin B, and ovarian ultrasound imaging, i.e., antral follicle count and ovarian volume [1] (. Fig.  14.1). For general obstetrician-­gynecologists, the most appropriate ovarian reserve screening tests to use in practice are basal FSH plus estradiol levels or anti-Müllerian hormone (AMH) levels. An antral follicle count (AFC) may also be useful  

14.1

Introduction

The general purpose of ovarian reserve testing is to assess the quantity and quality of the remaining oocytes in an attempt to predict Poor Response to Ovarian Stimulation Test

Nonpregnancy*

Cutpoint Sensitivity Specificity Sensitivity Specificity Reliability Advantages

FSH 10–20 (international units/L)

10–80

83–100

7–58

43–100

Limited

AMH (ng/mL) 0.2–0.7

40–97

78–92

†

†

Good

AFC (n)

3–10

9–73

73–100

8–33

64–100

Good

Inhibin B (pg/mL)

40–45

40–80

64–90

†

–

Limited

CCCT, day 10 10–22 FSH (international units/L)

35–98

68–98

23–61

67–100

Limited

Limitations

Widespread Reliability use Low sensitivity Reliability

14

Limit of detectability Two commercial assays Does not predict nonpregnancy

Reliability Low sensitivity Widespread use –

Reliability Does not predict nonpregnancy

Higher Reliability sensitivity Limited additional than basal value to basal FSH FSH Requires drug administration

Abbreviations: AFC, antral follicle count; AMH, antimüllerian hormone; CCCT, clomiphene citrate challenge test; FSH, follicle-stimulating hormone. Note: Laboratories ELISA. *Failure to conceive †Insufficient evidence Testing and interpreting measures of ovarian reserve: a committee opinion. Practise Committee of the American Society for reproductiveMedicine. Fertile Steril 2012;98:1407-15.

..      Fig. 14.1  Available tests for ovarian reserve include biochemical markers, i.e., FSH, estradiol, AMH, and inhibin B, and ovarian ultrasound imaging, i.e., antral follicle count and ovarian volume

325 Ovarian Reserve Testing

Advanced reproductive age (older than 35 years) Family history of early menopause Genetic conditions (eg, 45, X mosaicism) FMR1 (Fragile X) premutation carrier Conditions that can cause ovarian injury (eg, endometriosis, pelvic infection) Previous ovarian surgery (eg, for endometriomas) Oophorectomy History of cancer treated with gonadotoxic therapy or pelvic irradiation History of medical conditions treated with gonadotoxic therapies Smoking Data from Testing and interpreting measures of ovarian reserve:a committee opinion. Practice Committee of the American Society for Reproductive Medicin e. Fertile Steril 2012;98:1407–15; Gurtcheff SE, Klein NA_Diminished ovarian reserve and infertility. Clin Obstet Gynecol 2011;54:666–74; te Velde ER, Pearson PL Thevariability of female reproductive ageing. Hum Reprod Update 200;8:141–54; and Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. ESHRE working group on poor Ovarian Response Definition. HUM Repord 2011;26:1616–24. ..      Fig. 14.2  Risk factors for diminished ovarian reserve

if there is an indication to perform transvaginal ultrasonography. These screening tests are better predictors of oocyte yield from ovarian stimulation during in vitro fertilization (IVF) than rate of pregnancy. Low ovarian response to stimulation, usually defined as fewer than three to five developing follicles during an IVF cycle, is an indicator of a poor reproductive outcome. It is important to recognize, however, that a poor result from ovarian reserve testing does not signify an absolute inability to conceive and should not be the sole criteria considered to limit or deny access to infertility treatment. Although these tests are used to assess oocyte quantity and quality, the best surrogate marker for oocyte quality is age. At this time, ovarian reserve testing results cannot be extrapolated to predict the likelihood of spontaneous conception.

As women age oocytes decrease in quality and quantity and do not regenerate. The number of human oocytes in a female peaks at 6–7 million during fetal life around midgestation, followed by profound atresia. Approximately one to 2 million oocytes are present at birth, 300,000–500,000 at the start of puberty, and 1000 at 51 years of age, which is the average age of menopause in the USA [2]. Factors such as genetics, lifestyle, environment, and medical issues including endometriosis, ovarian surgery, chemotherapy, and radiation can influence the quantity and quality of a woman’s oocytes [1] (. Fig. 14.2). Cross-sectional studies suggest that fertility declines before the onset of the premenopausal transition. The goal of ovarian reserve testing is to add more prognostic information to the counseling and planning process so as to help couples  

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P. Amato

chose among treatment options. Ovarian reserve tests should not be the sole criteria used to deny patients access to assisted reproductive technology or other treatments. Evidence of decreased ovarian reserve does not necessarily equate with inability to conceive. In women from the general population, with no known history of infertility, who are attempting to conceive naturally, cumulative probability of pregnancy has been shown to decrease with age [3]. Cross-sectional studies have shown that chronological age is correlated with ovarian reserve, as measured by the size of the follicle pool in histologic studies of ovaries. Chronological age is strongly associated with other biomarkers of ovarian reserve including antral follicle count, anti-Müllerian hormone (AMH) levels, and early follicular phase follicle-stimulating hormone (FSH) levels. Chronological age is an excellent predictor of fertility among infertile women undergoing assisted reproduction [4]. Existing research on ovarian reserve testing is often confusing because of heterogeneity among tested populations (the general population, infertility patients of all ages, infertility patients more than 35  years old, etc.). No single result is definitive, since findings must be interpreted in context and should be repeated or supplemented as appropriate. This chapter will discuss the application of ovarian reserve tests in evaluating fertility. Case Vignette

A 38-year-old nulligravid female and her male partner present with a 3-year history of infertility. She has regular cycles. A hysterosalpingogram shows a normal uterine cavity and bilateral patent tubes. Her AMH level is 0.7  ng/mL.  Day 3 FSH and estradiol levels are 11 IU/L and 20 pg/dL, respectively. Her partner had a semen analysis which showed normal semen parameters. The couple has failed three cycles of controlled ovarian stimulation using clomiphene citrate in combination with intrauterine insemination (IUI). How would you counsel this patient regarding her treatment options and chance of pregnancy success?

14.2

 asic Principles of  B Screening Tests

The purpose of using ovarian reserve testing as a screening test is to identify infertility patients at risk for decreased ovarian reserve, who are likely to exhibit a poor response to gonadotropin stimulation and to have a lesser chance of achieving pregnancy with IVF.  Good screening tests have validity as measured by sensitivity and specificity. A valid test correctly categorizes persons who have disease as test positive (highly sensitive) and those without disease as test negative (highly specific). For clinical purposes, specificity is the test characteristic that should be optimized to decrease false positives or wrongly categorizing patients with normal ovarian reserve as having decreased ovarian reserve (DOR). Graphically, the sensitivity and specificity of different cut-off points of a diagnostic test can be plotted as receiver operating characteristic (ROC) curves. Positive predictive value (PPV) and negative predictive value (NPV) are screening test characteristics that change with the prevalence of disease (DOR) in the study population. The PPV is the probability that a woman who tests positive truly has DOR. The NPV is the probability that a woman who tests negative has normal ovarian reserve. Ovarian reserve testing is most useful in identifying DOR in women at high risk for DOR. Ovarian reserve testing in women at low risk for DOR will yield a larger number of false-­positive results (lower PPV).

14.3

A Shortened Menstrual Cycle

As the ovary ages, the size of the follicle pool declines. Fewer follicles result in less production of AMH and inhibin. Because of lower inhibin levels, FSH rises prematurely or more rapidly leading to elevated early follicular phase serum FSH levels. Premature and rapid follicular growth results in elevated early follicular phase estradiol levels and a shortened follicular phase and overall shortened men-

327 Ovarian Reserve Testing

strual cycle. A short menstrual cycle length is associated with a lower probability of conceiving naturally or following IVF [5]. The cut-off value to define “short” cycle length varies by study ranging from 25 to 26 days.

14.4

Biochemical Markers of Ovarian Response

14.4.1

 asal Follicle Stimulating B Hormone

Follicle stimulating hormone is released by the pituitary gland in response to gonadotropin-­ releasing hormone from the hypothalamus and is subject to negative feedback from estradiol and inhibin B. In the setting of a smaller follicular cohort and decreased estradiol and inhibin B levels, an increase in pituitary FSH secretion occurs, which can be identified as an elevated early follicular phase FSH level. This higher FSH level stimulates rapid ovarian follicular growth, which results in higher estradiol levels as well as a shorter follicular phase and menstrual cycle. FSH is typically measured by immunoassay on cycle day 3. The basal FSH level can vary, so a single FSH value has limited reliability. Moreover, there is variability among different FSH assays. Although basal FSH is commonly used to assess ovarian reserve, and high values (>10–20 IU/L) are associated with diminished ovarian reserve and poor response to ovarian stimulation, the test is not predictive of failure to conceive [6]. If FSH values are consistently elevated, a poor reproductive prognosis is likely; in contrast, a single elevated FSH value in women younger than 40 years predicts a lower oocyte yield during IVF but does not predict the rate of pregnancy [7]. Early follicular phase FSH levels have not been a sensitive test for nonpregnancy, suggesting that an elevated FSH is an excellent predictor of nonpregnancy following ART, but a normal level is not predictive of preg-

nancy. The value of serum or urinary FSH levels as predictors of reproductive potential in the general population has not been determined. Testing is cycle day specific (cycle days 2–4), limiting flexibility. Women having an abnormally elevated FSH value will have DOR. The PPV of FSH for poor response to ovarian stimulation or failure to conceive is higher in older women. Limited evidence suggests that women with fluctuating FSH levels should not wait for the ideal cycle, wherein the FSH concentration is normal, to undergo IVF stimulation [8]. FSH is a late marker of dwindling ovarian function. With AMH and AFC demonstrating better predictive value for ovarian response than FSH, these are more likely to be the tests of choice. It remains unknown whether high FSH levels in women of reproductive age predict an earlier onset of menopause.

14.5

Basal Estradiol

Estradiol levels vary over the course of a menstrual cycle, peaking in both the late follicular and mid-luteal phases. As ovarian reserve declines, the follicular phase shortens because of decreasing feedback inhibition by follicles recruited during the previous cycle. As a result, an elevated day 3 estradiol level could reflect diminishing ovarian reserve. Estradiol is released from the ovary during follicular development. The estradiol level is usually low (60– 80  pg/mL) in the early follicular phase can indicate reproductive aging and hastened oocyte development. Through central negative feedback, a high estradiol level can suppress an elevated FSH concentration into the normal range. The value of obtaining an estradiol level is that it allows the correct interpretation of a normal basal FSH level. Basal estradiol has low predictive accuracy for poor ovarian response and failure to conceive and, therefore, this test should not be used in isolation to assess ovarian reserve [9].

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14.6

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P. Amato

Anti-Müllerian Hormone

AMH is a homodimeric glycopeptide that is produced predominantly by granulosa cells. AMH is believed to downregulate FSH-­ ­ mediated folliculogenesis. Its expression is highest in secondary, preantral, and small antral follicles. AMH seems to have a role in selecting the dominant follicle in addition to generally mediating preantral follicular recruitment. AMH levels start undergoing a log-linear decline approximately 15 years prior to menopause and drop to very low levels approximately 5 years before menopause [10]. The anti-Müllerian hormone concentration is fairly stable within and between menstrual cycles [11]. As the number of ovarian follicles decreases with age, a concomitant decrease in AMH levels occurs, which reflects this age-related oocyte depletion [12]. Although an undetectable AMH level suggests diminished ovarian reserve and can identify individuals at risk of poor ovarian response to stimulation, undetectable and low AMH levels (0.2–0.7 ng/mL DSL ELISA) are not predictive of failure to conceive [13]. AMH levels may allow treatment to be tailored to each individual. Lower AMH levels are associated with reduced ovarian response to stimulation, and high levels are associated with a brisk ovarian response to stimulation [13]. Although the AMH level is a good predictor of oocyte quantity, it may not provide information about egg quality. Young women with low AMH levels may have a reduced number of oocytes but normal age-­appropriate oocyte quality [14]. One limitation of AMH level testing is the variability of results between the available assays. In clinical practice, individual AMH-­ level test results must be interpreted based on the normal range of the assay used [15]. AMHlevel testing is a useful screening test in women at high risk of diminished ovarian reserve and in women undergoing IVF [16, 17]. The nonpregnancy predictive value of a low AMH value appears to increase if older women at risk for ovarian aging are tested. The use of AMH as a routine screening tool for DOR in a low-risk population is not recommended.

AMH-level testing may be valuable in assessing ovarian reserve in young women with cancer before and after chemotherapy [18]. AMH may enable assessment of ovarian reserve before and after ovarian surgery and for women at high risk of primary ovarian insufficiency. AMH-level testing may in future provide an accurate method of predicting the reproductive lifespan and the timing of menopause [19]. AMH has the advantage over FSH in that AMH levels remain relatively stable over the menstrual cycle; thus measurement does not need to be cycle day specific. A recent meta-­ analysis of earlier studies showed no significant association between AMH, modeled as a continuous variable, and pregnancy following ART [20]. However, more recent studies of larger sizes, modeling AMH using cut-off values, have shown lower odds of pregnancy and live birth following ART among women with low AMH levels [21–24]. High AMH values are associated with polycystic ovary syndrome (PCOS) and may identify women at risk of ovarian hyperstimulation syndrome (OHSS). It is believed that AMH remains a valid assay even when ovarian suppression occurs through oral contraceptives, although age-specific AMH percentiles decrease by 11% with oral contraceptives [25].

14.7

Inhibin B

Inhibin B is a glycoprotein hormone that is secreted primarily by preantral and antral follicles. The serum concentration of inhibin B decreases with the age-related decrease in the number of oocytes. Inhibin B has central negative feedback that controls FSH secretion. Therefore, a decrease in inhibin B levels leads to increased pituitary FSH secretion and higher early follicular FSH levels. Inhibin B levels exhibit high intra-cycle variability [16]. Inhibin B levels also vary significantly between menstrual cycles [16]. Inhibin B levels are a late finding for diminished ovarian reserve and typically start falling around 4 years prior to menopause [10],

329 Ovarian Reserve Testing

and are thus suboptimal. Inhibin levels are measured by immunoassay. Inhibin B is typically measured on the third day of the menstrual cycle. It has limited sensitivity and specificity. This marker does not reliably predict a poor response to ovarian stimulation and thus is not a recommended test.

14.8

Clomiphene Citrate Challenge Test

Clomiphene is a selective estrogen receptor modulator (SERM) that inhibits negative feedback inhibition by estradiol on the hypothalamus, thereby increasing FSH secretion, which enhances follicular recruitment. Clomiphene can be used for ovulation induction and superovulation. The clomiphene citrate challenge test is performed by measuring serum FSH on cycle day 3, administering 100  mg clomiphene citrate daily on cycle days 5–9, and again measuring serum FSH on cycle day 10. An elevated FSH level on day 10 of the CCCT is suggestive of diminished ovarian reserve. However, cycle-to-cycle variability in ovarian biomarkers limits the reliability of this provocative test [26]. The stimulated FSH level on cycle day 10 of the CCCT is predictive of poor ovarian response but is not predictive of failure to conceive [27]. Compared with the basal FSH level and the antral follicle count, the cycle-day-10 FSH level does not improve the prediction for poor ovarian response [27]. In studies comparing the test performance of basal (cycle day 3) and stimulated (cycle day 10) FSH values, stimulated FSH levels have higher sensitivity but lower specificity than basal FSH concentrations [27]. In summary, basal measure of FSH may be preferable to the CCCT, unless one is using the test to purposely increase sensitivity. It is unclear if the CCCT confers any benefit over basal FSH alone, and it is less cost-effective. The CCCT may have a role in helping discriminate normal ovarian reserve from poor ovarian reserve in patients with potentially borderline function.

14.9

Home Fertility Tests

Available home fertility tests use a urine sample to assess the FSH level on cycle day 3. The tests are marketed directly to consumers. The limitations of these tests include misinterpretation of instructions and results and the unavailability of a medical professional to interpret and explain the results [1]. Although these tests are used commonly by women at low risk of diminished ovarian reserve, the results may provide false reassurance or raise unnecessary concern.

14.10

Ultrasound Evaluation of Ovarian Reserve

14.10.1

Antral Follicle Count

The antral follicle count records the number of visible ovarian follicles (2–10  mm mean diameter) that are observed during transvaginal ultrasonography in the early follicular phase (cycle days 2–5). The number of antral follicles correlates with the quantity of remaining follicles and with the ovarian response during controlled ovarian stimulation. Good intercycle and interobserver reliability has been demonstrated [16]. A low antral follicle count is considered three to six total antral follicles and is associated with poor response to ovarian situation during IVF, but it does not reliably predict failure to conceive; in a meta-analysis, a low antral follicle count was a mean of 5.2 (2.11 SD) total antral follicles [28]. When AFC was compared to age, basal FSH, basal estradiol, AMH, inhibin B, and ovarian volume, antral follicle count and AMH were the most significant predictors of poor response to ovarian stimulation but were not predictive of failure to conceive [29]. Low AFC cut-off points are highly specific for predicting poor ovarian response but have lower sensitivity [28]. The high specificity of a low AFC makes the test useful for predicting poor ovarian response and treatment

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failure, but its clinical utility is limited by its low sensitivity. Inter- and intra-observer variability also may be limiting. There is a debate regarding the effect of oral contraceptives on the measurement of antral follicle count.

14.11

14

Ovarian Volume

The calculation of ovarian volume requires ovarian measurements in three planes and the use of the formula for the volume of an ellipsoid: D1 × D2 × D3 × 0.52. Mean ovarian volume, the average volume calculated for both ovaries from the same individual, is the value used to assess ovarian reserve. With age, changes in ovarian volume are concordant with the age-related decrease in ovarian ­follicles. Several studies have demonstrated that low ovarian volume, typically   4 mIU/L during pregnancy is associated with miscarriage and routine screening with TSH levels should be offered in RPL [63]. 15.6.3.2

Thyroid Autoimmunity

The presence of anti-thyroid antibodies may imply abnormal T-cell function, suggesting an additional immune-mediated role in causing pregnancy loss. For women with thyroid antibodies and a serum TSH 2–4mIU/L, treatment should be considered in early pregnancy [67]. Selenium is postulated to play a key role in thyroid homeostasis through integration into thyroid enzymes responsive for protection against immune-mediated oxidative damage. There have been several studies suggesting selenium treatment to reduce antibody levels, which may allow for lower doses or thyroxine supplementation in women with Hashimoto’s thyroiditis. Unfortunately, there are no current randomised controlled trials to support this treatment in RPL [68]. 15.6.3.3

15

Hyperthyroidism

Hyperthyroidism, found in 0.1–0.4% of pregnancies, is not a known causative factor of RPL.  Nevertheless, it is noted that women with untreated overt hyperthyroidism are at high risk of thyroid storm, congestive heart failure, pre-eclampsia, preterm birth and spontaneous miscarriage [69, 70]. 15.6.4

Management of Thyroid Dysfunction in RPL

In conclusion, screening with TSH and thyroid autoantibodies and treatment of subclinical hypothyroidism are recommended in women with RPL.  Thyroxine administration, commencing at a low dose such as 50 microg daily, is a safe and effective method in reducing early pregnancy loss in women with overt hypothyroidism or in euthyroid women with antithyroid antibodies. Current recommendations support thyroxine administration for TSH >4

mIU/L but not at TSH of 2.5–4 mIU/L in the absence of thyroid antibodies [63, 71]. 15.6.5

Abnormal Glucose Metabolism

Pregestational diabetes complicates around 1% of pregnancies, and many studies have shown patients with poorly controlled diabetes are known to have an elevated risk of spontaneous miscarriage, preterm birth and hypertensive disorders. The main underlying cause of miscarriage is thought to be lethal embryonic malformations due to glucose teratogenicity if the patient has poorly controlled diabetes in the periconceptional period [72, 73]. Current evidence suggests that well-­controlled diabetes is not a risk factor for RPL and that optimal metabolic control for diabetic women is crucial in the periconceptional period and first trimester [1, 4]. Metformin is known to be a safe, effective and low-risk oral hypoglycaemic agent for management of diabetes [73]. 15.6.6

Hyperprolactinaemia

Prolactin is commonly measured because elevated prolactin levels are associated with ovulatory dysfunction. The underlying mechanism is unclear, but prolactin is postulated to maintain corpus luteum function and progesterone secretion, although the mechanism is still unclear [74]. Normalisation of prolactin levels in RPL population, with a dopamine agonist such as bromocriptine, was effective in preventing miscarriages but showed no significant difference in conception and live birth rates [75]. Due to the absence of consistent evidence on its association with RPL, prolactin testing is not routinely recommended in the absence of symptoms of hyperprolactinaemia such as oligo- or amenorrhoea [1]. 15.6.7

Diminished Ovarian Reserve

Diminished ovarian reserve (DOR), defined as reduced ovarian reserve markers with ­regular

345 Recurrent Early Pregnancy Loss

menstrual cycles, has been suggested to be a causative or prognostic factor in RPL. Ovarian reserve can be assessed with measurements of FSH, oestrogen (E2), inhibin B and anti-­ Mullerian hormone (AMH) or ultrasound investigation to determine antral follicle count (AFC) and ovarian volume [1, 2, 3]. DOR may be seen following pelvic surgery, chemotherapy and radiotherapy but also conversely in the general population of young women conceiving naturally and is not necessarily considered as a pathological entity. Additionally, ovarian aging may lead to increased rates in foetal aneuploidy, which makes investigation into a direct causative effect with RPL difficult [76, 77]. A recent systematic review and meta-analysis has found an apparent association between DOR and RPL as measured by low AMH levels and AFC [78]. However, more studies are required to evaluate their prognostic value in RPL, and assessment of ovarian reserve is not recommended as part of routine screening [1, 2, 4, 5]. 15.7  Immunological Factors

The immune system of pregnant women is tightly controlled to defend against microbial infections and to accept an embryo or the foetus, and inflammation-like processes are crucial for tissue growth, remodelling and differentiation of the decidua during pregnancy. A failure in normal immune control mechanisms may result in an autoimmune response to a developing foetus, like those that develop after rejected grafts in organ transplantation [79]. Autoantibody formation against phospholipids, thyroid antigens and nuclear antigens has been investigated as a potential causative factor in RPL, and 20% of women with RPL will have increased serum levels of autoantibodies, most commonly antiphospholipid antibodies [80]. There is currently insufficient evidence to recommend immune testing such as human leukocyte antigen (HLA) determination, cytokine levels and natural killer cell analyses [81]. Antinuclear antibodies (ANA) will be detected in 10–15% of women, with no clear relationship with pregnancy outcomes. However,

some studies have shown a weak association between ANA and RPL, and there is evidence that the presence of ANA may confer a poorer prognosis [82, 83]. Overall, there is no evidence that available immunotherapies such as intravenous immunoglobulins, paternal cell immunisation or donor leukocytes provide any benefit for improving live birth rates. Hence, no immunological tests are recommended as part of routine RPL workup [84]. 15.8  Thrombophilia 15.8.1

Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is the only proven thrombophilia associated with recurrent pregnancy loss, with international consensus diagnostic criteria outlined in . Table  15.2 [85]. Between 15 and 20% of women with RPL have positive antiphospholipid antibodies, with the three most clinically  

..      Table 15.2  International consensus classification criteria for antiphospholipid syndrome (APS), which is diagnosed with one of the following clinical and one of the following laboratory criteria are met Clinical criteria

Laboratory criteria

Vascular thrombosis: defined as one or more clinical episodes of vascular thrombosis (venous, arterial or small vessel)

Lupus anticoagulant present in plasma, on two or more occasions at least 12 weeks apart

Pregnancy morbidity such as:   Three or more consecutive spontaneous pregnancy losses at less than 10 weeks   One or more premature birth 40 GPL or MPL or 99th percentile), on two or more occasions at least 12 weeks apart Anti-beta-2 glycoprotein I antibody in high titre (>99th percentile), on two or more occasions at least 12 weeks apart

15

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K. Y. Chong and B. W. Mol

recognised and relevant antibodies including lupus anticoagulant (LA), anticardiolipin antibody and anti-beta-2 glycoprotein I which contribute to the laboratory diagnosis of APS. It has been suggested that the presence of anti-beta-2 glycoprotein may indicate an increased risk of thrombosis [86, 87]. The diagnosis of antiphospholipid syndrome can be complex and is based on a combination of clinical manifestations of vascular thrombosis or pregnancy morbidity, as well as the presence of autoantibodies, on two tests performed 12 or more weeks apart [85]. The hypothesis behind APS and recurrent miscarriage is the encouragement of a hypercoagulable state, inflammatory processes and defective angiogenesis. This is corroborated by the presence of microthrombi within placental vasculature and decidua in pregnancy samples of women with RPL [87, 88]. Standard treatment for APS includes a combination of low-dose aspirin and low-­ dose heparin, which may reduce pregnancy loss by 54% [89]. Aspirin may be commenced in the periconceptual period, whilst heparin should be commenced after the first positive pregnancy test, with both continued until delivery [90]. The use of prednisolone

increases risks of hypertensive disorders, gestational diabetes and preterm birth and is not recommended for treatment of APS [91]. Postpartum thromboprophylaxis is considered for a short interval, and women with known APS should consider avoiding oestrogen containing oral contraceptives due to the persistent thrombotic risk [89, 90]. 15.8.2

Hereditary Thrombophilia

Hereditary thrombophilia predisposing patients to venous thromboembolisms include Factor V Leiden mutation, prothrombin mutation, protein C, protein S and antithrombin deficiency. The prevalence of hereditary thrombophilia in women with RPL is unclear, and there is no clear association between RPL and hereditary thrombophilia [92]. Current guidelines recommend screening only in the presence of additional risk factors, such as a positive family history of thrombophilia or a personal history of VTE [93]. Where possible, this should occur 6  weeks following a pregnancy loss or thrombotic event and whilst not on anticoagulants, with suggested testing methods outlined in . Table 15.3.  

..      Table 15.3  Inherited thrombophilia testing Thrombophilia

Testing method

Is testing reliable in pregnancy

Is testing reliable during acute thrombosis

Is testing reliable with anticoagulation

Factor V Leiden mutation

Activated protein C resistance assay

Yes

Yes

No

If abnormal, then DNA analysis

Yes

Yes

Yes

Prothrombin gene mutation G20210A

DNA analysis

Yes

Yes

Yes

Protein C deficiency

Protein C activity ( 2 3

*Point assignment changed to 16 **Point assignment doubled

–6

–16

L OVARY Deep endo – 1–3cm –16 Dense adhesions – > 2 –16 3 114 TOTAL POINTS

..      Fig. 24.2  ASRM revised classification of endometriosis

24.7

Ovarian Endometriosis

Ovarian endometriosis or endometriomas increase with age and are generally associated with a more advanced stage of the disease [2]. This form of endometriosis can be diagnosed with a high level of accuracy by serial ­ultrasounds. They may be confused with a hemorrhagic corpus luteum, which will disappear over the course of a few months. These ovarian forms of endometriosis of 10 have associated peritoneal implants (77% of the time and 85.4% of these women experienced pelvic pain whereas only 38.3% of those with  an isolated endometrioma experienced

pain [11]). Only a small percentage of patients with peritoneal implants will eventually develop an endometrioma. Endometriomas can be uniloculated or multiloculated. They are more commonly localized in the left ovary, as with peritoneal implants, likely due to the natural peritoneal fluid flow subsequent to menstrual regurgitation.

24.8

Deep Endometriosis

Invasion of endometriotic cells deeper than 5  mm has been associated with increased pain  [12]. A recto vaginal exam during the

541 Endometriosis

menstrual period in the office setting or a thorough exam under anesthesia prior to laparoscopy may alert the surgeon to the presence of these types of lesions. In a study looking at 93 women with deep in filtrating peritoneal endometriosis, 61% had concomitant superficial implants and 51% had endometriomas. Deep nodules were the only form of the disease in just 7% of the women.

24.9

Extrapelvic Endometriosis

Cutaneous endometriosis has been reported in abdominal scars following cesarean sections, hysterectomy, appendectomy, and laparoscopy. Rare lung cases of endometriosis leading to cyclical hemoptysis or even catamenial pneumothorax have been reported and imply that hematogenous and/or lymphatic dissemination of endometrial cells is possible. This mechanism can also explain the possible spread to rare locations, such as the brain, liver, pancreas, kidney, vertebra, and bones.

24.10

Predisposing Factors for Endometriosis

Endometriosis is mainly present during the reproductive years (average age of 28) and usually regresses during menopause, suggesting that the development and growth of endometriosis is estrogen dependent. Accordingly, the Nurses’ Health Study prospectively assessed predisposing factors for endometriosis and observed an association with early age of menarche, shorter length of menstrual cycles during late adolescence, and nulliparity. Furthermore, women with low estrogen levels and low bodymass index, who use alcohol, who are infertile smokers, and who exercise intensely appear to be at decreased risk [13]. Heredity is an important predisposing factor for endometriosis since the prevalence is increased seven fold among first-degree relatives. In monozygotic twins, the prevalence increased 15-fold. Exposure to pollutants, especially endocrine-disrupting compounds such as dioxins or polychlorinated biphenyls

(PCBs), might also play a role in the predisposition to endometriosis. Data from the Nurses’ Health Study II suggests that specific dietary fat consumption may influence the risk of developing endometriosis—long-chain omega-3 fatty acids were protective, whereas trans-unsaturated fats led to a greater risk.

24.11

Pathophysiology

Managing endometriosis receives the lion share of attention, although investigation into the genesis of the disease does not lag far behind. In fact, it is likely that only with the discovery of the true pathogenesis of endometriosis will more efficacious therapy emerge as well as preventative measures for younger women. The three different endometriosis entities—endometriomas, implants, and retrocervical septum disease—could develop along distinct routes, but overlapping ­mechanisms are probably at play for at least some of these. The disease has multitudinous theories for pathogenesis, yet only a handful continue to be proffered as valid: (1) retrograde menstruation (Sampson’s theory), (2) metaplastic transformation (Meyer’s theory), (3) lymphatic or hematogenous embolization (Halban’s theory), (4) tissue relocation (i.e., iatrogenic surgical displacement of endometrium during laparoscopy or cesarean section), and (5) immune dysregulation leading to deficient clearance of ectopic endometrial tissue. Over the years, each theory has received indirect corroboration. Retrograde menstruum from the fallopian tubes into the pelvis and beyond has been supported by identifying menstrual tissue refluxing from the fallopian tubes during surgery and the identification of fresh endometrial lesions during menstrual phase laparoscopy. In addition, the baboon model of endometriosis is, in effect, iatrogenic retrograde menses in variably leading to the development of scattered lesions [14]. Lastly, a greater frequency of lesions in the right subphrenic region and left hemipelvis/ovary supports retrograde menses,

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since these locations follow the natural tendency of intra-abdominal peritoneal flow and obstruction via the falciform ligament. Unclear, however, is why endometriosis is not found in all women, given the ubiquitous nature of retrograde menstruation. Metaplasia of the coelomic epithelium seems equitable given that both peritoneal and endometrial tissues emanate from coelomic cells. Zheng et al. have shown histologic, morphologic evidence of transitioning ovarian surface epithelium into endometriotic cells, corroborating a metaplastic process [15]. A corollary to this postulate is that of the embryo genetic theory or Müllerianosis: misplaced endometrial tissue during the embryologic period of organogenesis. Signorile et al. demonstrated the presence of ectopic endometrium in 9% of 101 human female fetuses [16]. With endogenous estradiol stimulation later in life, this tissue could grow and thus present as ectopic implants. Theoretically, deep retrocervical septum lesions could derive from such abnormal embryogenesis. Newer, exciting pathophysiology theories borrow from the traditional theories and, most significantly, build upon these premises in order to better grasp the true etiology. For instance, stem cells originating from the bone marrow (Meyer’s theory) have been found to populate eutopic endometrium (Halban’s theory) that may then be shed (Sampson’s theory) into the peritoneal cavity. Vercellini et al. provided another concept for the development of endometriomas when they described how a hemorrhagic corpus luteum may progress to an endometrioma [17]. If this were truly an endometrioma, then retrograde menses (Sampson’s theory) would be a prerequisite to seed the cyst contents with endometrial cells. Underlying virtually all of these theories is the molecular underpinnings of the disease and, in particular, the inherent immune dysfunction that could at once promote and sustain endometriosis [18]. The aberrant immune factors found in women affected with endometriosis could explain why some develop the disease while others do not. The chronic inflammatory milieu can impair normal clearance of endometrial tissue and encourage

adherence/invasion, angiogenesis, and nerve fiber innervation [19]. 24.12

Mechanism of Infertility

Even though there is a purported association between infertility and endometriosis, the mechanism of this association remains complex and is not completely understood [20]. A population-based cohort study using record linkage comparing 5375 women with surgically confirmed endometriosis with outcomes in 8710 women without endometriosis revealed an increased risk of miscarriage [21]. The following factors may explain a diminished fecundity: 55 Anatomical changes. Endometriosis, when moderate or severe, will often lead to peritubal or periovarian adhesions, thus compromising tubal motility and ovum capture. 55 Immunological factors. The peritoneal fluid of women with endometriosis has an abnormal level of cytokines, prostaglandins, growth factors, and inflammatory cells, which are likely to participate in the etiology and/or sustenance of endometrial implants. These alterations negatively affect sperm motility, oocyte maturation, fertilization, embryo survival, and tubal function. 55 Effect on embryo development and implantation. Patients with stage I and II endometriosis have high levels of anti-endometrial antibodies, which may reduce implantation. IL-1 and IL-6 are elevated in the peritoneal fluid of patients with endometriosis and are embryotoxic. Expression of HOXA10 and HOXA11 genes, which are usually upregulated during the secretory phase of the menstrual cycle, is not upregulated inpatients with endometriosis. These genes regulate the expression of α(alpha) vβ(beta)3 integrin, which plays a crucial role in the embryo’s ability to attach to the endometrium. A decrease in α v β3 and l-selectin expression has been reported in patients with endometriosis, which might explain the decrease in implantation.

543 Endometriosis

24.13

Mechanism of Pain

Pain associated with endometriosis is quite complex. Pain associated with advanced disease can be caused by extensive adhesions, ovarian cysts, or deeply infiltrating endometriosis. Expression of nerve growth factor is associated with endometriosis pain. Sensory nerve fibers have been found more frequently in the functional layer of the endometrium of women with endometriosis than those unaffected by the disease. Finally, discrete changes in the central pain system (i.e., regional gray matter volume) may contribute to chronic pain in women with endometriosis [22]. Even patients with early-stage disease (few scattered implants) can experience severe pain. This pain can be explained in part by the increase in prostaglandins. In contrast to the normal endometrium (referred to as eutopic endometrium), ectopic endometrium (endometriosis) is the site of at least two molecular aberrations that result in the accumulation of increasing quantities of estradiol and prostaglandin E2 (PGE2). With the first aberration, activation of the gene that encodes aromatase increases, leading to increased aromatase activity in endometriotic tissue. This activation is stimulated by PGE2, which is the most potent inducer of aromatase activity in the endometriotic stromal cells. The second important molecular aberration in endometriotic tissue is the increased stimulation of COX-2 by estradiol, which leads to increased production of PGE2. This establishes a circular event leading to accumulation of PGE2 in the endometriotic tissue.

24.14

Treatment of Endometriosis in the Infertile Couple

It is estimated that in an infertile couple with stage I or II endometriosis, the monthly fecundity rate is 3% per cycle. Medical suppressive therapy with an oral contraceptive agent or gonadotropin-releasing hormone agonist (GnRHa) does not improve the pregnancy rate prior to trying non-assisted reproductive technology.

24.15

Surgical Treatment

Surgical treatment of minimal or mild (stage I-II) endometriosis improves the spontaneous pregnancy rate; however, the absolute benefit is small. A meta-analysis of the two randomized clinical trials investigating this question showed a mild improvement with a number needed to treat (NNT)—that is, the number of persons that would need to be treated surgically to achieve an extra pregnancy—of 12 (95%CI,7,49). Postoperative suppressive medical therapy after surgical treatment does not improve fertility. The only value of medical suppressive therapy (i.e., GnRHa) may be before in vitro fertilization (IVF) [23]. In these cases, the use of GnRHa for 3–6  months prior to IVF increases the clinical pregnancy rate by a factor of 4 (OR 4.28, 95% CI, 2,9.15). There are few studies along these lines with significant design heterogeneity giving one pause as to its validity. Moreover, it is not clear for the moment if a specific disease severity may have a better response to such suppressive therapy. If the patient does not wish surgical therapy, then the next step is either IV for treatment with superovulation and intrauterine insemination (IUI) followed by gonadotropins and IUI. There is insufficient evidence to recommend surgery prior to IVF. In advanced disease, surgical management improves fertility. However, this surgery is complex and requires meticulous dissection. If an initial surgery for advanced disease fails, subsequent surgery is less successful than IVF in establishing a pregnancy and should be reserved for patients who require management of pain.

24.16

In Vitro Fertilization

In a retrospective cohort study, the diagnosis of endometriosis (without endometriomas) was associated with similar IVF pregnancy rates [24] compared with tubal factor infertility. IVF offers the best fecundity rate for those with endometriosis. Endometriosis patients undergoing IVF had no greater aneuploidy

24

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D. I. Lebovic and T. Falcone

rate compared with age-matched women without endometriosis [25]. Moreover, similar implantation rates were observed when transferring euploid embryos in women with endometriosis compared with controls suggesting a normalized endometrium with ovarian suppression from estradiol and intramuscular progesterone [26], Admittedly, cost and fewer supernumerary embryos maybe a limiting factor. Initial studies proposed using prolonged GnRH agonists prior to IVF in endometriosis patients (especially those with more advanced disease), and yet most of these studies were of low quality, and subsequent randomized trials have not substantiated any improved outcome [27, 28 29]. The same can be concluded from using extended GnRH agonists prior to frozen embryo transfers.

24.17

Endometriomas

Endometriomas larger than 4  cm should be removed to confirm they are benign. In a randomized trial, excision of the endometrioma was associated with less recurrence and higher spontaneous fertility rates than fenestration and bipolar coagulation [30]. IVF outcomes have been reported to be similar in patients with and without endometriomas. However, the number oocytes, fertilization rates, and the number of embryos obtained were decreased in women with endometriomas compared with those without endometriomas. The preponderance of evidence suggests that in symptomatic women, one can safely remove endometriomas without compromising ovarian function or the success of assisted reproduction. Accumulating studies reflect a detrimental impact from surgery on ovarian reserve as assessed by anti-Müllerian hormone levels [31]. Accidental puncture of an endometrioma during oocyte retrieval may cause infection or contamination of follicular fluid. Histologic confirmation of the benign nature of a large endometrioma may be prudent. Given the negative effect on ovarian reserve by endometriosis, it is not unrea-

sonable to offer patients oocyte vitrification as a means to preserve their future fertility and allow them to take suppressive hormonal therapy in the interim [32]. Interestingly, in a retrospective chart review, the higher the rate of endometrioma recurrence, the greater the antral follicle count in the affected ovary. This may be a consequence of less ovarian trauma at the time of cystectomy [33]. Simple drainage of an endometrioma has been shown to be ineffective.

24.18

Treatment of Patients with Chronic Pelvic Pain

24.18.1

Medical Management for Pain

Several classes of drugs have traditionally been used to manage pain associated with endometriosis (. Table  24.1). Progestins or combined oral contraceptives and nonsteroidal anti-inflammatory drugs are used as first-­ line therapy for chronic pain associated with endometriosis. In a prospective, randomized controlled trial comparing combined oral contraceptives with GnRHa, both treatment arms led to similar pain relief [34].  

24.18.2

Progestins

Subcutaneous medroxyprogesterone acetate (Depo-subQprovera104, Pfizer, New  York, NY, USA)administered every 12–14weeks subcutaneously was approved by the US Food and Drug Administration (FDA) for the treatment of endometriosis-related pelvic pain. The bone loss seems to be less pronounced than with the use of GnRHa without add-­ back therapy. However, there are no data yet with the prolonged use of Depo-subQ, and the recommendation is not to use the drug for more than 2 years unless other methods are unacceptable. Note that the rate of abnormal vaginal bleeding while on Depo-subQ was 17%. There are several other progestins that have been used for the treatment of

545 Endometriosis

..      Table 24.1  Drugs used for the treatment of endometriosisa Class

Drug

Dosage

Androgen

Danazolb

100–400 mg PO twice a day 100 mg per vagina daily

Anastrozolec

1 mg PO daily

Letrozolec

2.5 mg PO daily

Estrogen–progestin combinations

Monophasic estrogen/ progestinb

Low ethinylestradiol dose continuously

Gonadotropin-­releasing hormone agonist

Goserelinb, c

3.6 mg SC monthly (10.8 mg IM every 3 months)

Leuprolide depotb, c

3.75 mg IM monthly (11.75 mg IM every 3 months)

Nafarelinb, c

200 μg intra nasally twice a day

Elagolixb

150 mg PO daily or 200 mg PO twice daily

Cetrorelix

3 mg SC weekly

Depo-subQ provera 104b

104 mg/0.65 mLSC every 3 months

Dienogest

2 mg PO dailyd

Etonogestrel-­releasing implant

1 for 3 years

Levonorgestrel-­releasing IUS

1 for 5 years

Medroxyprogesterone acetate

30 mg PO daily for 6 months, followed by 100 mg IM every 2 weeks × 2 months, then 200 mg IM monthly × 4 months

Norethindrone acetateb

5 mg PO daily

Aromatase inhibitor

Gonadotropin-­releasing hormone antagonist

Progestin

SC subcutaneously, IM intramuscularly, IUS intrauterinesystem from [4] bFDA approved for endometriosis cWith add-back therapy, that is, norethindrone acetate 5 mg daily + vitamin D 800 IU daily + calcium 1.25 g daily dDienogest is a 19-nortestosterone derivative that is approved in the European Union for the treatment of endometriosis. It is not available in the United States as a separate drug. It is only available in the oral contraceptive Natazia (Bayer Pharmaceuticals, Montville, NJ, USA) (estradiolvalerate/dienogest), which is a newer four-­phasic pack that contains dienogest. aAdapted

endometriosis-­ associated pelvic pain. The FDA also approved norethindrone acetate (NETA) 5 mg daily with a GnRHa. Through NETA’s estrogenic activity, there is a beneficial effect on both bone mineral density and vasomotor symptoms; 5  mg of NETA is equivalent to 20–30 μg of oral ethinylestradiol. There

seems to be merit in reverting to NETA if oral contraceptives alone are ineffective at relieving pain [35]. The levonorgestrel intrauterine system has been successfully used for symptomatic endometriosis. Trials have demonstrated pain relief and decreased menstrual blood loss.

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D. I. Lebovic and T. Falcone

24.18.3

24

Gonadotropin-Releasing Hormone Agonists

GnRH agonists can be given via an intramuscular (leuprolide acetate), subcutaneous (goserelin), or nasal (nafarelin) route. After an initial increase in gonadotropins during the first 10  days, there is a decrease in pituitary secretion secondary to GnRH receptor downregulation. These drugs are typically given for an initial 6-month course. The majority of patients (75–80%) in clinical trials responded. However, many patients will have recurrence of pain within five months. A main concern is the progressive loss in bone mineral density. Menstrual periods return between 2 and 3 months after the last monthly injection, but recovery of bone mineral density takes more time. Add-back therapy with estrogens or progestins was introduced as a way to reduce the hypoestrogenic side effects of GnRHa, especially the loss in bone mineral density, but also vasomotor symptoms and atrophic vaginal mucosa. Other symptoms such as insomnia, mood disorders, and cognitive dysfunction may occur. The mean decrease in bone mineral density after 1 year of GnRH a treatment without add-back is between 3% and 7%. Add-back therapy has been proposed for both short-term (less than 6  months) and long-term use (more than 6  months). Many studies have shown that the efficacy is not reduced. Norethindrone (5 mg orally daily) is the most commonly used add-back regimen. Low-dose estrogen (conjugated equine estrogen 0.625 mg) can also be added to the norethindrone without loss of benefit in symptom control. Higher doses of estrogen (i.e., ­combined oral contraceptives) are associated with diminished efficacy in relieving pain symptoms. 24.18.4

Gonadotropin-Releasing Hormone Antagonist

over 6 months, but we do not recommend its use as empiric therapy [36]. There are two doses of elagolix, 150 mg once daily (diminution in dysmenorrhea and nonmenstrual pelvic pain) and 200  mg twice daily (significant decrease in dyspareunia as well as dysmenorrhea and nonmenstrual pelvic pain). There are several drawbacks to advocating elagolix as a first-line therapeutic [37]. Since there is a dose-dependent decrease in bone mineral density after six  months of treatment, add-back therapies should be prescribed if one is using the higher elagolix dose. Since estrogen-­ containing oral contraceptives can reduce the efficacy of elagolix, and ovulation is not sufficiently inhibited with low elagolix doses, women should use a nonhormonal method of contraception during treatment. How elagolix compares with currently used progestogens and low-dose hormonal contraceptives is yet to be determined and should factor into a stepped-care approach to these patients, especially given the much higher cost of elagolix.

24.18.5

Aromatase Inhibitors

Aromatase inhibitors have been successfully used in a limited number of cases of persistent disease after hysterectomy and bilateral oophorectomy, as well as inpatients with intact pelvic organs. The putative mechanism is by suppression of locally produced estrogens from aromatase activity expressed by the endometriotic cells. Typically, an aromatase inhibitor such as letrozole 2.5 mg or anastrozole 1  mg daily is given with NETA (5  mg daily) to prevent ovarian cyst formation and a possible decrease in bone mineral density. 24.18.6

Surgical Management for Pain

Two prospective randomized controlled studies have clearly shown that surgical therapy is superior to no treatment for relief of pain Elagolix is an oral, nonpeptide gonadotropin-­ from endometriosis [38]. One randomized releasing hormone antagonist used for mod- controlled trial with only 16 women did not erate to severe endometriosis-related pain

547 Endometriosis

show a statistically significant difference in pain relief [39]. Several observations can be surmised from these studies: (1) surgery is more effective than simple diagnostic laparoscopy in the treatment of pain associated with endometriosis; (2) there is a significant placebo effect associated with surgery, especially early on (3  months), that persists in approximately 20% of patients; (3) between 20 and 40% of patients will not respond to surgery and will continue to experience pain and (4) surgery is least effective for early-stage disease. It is unclear if excision of endometriosis is superior to simple ablation by cautery or laser [40]. Postoperative treatment with hormonal suppressive therapy can delay recurrence of disease and associated symptoms [41]. 24.18.7

Neurectomy

Interruption of the cervical and uterine sensory nerves by transaction of the utero sacral ligaments, an uterosacral nerve ablation, has been shown not to have any long-term benefit [42]. A presacral neurectomy has been shown to be beneficial in patients with chronic pelvic pain and endometriosis when performed with surgical treatment of the endometriosis lesions [43]. The procedure is associated with greater relief of midline pain rather than lateral pain. The success of the procedure is dependent on excision of the superior hypogastric plexus (presacral nerve) before extensive branching has occurred. The most common postsurgical complications that have limited its use are constipation and urinary urgency. 24.18.8

Hysterectomy

Hysterectomy with or without bilateral salpingo-­oophorectomy can be considered in patients whose disease fails to respond to conservative management and who do not desire future fertility. Most studies have shown significant pain relief from definitive surgery. Caution should be used in recommending

24

oophorectomy in women less than 40 years of age [44, 45]. 24.18.9

Posthysterectomy Recurrence

Endometriosis can recur in 5–10% of patients after hysterectomy and bilateral salpingo-­ oophorectomy. The role of hormone replacement therapy after surgical castration is controversial. There is a possibility of symptom or disease recurrence (3.5%). However, there is the real possibility of severe vasomotor symptoms and osteoporosis. Hormone replacement therapy is not contraindicated, and the risks and benefits should be discussed with the patient. 24.18.10

Retrocervical Septum Endometriosis

The management of retrocervical septum endometriosis is extremely difficult and usually involves the recto sigmoid. Patients usually have severe symptoms that may involve the gastrointestinal tract such as constipation, diarrhea, and painful bowel movements. However, some patients with retrocervical endometriosis are asymptomatic. These patients do not need treatment. 24.19

Management of Endometriosis on Extragenital Organs

24.19.1

Gastrointestinal Endometriosis

Although gastrointestinal symptoms are quite common in women with endometriosis, the overall incidence of bowel involvement is reported to be around 5%. Endometriosis of the gastrointestinal system typically involves the rectum or recto sigmoid. Recurrence of disease after hysterectomy and oophorectomy more commonly involves the bowel. Excision of disease or intestinal resection can be

548

D. I. Lebovic and T. Falcone

a

b

24

..      Fig. 24.3  a This figures how fibrotic-type endometrios is involving the right hemidiaphragm. The lesions are seen above the liver. Most of the lesions are obscured

by the liver. b Hemorrhagic-type endometriosis lesions of the right hemidiaphragm

­ erformed by laparotomy or by laparoscopy. p Rectovaginal fistula and abscess formation are the most serious complications reported.

24.19.3

24.19.2

Respiratory System

Diaphragmatic endometriosis can be a symptomatic and noted incidentally at diagnostic laparoscopy (. Fig.  24.3). Symptomatic patients often report right-sided chest pain or shoulder pain in association with menstruation that occasionally radiates into the neck or arm and dyspnea. Asymptomatic diaphragmatic lesions do not need treatment. Electrosurgery, laser, or surgical excision should be performed carefully because the thickness of the diaphragm ranges between 1 and 5 mm. Thoracic endometriosis most commonly presents as a right-sided catamenial pneumothorax but the canal can be manifested by hemothorax, hemoptysis, or pulmonary nodules. The typical symptoms are chest pain and dyspnea. Approximately 30% of these women have pelvic endometriosis at the time of surgical management of the thoracic disease. A chest CT scan may demonstrate pulmonary or pleural nodules, especially if performed during a menstrual period. Chemical pleurodesis is associated with a lower recurrence rate of catamenial pneumothorax than hormonal treatment. However, initial treatment with hormonal therapy is indicated.  

Genitourinary System

Endometriosis often involves the peritoneum over the ureter. However, direct ureter involvement is uncommon and has been reported in less than 1% of patients; it is predominantly left-sided (63%) when this is observed. Ureteral involvement can be the result of extrinsic compression from extensive endometriosis that surrounds the ureter with significant fibrosis. The majority of the patients have significant involvement of the retrocervical septum with nodules that are often greater than 3 cm. Preoperative imaging studies such as MRI with contrast should be used to evaluate the renal system preoperatively in patients with retrocervical disease. Medical therapy has been used successfully in a limited number of patients. Most cases of ureteral endometriosis can be treated with excision of the periureteral fibrosis and active lesions without ureter resection. Complications such as ureteral fistulae (5% incidence) can occur with extensive ureterolysis in women with deeply infiltrating disease. 24.19.4

Sciatic Nerve Involvement

Patients with endometriosis of the sciatic nerve can present with hip pain, which is usually localized to the buttock. The pain radiates down to the back of the leg, and numbness occurs in areas innervated by the sciatic nerve.

549 Endometriosis

The symptoms typically occur in association with a menstrual period but then extend in to other times of the cycle. Progressive leg and foot muscle weakness with electromyogram studies showing denervation can be demonstrated. MRI typically shows a lesion infiltrating the sciatic nerve. CT-guided biopsy can be used to confirm the diagnosis. Two-thirds of cases are localized to the right-side. Most cases have pelvic endometriosis associated with this disease. Treatment with a GnRHa and add-back therapy have been shown to reverse the neurologic abnormalities.

24.20

Review Questions

?? 1. What is the positive predictive value of laparoscopic visualization of endometriosis? A. 10% B. 30% C. 50% D. 80% ?? 2.  Which of the following is associated with a lower risk of developing endometriosis? A. Long-chain omega-3 fatty acids B. Exposure to dioxins C. Elevated body mass index D. Trans-unsaturated fats ?? 3. Endometriosis can recur in what percent of patients undergoing hysterectomy and bilateral salpingo-­oophorectomy? A. 10 years) [22]. It has been proposed that CHC use

during estrogen-­deficient states may reduce fracture risk.

Combination Oral Contraceptive Pills The development of the combined oral contraceptive pill (COC) is often regarded as one of the most important public health achievements in the twentieth century, and COCs have been used by women worldwide since 1960 [23]. Oral contraceptive formulations vary widely by hormone type, dosage, and hormone-free duration, although they typically contain ethinylestradiol (EE) and a progestin. Most available pills contain 20–35 mcg of EE, but some formulations contain as little as 10 mcg EE. Reduced doses of EE are suspected to confer a decreased risk of venous thromboembolism compared to higher doses of COCs, but low-dose formulations may be associated with higher rates of irregular bleeding. There are more than a dozen different progestins in COCs. Theoretically, progestins derived from testosterone, such as norethindrone or levonorgestrel, were thought to have more androgenic side effects such as acne and excess hair growth. The newer progestins derived from progesterone and spironolactone, such as drospirenone, were designed to bind more selectively to progesterone receptors and minimize estrogenic, androgenic, and glucocorticoid side effects [23]. However for most women, there are no significant clinical differences between the various progestins [24, 25]. Traditional pill packs have active pills for 21 consecutive days followed by 7 days of nonhormonal pills; the sudden decrease in progestin during the hormone-free week leads to withdrawal bleeding. Extended or continuous COC regimens refer to regimens that eliminate the hormone-free interval, allowing patients to plan withdrawal bleeding on a more flexible schedule or eliminate it entirely. Disadvantages of COCs include once daily dosing and lack of privacy with pilltaking. Side effects such as breast tenderness, nausea, headache, bloating, mood changes, and irregular bleeding may occur.  Most of these symptoms will improve within a few months of pill initiation. Rare, adverse effects

559 Contraception: Evidence-­Based Practice Guidelines and Recommendations

of COCs include venous thromboembolism (VTE) and hypertension. Despite a 2-3-fold relative risk of VTE in COC users compared to nonusers, the absolute risk remains low [23]. Among COC users, the risk of VTE is 3–9/10,000 woman-years, compared to 1–5/10,000 woman-years among nonusers [26]. The risk of VTE in pregnancy is 5–20/10,000 woman-­years and the risk in the postpartum period is 40–65/10,000 womanyears [27]. Scenarios in which the risks of COC outweigh the benefits include cigarette smoking in older women (>15 cigarettes/day in women 35 years or older), multiple risk factors for arterial cardiovascular disease, uncontrolled hypertension (blood pressure >160/100), and migraines with aura. Typical use failure rates are 9% compared to 0.3% with perfect use (. Table 25.1) [28].

Important considerations for patch use include increased serum estrogen levels compared to COCs, which may translate to increased risk of VTE and cardiovascular events. Women using the 150 mcg norelgestromin and 35 mcg EE TDS (Xulane®) were found to have 60% higher serum estrogen levels compared to those using conventional pills [29]. In addition, Xulane® is only approved for patients with a BMI