Ovulation Induction [2 ed.] 9351520870, 9789351520870

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Step by Step®

OVULATION INDUCTION

Step by Step®

OVULATION INDUCTION Second Edition Editor

Surveen Ghumman MD FICOG FICMCH

Senior Consultant IVF and Reproductive Medicine Unit Max Super Specialty Hospitals Panchsheel and Saket, New Delhi, India

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi • London • Philadelphia • Panama

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Jaypee Brothers Medical Publishers (P) Ltd Bhotahity, Kathmandu, Nepal Phone: +977-9741283608 Email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2014, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/ editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. Inquiries for bulk sales may be solicited at: [email protected] Step by Step® Ovulation Induction First Edition: 2006 Second Edition:  2014 ISBN 978-93-5152-087-0 Printed at

Dedicated to Sandeep Whose support and encouragement has been pivotal in enabling me to accomplish every venture of mine

Contributors Abha Majumdar MD

Consultant and Head Center of IVF and Human Reproduction Sir Ganga Ram Hospital New Delhi, India

Deepak Chawla MD

Consultant and Head Department of Ultrasound Sir Ganga Ram Hospital New Delhi, India

Lalita Badhwar MD

Senior Consultant Department of Obstetrics and Gynecology Indraprastha Apollo Hospitals New Delhi, India

Monika Gupta MD DNB MNAMS MICOG

Assistant Professor Department of Obstetrics and Gynecology Hamdard Institute of Medical Sciences and Research HAHC Hospital New Delhi, India

Neerja Goel MD

Professor Department of Obstetrics and Gynecology University College of Medical Sciences and Guru Teg Bahadur Hospital New Delhi, India

Reeti Sahani MD (Radiology)

Senior Consultant Radiology and Imaging Sciences Indraprastha Apollo Hospital New Delhi, India

Ritika Kaur MD

Resident Department of Obstetrics and Gynecology Maharishi Markandeshwar Institute of Medical Sciences and Research Ambala, Haryana, India

Shashi Prateek MD FICOG FICMCH

Professor and Head Department of Obstetrics and Gynecology Subharti Medical College Meerut, Uttar Pradesh, India

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Step by Step Ovulation Induction

Shweta Mittal

Surveen Ghumman

MD FNB (Reproductive Medicine)

MD FICOG FICMCH

Consultant Center of IVF and Human Reproduction Sir Ganga Ram Hospital New Delhi, India

Senior Consultant IVF and Reproductive Medicine Unit Max Super Specialty Hospitals Panchsheel and Saket New Delhi, India

Preface to the Second Edition In the recent years, the subject of infertility has changed completely as far as protocols and management are concerned. The rapidly progressive research and innovations in this field are difficult to keep up with. Like the First Edition, the Second Edition of this book attempts to roadmap these latest therapies defining their current relevance to treatment in a stepwise form. Not only is it practical but also touches and introduces the readers to the latest research done in the field in a manner that it can be translated into application in their day-to-day practice. All chapters have flow charts and tables to make reading simplified. Five new chapters have been added which include, Premature Luteinization, Ovarian Stimulation for the Poor Responder, Hypogonadotropic Hypogonadism and Ovulation Induction, Role of Androgens in Ovulation Induction, and Mild Ovarian Stimulation. Androgens are a recent addition to ovulation induction. Mild ovarian stimulation are now being used extensively where cost is a major deterrent. Premature luteinization has been discussed extensively as it has an important role in any stimulation protocol and is often illunderstood. The older chapters have been updated with recent information in a manner that it can be easily applied in dayto-day practice. In this age of information overload, this book is an attempt to integrate information into a practical management protocol that is rational, logical and rewarding to the reader. This book attempts to bring forth practical information with recent advances in ovulation induction and attempts to solve

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dilemmas in management of infertile couples bringing the reader closer to the desired goal—a successful pregnancy in these patients. I hope, it is helpful to those who read it and can be applied in day-to-day practice, which is the purpose with which this book was written. Surveen Ghumman

Preface to the First Edition In the recent years, there has been a revolution in the field of ovulation induction as new concepts and therapies are coming up into picture each year with the explosive amount of research being done in this field. This has left many practicing infertility specialists puzzled over the options and their indication. This book attempts to roadmap these latest therapies, defining their current relevance to treatment, in a simplified, easy-to-follow protocol for the practicing infertility specialists. At the same time, besides giving practical tips, it also touches on the latest research work done in the field. Most chapters are accompanied by flow charts for managements providing guidance in a step-by-step manner. Over the last many years, my interest in infertility deepened to the extent of organizing my research and clinical work around this subject. This book is a summary of the clinical and research work done in ovulation induction by me over the years. An attempt has been made to touch every aspect related to the subject in such a manner that would be understood by all. The chapters on clomiphene, resistance to clomiphene, gonadotropins and GnRH analogs solve the practical dilemmas many practicing clinicians are faced with. Problems of hyperprolactinemia, endometrial receptivity, luteal phase defect and fertility in older women are encountered frequently when treating an infertile patient. These have been dealt with extensively in separate chapters. The chapter on polycystic ovarian syndrome highlights recent advances especially with insulin sensitizers. Besides medical therapy, it also details on the technique of laparoscopic ovarian drilling as a surgical treatment for

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ovulation induction. This is becoming an important option with the increase in usage of laparoscopic surgery. Multifetal pregnancy reduction technique has been discussed keeping in view the fact that it is an option for which the treating infertility clinician often has to counsel. The chapter on ultrasound gives an extensive review of the role of color Doppler in cycle assessment during ovulation induction—a must-know subject for the practicing infertility professionals. The book attempts to cover all aspects of ovulation induction, current stimulation protocols, their indication in clinical situations and their complications. It is a guide to problem solving needed while handling such patients. This subject is changing explosively with newer recombinant gonadotropins and long-acting preparations being introduced. I hope this book will solve the dilemmas of many and you may enjoy reading it as much as I did while writing it. Surveen Ghumman

Acknowledgments I thank all the contributors, for their well-researched chapters and for sparing their invaluable time and intellectual skills. I have thoroughly enjoyed interacting with all the authors during this academic venture. I would also like to acknowledge the invaluable contribution of Dr Neerja Goel, my teacher and guide. She has been instrumental in guiding and encouraging me through all my academic exercises. The unstinting support, help and encouragement that I received from my husband went a long way in bringing this book together and making this dream a reality. I would also like to thank my parents and my daughters for all the help they gave. Although this book has my name on it, but it is the combined effort of all those who have given it the face it has.

Contents 1. Anovulation and Tests for Ovulation Surveen Ghumman, Ritika Kaur

1

• Tests for Ovulation  4

2. Oral Ovulogens

Surveen Ghumman

14

• Clomiphene 14 • Tamoxifen 24 • Letrozole 25

3. Clomiphene Resistance—What Next? Surveen Ghumman

31

• Management of Clomiphene Failure or Resistance  32

4. Gonadotropins

Surveen Ghumman

50

• Follicle Stimulating Hormone  51 • Recombinant LH  65 • Human Chorionic Gonadotropin  66

5. Role of GnRH Agonists and Antagonists in Assisted Reproductive Technology Surveen Ghumman

71

• GnRH Agonist (GnRHa)  71 • GnRH Antagonists  80 • Gonadotropin-releasing Hormone  86

6. Mild Ovarian Stimulation Surveen Ghumman

• Role of GnRH Antagonist in Mild Stimulation  93

92

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Step by Step Ovulation Induction • Clomiphene, Gonadotropins and GnRH Antagonist  94 • Mild vs Conventional Protocols  94

7. Premature Luteinization 106 Surveen Ghumman, Monika Gupta • • • • •

Diagnosis 106 Incidence 107 Causes 107 Effect on Reproductive Outcomes  108 Prevention 109

8. Polycystic Ovarian Syndrome and Insulin Sensitizers Surveen Ghumman • • • • •

114

Diagnosis 114 Insulin Resistance  115 Clinical Presentation  118 Treatment 119 Treatment in those who do not Desire Pregnancy  133

9. Surgical Ovulation Induction

Lalita Badhwar, Surveen Ghumman

141

• Mechanism of Action  142 • Indications 142 • Techniques 142

10. Hypogonadotropic Hypogonadism and Ovulation Induction Surveen Ghumman • • • •

Causes 155 Clinical Presentation  157 Diagnosis 157 Treatment 158

155

Contents 

11. Hyperprolactinemia

Surveen Ghumman, Ritika Kaur • • • • • •

xvii 170

Prolactin and Ovarian Function  171 Incidence 171 Etiology 171 Clinical Features of Hyperprolactinemia  173 Diagnostic Evaluation  175 Treatment of Hyperprolactinemia  177

12. Role of Androgens in Ovulation Induction 188 Shashi Prateek, Surveen Ghumman • Impact of Androgens on Reproductive Outcome  189

13. Ovarian Reserve and Fertility in Older Women Neerja Goel, Surveen Ghumman

200

• Age and Fertility  201 • Management of Older Women with a Fertility Problem  202 • Treatment of Patients with Reduced Ovarian Reserve  210

14. Ovarian Stimulation for the Poor Responder Surveen Ghumman

215

• Prediction 216 • Treatment 216

15. Endometrial Receptivity—A Vital Role Surveen Ghumman • • • •

Histological Changes  235 Biochemical and Molecular Changes  235 Endometrial Vascular Changes  241 Role of Chronic Endometritis in Endometrial Receptivity  241

231

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Step by Step Ovulation Induction • Current Strategies to Assess Endometrial Receptivity 245 • Treatment of Poor Uterine Receptivity  249 • Endometrial Preparation for Frozen Embryo Transfer  253

16. Luteal Phase Defect

Surveen Ghumman, Neerja Goel

260

• Pathophysiologic Mechanism  260 • Diagnosis of Luteal Phase Inadequacy  262 • Treatment of Luteal Phase Defect  264

17. Complications of Ovulation Induction Surveen Ghumman • • • •

276

Ovarian Hyperstimulation Syndrome  277 Management of OHSS  282 Multiple Pregnancy  293 Ovarian Cancer and Ovulation Induction  294

18. Selective Multifetal Pregnancy Reduction

Shweta Mittal, Deepak Chawla, Abha Majumdar

299

• Methods of Multifetal Pregnancy Reduction  300

19. Ultrasonography and Color Doppler Imaging in Ovulation Induction Reeti Sahani

309

• Examination Technique  309 • Color Doppler Imaging (CDI)  312

Index

331

cHAPTER

1

Anovulation and Tests for Ovulation Surveen Ghumman, Ritika Kaur

Disorders of ovulation account for approximately 30–40% of the problems identified in infertile women. They may present with oligomenorrhea or amenorrhea. Classification of ovulatory problems was done by WHO into 3 groups: • Group I Hypothalamic pituitary failure (Hypo­ gonadotropic hypo­gonadism). • Group II Hypothalamic pituitary dysfunction (Normogonadotropic, e.g. PCOD). • Group III Ovarian failure (Hypergonadotropic hypogonadism). Usually treatment is simple and effective. However, not all cases of anovulation are amenable to treatment by ovulation induction.1 It is the cause of anovulation that will determine whether ovulation induction is possible (Tables 1.1 and 1.2). Before taking up a patient for ovulation induction a complete investigation for confirmation and cause of

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Step by Step Ovulation Induction Table 1.1: Causes of anovulation suitable for ovulation induction treatment1

Hypothalamic Low concentration of gonadotropin-releasing hormone (hypogonadism) Weight or exercise related amenorrhea Kallmann syndrome Stress Idiopathic Pituitary Hyperprolactinemia Pituitary failure (hypogonadotropic hypogonadism) Sheehan’s syndrome Craniopharyngioma or hypophysectomy Cerebral radiotherapy Ovarian Polycystic ovaries Other endocrine Hypothyroidism Congenital adrenal hyperplasia Table 1.2: Causes of anovulation not suitable for ovulation induction treatment1 Ovarian failure Idiopathic Radiotherapy or chemotherapy Surgical removal Genetic Autoimmune Chromosomal Turner’s syndrome (45,X)

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anovulation should be carried out (Table 1.3). This is necessary to determine which ovulation inducing drugs are to be used, in how much dose and whether any adjuvants are needed. Table 1.3: Investigations for anovulation1 Investigation

When done

Interpretation

Progesterone

Midluteal phase of cycle (day 21 of 28 day)

>3 ng/ml—confirms ovulation > 10 ng/ml—shows adequate luteal phase

Folliclestimulating hormone

Early follicular phase

>10 IU/L indicates reduced ovarian reserve > 40 IU/L indicates ovarian failure < 5 IU/L may indicate pituitary or hypothalamic problem

Luteinizing hormone

Early follicular phase

> 10 IU/L indicates polycystic ovaries < 5 IU/L may indicate pituitary or hypothalamic problem

Testosterone

Any time in cycle

>2.4 nmol/L indicates polycystic ovaries > 5 nmol/L suggests congenital adrenal hyperplasia; check DHEAS and 17-OHP

Prolactin

Any time in cycle (but not after exercise or stress)

>100 ng/ml indicates pituitary adenoma < 100 ng/ml—other causes of hyperprolactinemia

Thyroidstimulating hormone

Any time in cycle if woman has symptoms or signs of hypothyroidism or has hyperprolactinemia

High thyroid stimulating hormone indicates hypothyroidism

Contd...

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Contd... Investigation

When done

Interpretation

Transvaginal ultrasound scan

Day 2—baseline scan Day 9 onward— follicular monitoring

Identifies polycystic ovaries Ovulation documentation

MRI/CT of pituitary

If two prolactin levels >100 ng/ml

Identifies macroadenomas

Karyotype

Primary amenorrhea and premature menopause

Identifies karyotypic abnormalities—for example, Turner’s syndrome (45, X) translocations, and androgen insensitivity syndrome (46, XY)

Body mass index

Oligomenorrhea or amenorrhea

BMI > 30 suggests polycystic ovary syndrome BMI < 20 suggests hypogonadotropic hypogonadism

Tests for Ovulation Clinically ovulation is indicated by regular menstrual cycles, midcycle pain and changes in cervical mucus. There are many methods of confirming ovulation. They are all based on the effects of hormonal events taking place in the body during ovulation. These tests are also used to assess the effectiveness of any ovulation induction treatment.

Basal Body Temperature (BBT) It is body temperature under basal conditions at rest. For practical purposes BBT is measured each morning before arising from bed with an oral glass thermometer, having an expanded scale, typically ranging from 96ºF to 100ºF and marked in tenths of a degree. Irregular sleep patterns and smoking can interfere with tests results.

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BBT recordings are based on the thermogenic properties of progesterone. As levels rise after ovulation, BBT also increases. BBT varies between 97ºF and 98ºF during the follicular phase of the cycle. The thermogenic shift in BBT occurs when progesterone concentrations rise above approximately 5 ng/ml, 1 to 5 days after LH surge and up to 4 days after ovulation.2 The temperature rise is usually abrupt but may be gradual and difficult to define. BBT generally falls to its lowest level on the day before ovulation, but the nadir in BBT cannot be reliably identified until after the temperature rises and remains elevated.3 It then increases by 0.4 – 0.8° over the average preovulatory temperature during the luteal phase and falls again to baseline levels just before or after the onset of menses. A biphasic pattern usually is readily evident. A normal luteal phase documents temperature elevation for 11 days at least. Menses begin 12 days or more after the rise in temperature. In pregnancy BBT remains elevated because of the sustained production of progesterone by the corpus luteum stimulated by human chorionic gonadotropin. Advantages 1. Relatively low cost. 2. BBT recordings can also reveal an abnormally long follicular phase or short luteal phase. Disadvantages 1. Increases stress. 2. Women may menstruate regularly and predictably but do not exhibit a clearly biphasic BBT pattern. 3. The most fertile period passes once the rise in temperature is seen. BBT tracings are useful when recordings are viewed in retrospect to show ovulatory pathology.

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Step by Step Ovulation Induction

Luteal Serum Progesterone Levels Progesterone levels generally remain below 1 ng/ml during the follicular phase, rise slightly on the day of the LH surge (1–2 ng/ml) and steadily thereafter, peak 7 to 8 days after ovulation, and then decline over the days preceding menses. Any level greater than 3 ng/ml provides reliable objective evidence that ovulation has occurred.4 It is usually performed in the midluteal phase around day 21 of menstrual cycle. Serum progesterone levels have also been used to measure the adequacy of luteal function. Accurate judgment requires daily serum progesterone determination because the corpus luteum progesterone secretion is pulsatile in nature, closely correlating with distinct pulses in pituitary LH release. Levels ranging from as low as 2 ng/ml to as high as 40 ng/ ml can be observed, within brief intervals of time.5 However, daily estimations are both costly and impractical. Sampling during the morning hours when progesterone concentrations are generally high and less erratic may be helpful.6 A sum of 3 measurements obtained between the 5th and 9th day after ovulation totaling 30 ng/ml or more have also been recommended.7 A single measurement greater than 10 ng/ ml at day 21 of menstrual cycle is often used. However, random serum progesterone concentrations defy confident interpretation of adequacy of luteal phase and have little value beyond documenting ovulation. Advantages 1. 2. 3. 4. 5.

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Simple Reliable Minimally invasive Widely available Assesses adequacy of luteal phase also.

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7

Disadvantages 1. False-negative or-positive due to fluctuating levels. 2. Multiple samples required for accuracy.

Midcycle LH Surge It is a relatively brief event, typically lasting for 48 and 50 hours. LH has a short half-life and is rapidly cleared via the urine. Ovulation predictor kits turn positive when the urinary LH concentration exceeds a threshold level normally seen only during the LH surge. The threshold level for the Elisa kit is 40 mIU/ml. Methods LH surge can be detected by the following methods: 1. ELISA: It is the commonly used method. 2. RIA: It is very accurate. 3. Slide test. Principle of ELISA Test It contains 2 antibodies one directed against a subunit which is attached to enzyme alkaline phosphates and the other against the b subunit which is attached to test pad. When LH is present in urine, a sandwich is formed and the enzyme is available to convert a noncolored substance to chromo­ gen (blue). The color intensity produced is proportional to the concentration of LH in the urine sample. Time of test: The first morning void would be an ideal speci­ men to test because it is typically the most concentrated. How­ever, results correlate best with the serum LH peak when test­ing is performed in the late afternoon or early evening hours (4.00 to 10.00 pm), probably because LH surges often

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begin in the early morning hours and are not detected in urine until several hours later.2 Twice daily testing decreases the fre­quency of false-negative results. Precautions: 1. Testing must be done on a daily basis as test is positive on only a single day, occasionally on two consecutive days. 2. Patients should be advised to avoid drinking large volumes of fluids a short time before they plan to test as results are sensitive to the volume of fluid intake. Interpretation: Ovulation generally follows within 14 to 26 hours after detection of the urine LH surge and almost always within 48 hours.8 The period of greatest fertility includes the day of LH surge detection and the following 2 days. The day after the first positive test generally is the one best for timed intercourse and artificial insemination.8,9 Accuracy of test: The accuracy of many ovulation predictor kits available varies. The kits predict ovulation with greater than 90% probability.9,10 The positive and negative predictive values of these tests are 90% and 96%, respectively. If the urine is checked twice a day sensitivity increases to 97–99%. About 5–10% of women do not produce positive results either be­cause of failed recognition by the antibody used or because their peak urinary LH concentration does not rise above the threshold set by the kit manufacturers. True false-positive tests are rare but equivocal results are not and can be both confusing and frustrating. About 28.7% of patients undergoing ultrasound-monitored IUI (intrauterine insemination) cycle had a spontaneous  LH  surge  before ovulation triggering was scheduled. This could affect pregnancy rates following IUI. Hence, LH surge may have a more important role than ultrasound monitoring in timing IUI or coitus.11

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False-positive: False-positive results may occur with intake of these drugs. 1. Oral contraceptive pill 2. Danazol 3. Exogenous hCG 4. hMG 5. Clomiphene citrate. Advantages 1. 2. 3. 4.

Noninvasive Widely available Not time consuming Predict when ovulation will occur unlike other methods which are analyzed in retrospect 5. Helps to define the length of the follicular and luteal phase and to identify other cycle abnormalities. Disadvantages 1. Tedious 2. False-negative results because of short duration of LH surge. 3. Accuracy is affected by fluid intake.

Endometrial Biopsy Endometrial biopsy is a test of ovulation based on the charac­ teristic histological changes in the endometrium resulting from the action of progesterone. During the follicular phase of the menstrual cycle, the endometrium exhibits a proliferative pattern, reflecting the growth stimulated by rising levels of estrogen derived from the dominant ovarian follicle. During the luteal phase, progesterone secreted by the corpus luteum causes the secretory transformation of the endometrium.

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An­ovulatory women are always in the follicular phase and have a proliferative endometrium which can become hyperplastic with extended exposure to a cons­tant estrogen growth stimulus. The histologic features of the secretory endometrium change, with the duration of progesterone exposure. The experienced pathologists can “date” the endometrium, providing a retrospective estimate of how many days have passed since ovulation occurred. The observed date can then be compared to the actual date of sampling. In recent years it has been more accurately defined prospectively, by the number of days elapsed since the detection of the LH surge or ultrasound observation of follicular collapse. Histologic and sampling dates that agree, within a 2-day interval, have generally been considered normal. Dates more than 2 days “out of phase” in two consecutive cycles is the standard criterion for the diagnosis of luteal phase deficiency.12 The best time for the biopsy is controversial. Some advocate the premenstrual phase, when the endometrium might best reflect the cumulative effects of corpus luteum function, while others have argued that the midsecretory phase, coinciding with the putative implantation window, is more relevant being able to identify abnormalities of endo­metrial maturation which may go undetected.13 A careful and systematic study has revealed that normal variations in histologic characteristics among individuals, between cycles in individuals and among different observers are simply too great to reliably define a specific luteal day or even a narrow interval of days. To conclude the body of the available evidence supports the conclusion that the traditional endometrial histologic dating is not a valid diagnostic tool. Consequently, endo­ metrial dating cannot be used to guide the clinical manage­ ment of women with reproductive failure and should no lon­ ger be regarded as an important element of their evaluation.

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Advantages 1. Simple office procedure. 2. Few complications. Disadvantages 1. Invasive. 2. Costly. 3. Not very accurate: Numerous studies and analyzes have described significant intraobserver and interobserver variations in histologic interpretation that are great enough to affect diagnosis and management in 20 to 40% of indi­ vidual women.14

Ultrasonography Although not providing definite positive proof that ovulation actually occurred, serial transvaginal ultrasound exami­nations offer details about the size and number of preovulatory follicles and provide the most accurate estimate of when ovulation occurs (See Chapter 14). In its final stages of development, the preovulatory follicle grows at a predictable pace, approximately 2 mm per day (range of 1–3 mm/day). After ovulation, the follicle abruptly decreases in size, its margins become less distinct, the density of internal echoes increases and fluid in cul-de-sac is seen Table 1.4.15 Abnormal patterns of follicle develop­ment can Table 1.4: Signs of ovulation on ultrasonography 1.  Margins of follicle become indistinct 2.  Increase in density of internal echoes in follicle 3.  Irregularity of follicle 4.  Abrupt decrease in size of follicle 5.  Fluid in cul-de-sac

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also be observed. The follicle may grow at an abnormal pace, collapse when still relatively small (atresia), or continue to grow or fail to rupture, persisting as a cyst for days after the LH surge (luteinized unruptured follicle).16 3D ultrasound monitoring is a new introduction and is more closer to physiological monitoring.17 Each of the available tests is useful and no one test is necessarily the best. Some are very simple, noninvasive, and inexpensive, and others are more complicated, invasive and costly. Pregnancy is the only sure positive proof of ovulation.

References 1. Fairley DH, Taylor A. Anovulation. Br Med J. 2003;327:546-9. 2. Luciano AA, Peluso J, Koch El, Maier D, Kuslis S, Davison E. Temporal relationship reliability of the clinical, hormonal, and ultrasonographic indices of ovulation in infertile women. Obstet Gynecol. 1986;75:412-6. 3. Quagliarello J, Arny M. Inaccuracy of basal body temperature charts in predicting urinary luteinizing hormone surges. Fertil Steril. 1990;45:334-7. 4. Wathen NC, Perry L, Lilford RJ, Chard T. Interpretation of single progesterone measurement in diagnosis of anovulation and defective luteal phase: Observations on analysis of the normal range. Br Med J. 1984;288:7-9. 5. Fillcori M, Butler JP, Crowley WF. Neuroendocrine regulation of the corpus luteum in the human: Evidence for pulsatile progesterone secretion. J Clin Invest. 1984;73:1638-47. 6. Syrop CH, Hammond MG. Diurnal variations in midluteal serum progesterone measurements. Fertil Steril. 1987;47:67-70. 7. Jordan J, Craig K, Clifton DK, Soules MR. Luteal phase defect: The sensitivity and specificity of diagnostic methods in common clinical use. Fertile Steril. 1994;62:54-62. 8. Miller PB, Soules MR. The usefulness of a urinary LH kit ovulation prediction during menstrual cycles of normal women. Obstet Gynecol. 1996;87:13-7.

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9. Martinez AR, Bernardus RE, Vermeiden JP, Schoemaker J. Time scheduled of intrauterine insemination after urinary lutenizing hormone surge detection and pregnancy results Gynecol Endocrinol. 1994;8:1-5. 10. Nielsen MS, Barton SD, Hatasaka HH, Stanford JB. Comparisons of several one step home urinary luteinizing hormone detection test kits to OvuQuick. Fertil Steril. 1998;76:384-7. 11. Antaki R, Dean NL, Lapensée L, Racicot MH, Ménard S, Kadoch IJ. An algorithm combining ultrasound monitoring and urinary luteinizing hormone testing: a novel approach for intrauterine insemination timing. J Obstet Gynaecol Can. 2011;33(12):1248-52. 12. Duggan MA, Brashert P, Ostor A, Scurry J, Billson V, Kneafsey P, Difrancesco L. The accuracy and interobserver reproducability of endometrial dating. Pathology. 2001;33:292-7. 13. Casteibaum AJ, Wheeler J, Coutiferis CB, Mastroianni L, Lessey BA Jr. Timing of the endometrial biopsy may be critical for the accurate diagnosis of luteal phase deficiency. Fertil Steril. 1994;61:443-7. 14. Scott RL, Snyder RR, Strickland DM, Tyburski CC, Bagnall JA, Reed KR, et al. The effect of interobserver variation in dating endometrial histology on the diagnosis of luteal phase defects. Fertil Steril. 1988;50:888-92. 15. de Crespigny LC, O’Herlihy C, Robinson HP. Ultrasonic observation of the mechanism of human ovulation. Am J Obstet Gynecol. 1981;139:636-9. 16. Matijevic R, Grigic O. Predictive value of ultrasound monitoring of menstrual cycle. Curr Opin Obstet Gynecol. 2005;17(4):405-10. 17. Murtinger M, Aburumieh A, Rubner P, Eichel V, Zech MH, Zech MH. Improved monitoring of ovarian stimulation using 3D transvaginal ultrasound plus automated volume count. Reprod Biomed Online. 2009;19(5):695-9.

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cHAPTER

2

Oral Ovulogens Surveen Ghumman

Clomiphene Clomiphene citrate (CC) is an orally active nonsteroidal triphenylethylene derivative approved for clinical trials in 1967. It has both estrogen agonist and antagonist effects by acting on a and b estrogen receptors. It is used in clinical practice as an antagonist, as the agonist properties manifest only when endogenous estrogen levels are very low (Fig. 2.1). The commercially available preparation is a racemic mixture of two sterochemicals in the ratio of 38% zuclomiphene or less active cis-isomer, and 62% enclomiphene or active transisomer which is responsible for the ovulation induction property of clomiphene.1 After oral administration, it undergoes enterohepatic circulation and may be found in serum up to 30 days. Enclomiphene is cleared rapidly, while zuclomiphene has a long half-life. The two clomiphene isomers have mixed estrogenic and antiestrogenic effects with zuclomiphene having a greater estrogenic activity than enclomiphene. Only

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Fig. 2.1: Mechanism of action

51% of the oral dose is excreted after 5 days. Significant levels of plasma concentration of zuclomiphene can be detected even after one month but there is no evidence of important clinical significance as it is less active isomer. In normally ovulating woman clomiphene increases GnRH pulse frequency, but in anovulatory PCOS women it increases the pulse amplitude as frequency is already very high.

Indications for Use 1. Anovulation or infrequent ovulation as in PCO (WHO category II).

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2. Infertility for causes other than ovulatory to time IUI or increase number of oocytes. 3. Luteal phase defects. 4. Unexplained infertility. The mechanism of inadequate corpus luteum can be due to insufficient FSH stimulation during follicular phase. Clomiphene acts by removing any dysfolliculogenesis. In patients of unexplained infertility, controlled ovarian stimulation increases the level of ovarian steroids and may overcome the subtle deficiencies that these women may have. It also increases the number of oocytes available in one cycle.

Contraindications 1. Liver disease 2. Ovarian cyst 3. Development of visual symptoms on administration of drug 4. Ovarian failure 5. Hypothalamic pituitary failure (WHO Group I)—as clomiphene requires an intact hypothalamic-pituitary ovarian axis for its action.

Prerequisites before Clomiphene Therapy 1. History and examination to determine duration and cause of infertility. 2. Evaluation of male partner. 3. Prolactin level assessment—as abnormal levels will require additional treatment besides clomiphene. 4. Thyroid function test—as specific treatment is needed.

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5. Pituitary function assessment by baseline hormonal evaluation—as clomiphene requires a functional hypothalamic pituitary ovarian axis for results. 6. Liver function tests. 7. Adrenal function assessment—if hirsutism and other evidence of androgen excess are present. 8. Determination of ovarian tissue responsiveness to gonado­ tropins. 9. Tubal factor evaluation—Done only if there is suspicion or evidence of tubal factor involvement, otherwise it is evaluated only on failure of clomiphene treatment. It may also be recommended in women above 35 years to avoid wasting time on ineffective treatment as fertility is rapidly declining.

Dose Clomiphene is started from day 2 to 5 of the spontaneous or progestin induced menstrual cycle and in amenorrheic patients; it can be started immediately if pregnancy is ruled out. Giving clomiphene on day 5 results in increased gonadotropins at the time when the dominant follicle is being selected. Starting it earlier stimulates multiple follicular development which is ideal in order to obtain more than one oocyte. Outcome is similar, if it is started on any day between 2 and 5 of the cycle.2 The starting dose of clomiphene is 50 mg for 5 consecutive days (Fig. 2.2). More sensitive patients may be started with a lower dose of 25 mg. Dose can be increased every month by 50 mg up to 250 mg till ovulation occurs. However, it is seen that cumulative conception rate does not increase substantially beyond a dose of 150 mg due to the adverse effect of clomiphene on cervical mucus and endometrium (Table 2.1).3 Recommendation: FDA recommends a maximum induction dose of 150 mg/day as there is not much advantage thereafter.

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Results There is an ovulation rate of 80% which decreases with BMI, age, free androgen index and history of oligomenorrhea.5 The cycle fecundity is 15% in women who respond to treatment and increases to 22% if no other infertility factor is present.6 Cycle fecundity for those with unexplained infertility ranges from 3.4 to 8%.7 This is increased up to 9.5% if IUI is added. However, a recent Cochrane review (2010) stated that there is no evidence of clinical benefit of clomiphene citrate for unexplained fertility.8 Recommendation: If there is no conception after three cycles, intrauterine insemination is recommended along with clomiphene.

Predictors of Response It is important to identify women who will be poor responders in order to timely recommend nonresponders to alternative treatments. Negative factors would be obesity, hirsutism, oligomenorrhea, high free androgens and increased mean ovarian volume. It was found that leptin and free androgen index were most accurate predictors of response in normogonadotropic oligomenorrheic women.9 However, there is no accurate way to predict what dose will be required for an individual woman. In a recent study, concentrations of En and Zu were analyzed and it was found that they accumulated throughout treatment but no statistically significant relationship between En or Zu concentrations, and the dose required to induce ovulation was established. The Zu and En concentrations were not different in the patients who failed to respond, and are not a predictor of the ovulation response to CC or of the dose requirement.10 Normograms have been used to predict response.  Age, body mass index, free androgen index, and cycle history were

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Fig. 2.2:  Ovulation induction with clomiphene

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Table 2.1: Ovulatory and conception rates with different doses of clomiphene4 Dose of clomiphene (mg)

Successful ovulation (%)

Cumulative conception rate (%)

50

52.1

52.8

100

21.9

20.7

150

12.31

9.8

200

6.9

4.8

250

4.9

2.2

used to assign a likelihood of response for each patient on the basis of a published nomogram in a study and predicted 80% nonresponders but could not predict the dose required for response.11

Duration of Treatment Duration of treatment can extend to 6 to 12 months but 75% conceptions occur in the first 3 months.12 Since fecundability declines with age, those women above 35 should not undergo prolonged treatment with clomiphene citrate and treatment strategy must move on to other forms earlier after an expanded diagnostic evaluation to exclude other factors.6 Recommendation: Clomiphene should be used for a maximum of 6 months consecutively or 12 months in a patient’s lifetime as 75% conceptions occur in the first 3 months. In older women, alternatives should be opted for earlier.13

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Monitoring Monitoring can be done as follows: 1. Basal body temperature is simple, inexpensive but tedious and time consuming. 2. Serum estradiol levels (each follicle secretes 150 to 300 pg/ml per follicle). 3. LH surge by home monitoring urine tests (best performed by second urination of the day between 7 am and 10 am). It usually occurs between 5 and 12 days of completion of treatment. 4. Ultrasonography—Follicular monitoring to be started on day 9. Optimal follicular parameters around ovulation are a follicular size of 18 to 20 mm with perifollicular blood flow of 50 to 75% and RI of 0.4 to 0.48. 5. Midluteal serum progesterone greater than 3 ng/ml is an evidence of ovulation. A level of progesterone more than 10 ng/ml is taken as an adequate luteal phase. However, this value is not reliable as progesterone levels are very variable. A study comparing cycle fecundity clomiphene cycle monitored by BBT, LH surge detection and ultrasonography are found no advantage of one over the other.14 Before starting the next cycle it is useful to do a ‘clomiphene check’ where previous treatment cycle is reviewed, and pelvic examination or ultrasound ensures that no residual cyst is present. In recent years, this practice has been thought to be unnecessary; however, a regular contact is recommended to review response to treatment and to ensure an additional evaluation and alternative treatment is not delayed.6

Antiestrogenic Effect of Clomiphene It is thought that the antiestrogenic effect on cervical mucus and endometrium may be responsible for the discrepancy

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between ovulation and conception rates in clomiphene induced cycle.

Cervical Mucus With clomiphene the quantity of cervical mucus is decreased. Effect is dose dependant and more readily apparent when the interval between the last dose of clomiphene and ovulation is short. However, it is seen that the effect is usually negated by high serum estradiol levels due to multi-follicular development or because of end-organ sensitivity. Randomized controlled trials have proved that cervical mucus is not very significant as the postcoital test has little predictive value.

Endometrial Growth Clomiphene inhibits estradiol induction of progesterone receptors in endometrium. The effect is usually inconsistent but is important if preovulatory endometrial thickness is persistently less than 6 mm. In such situation, clomiphene citrate can be replaced by tamoxifen or letrozole. Tamoxifen has an estrogen agonist rather than antagonist effect on the endometrium. Letrozole has no adverse effect on endo­ metrium as it acts by decreasing estrogen production rather than receptor antagonism. Its action is easily reversible when the drug is stopped. Patients can also be started on gonadotropins instead of clomiphene. In recent studies it has been seen that clomiphene affects endometrium thickness on late proliferative days but not on mid-secretory days, and does not alter the echogenic pattern of the endometrium. The endometrial echogenic patterns in mid-secretory phase of women taking clomiphene who had conceived, were not significantly different from those of women who had not conceived.15

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Side Effects and Risks Minor side effects are seen in 10 to 20% of cases. 1. Hot flushes occur in 10% and are due to central misperception that endogenous estrogens are low causing vasomotor symptoms. 2. Nausea and vomiting (2%). 3. Breast discomfort and bloating. 4. Hair loss and dryness. 5. Headache. 6. Visual disturbances (1.6%): Blurred vision, diplopia, scotoma and light sensitivity may occur and need cessation of the drug and change of treatment options. Rarely optic neuropathy develops. Cases of central retinal vein occlusion (CRVO) have been reported and clomiphene may predispose to this condition especially in patients with associated risk factors for CRVO. Patients should be well informed of this side effect before commencement of therapy. If visual disturbances occur, therapy should be terminated and the patient referred for specialist ophthalmic care.16,17 7. Ovarian cysts (6.4%): They resolve without treatment in a few weeks.13 8. Ovarian hyperstimulation syndrome (less than 1%): It can be avoided by establishing and using minimum effective dose. Severe forms are rarely seen. 9. Multiple pregnancy (5–8%): Usually twins (95%) and very rarely triplets may be seen. 10. Ovarian cancer: Although earlier studies showed a 3-fold increase in incidence of ovarian cancer, recent studies showed only a small increase of incidence (OR2.43) of borderline serous tumors but not of invasive cancer.18 A pooled analysis of 8 studies showed that

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neither any fertility drug use nor more than 12 months of use was associated with ovarian cancer. Hence, no change in prescribing practice is warranted on these grounds. 11. Congenital malformations are not increased. However, it was seen that an abnormal karyotype was present in nearly 50% of women undergoing preovulatory oocyte retrieval after clomiphene stimulation.19 Clomiphene has been found to increase interval of time required for oocytes to reach metaphase I compared with oocytes of natural cycle. The interval of time required for metaphase I to reach metaphase II is significantly reduced (2.4 hours versus 10 hours for natural cycle).20 Despite all the above clomiphene with its ease of administration, reduced need for monitoring and limited cost maintains an important place in treatment of anovulation.

Tamoxifen Tamoxifen is a triphenylethylene derivative with a strong anti­ estrogenic activity.

Mechanism of Action It inhibits estrogen negative feedback on hypothalamus and pituitary by binding to its receptors in a manner similar to clomiphene.

Dose It is administered orally on second or third day of menstrual cycle in a dose of 20 mg/day for 5 days. The dose can be increased to 40 mg/day.

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Results Ovulation is induced in 70 to 75% patients with a pregnancy rate of 35%. In a recent Cochrane review, no evidence of a difference in effect was found between clomiphene versus tamoxifen or clomiphene.21

Advantages Tamoxifen causes a raised estrogen levels due to multi-­ follicular development and a direct action on the ovaries to enhance estrogen production, hence leading to a favorable response on the cervical mucus and endometrium. It is an alternative to clomiphene when there is persistently poor endometrial response. It also gives better results in patients with poor cervical mucus score.22

Side Effects Side effects include hot flushes, nausea, vomiting, headache, dizziness, liver toxicity, abdominopelvic discomfort, endometrial hyperplasia and endometrial polyps. Compli­ cations, similar to clomiphene include multiple pregnancy, hyperstimulation and ovarian enlargement. Antiestrogens have an important role to play as first-line ovulation induction in infertile women. They are safe with minimal side effects. However, dose and length of treatment must be individualized. It is important to identify when they should be stopped and further treatment with other drugs initiated.

Letrozole Letrozole is an aromatase inhibitor used in breast cancer cases to suppress estrogen. Although it can be used to induce

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ovulation, it is not approved by FDA for this purpose. The use of this drug is not recommended for ovulation induction currently. It has no effect on plasma androstenedione and testos­ terone and so no accumulation of androgens (Fig. 2.3). Letrozole has no effect on endometrium and cervical mucus because of its short half-life and absence of estrogen receptor depletion. As can be seen in Table 2.2 although the estrogen levels are lower with letrozole compared to clomiphene the endometrial response is much better.23 It was also associated with lower rate of multiple pregnancy.24

Fig. 2.3:  Mechanism of action

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Table 2.2: Comparison of effect of clomiphene and letrozole23 Endometrial thickness

Ovulation rate

E2 levels

Number of mature follicles

Clomiphene

5 mm

67%

1278 pg/ml

1.9

Letrozole

8 mm

87%

392 pg/ml

2.4

Pregnancy

30%

Advantages 1. No antiestrogenic effect on endometrial lining and cervical mucus. 2. Induces monofolliculogenesis and hence does not cause hyperstimulation. 3. Easily reversible action as half-life is 2 days.

Dose It is given in a single dose of 2.5 to 5 mg/day from day 3 to 7 for 5 days. Recently single dose of 20 mg on day 3 has given comparable success rate for ovulation stimulation.25

Side Effects Hair thinning, nausea, hot flushes, peripheral edema and fatigue have been reported in 5% patients. Aromatase inhibitors warrant additional study to establish their role as treatment drug for ovulation induction and as a option for clomiphene resistant cases.

References 1. McDonough PG. The clomid twins: Waiting for a single isomer heaven (Editorial). Fertil Steril. 1997;68:186-7. 2. Wu CH, Wenkel CA. The effect of therapy initiation day on clomiphene citrate therapy. Fertil Steril. 1989;52:564-8.

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3. Kusata E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod. Update. 1997;3:359-65. 4. Gysler M, March CM, Mishell DR Jr, Baily EJ. A decade’s experience with an individualized clomiphene treatment regimen including its effect on the postcoital test. Fertil Steril. 1982;37:161-7. 5. Imani B,  Eijkemans MJ,  te Velde ER,  Habbema JD,  Fauser BC. Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab. 1998;83(7):2361-5. 6. Use of clomiphene citrate in women. The Practice Committee of American Society of Assissted Reproduction. Fertil Steril. 2006;86(5):S187-93. 7. Fisch P,  Casper RF,  Brown SE,  Wrixon W,  Collins JA,  Reid RL, et al. Unexplained infertility: evaluation of treatment with clomiphene citrate and human chorionic gonadotropin. Fertil Steril. 1989;51(5):828-33. 8. Hughes E, Brown J, Collins JJ, Vanderkerchove P. Clomiphene citrate for unexplained subfertility in women. Cochrane Database of Systematic Reviews. 2010; Issue 1. Art. No.: CD000057.  9. Imani B,  Eijkemans MJ,  de Jong FH,  Payne NN,  Bouchard P,  Giudice LC,  et al. Free androgen index and leptin are the most prominent endocrine predictors of ovarian response during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab. 2000;85(2):676-82. 10. Ghobadi C,  Amer S,  Lashen H,  Lennard MS,  Ledger WL,  Rostami-Hodjegan A. Evaluation of the relationship between plasma concentrations of en- and zuclomiphene and induction of ovulation in anovulatory women being treated with clomiphene citrate. Fertil Steril. 2009;91(4):1135-40. 11. Ghobadi C,  Nguyen TH,  Lennard MS,  Amer S,  RostamiHodjegan A, Ledger WL. Evaluation of an existing nomogram for predicting the response to clomiphene citrate. Fertil Steril. 2007;87(3):597-602.

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12. Speroff L, Glass R, Kase N. In vitro fertilization. In: Speroff L, Glass R, Kase N (Eds). Clinical Gynaecological Endocrinology and Infertility. William and Wilkins: Baltimore, London. 1989;611-9. 13. Rust LA, et al. An individualized graduated therapeutic regimen for clomiphene citrate. N Engl J Med. 1994;331:771-6. 14. Smith YR, et al. Comparison of low technology and high technology monitoring of clomiphene citrate ovulation induction. Fertil Steril. 1998;70:165-8. 15. Dehbashi S, Parsanezhad ME, Alborzi S, Zarei A. Effect of clomiphene citrate on endometrium thickness and echogenic patterns. Int J Gynaecol Obstet. 2003;80(1):49-53. 16. Lee VY, Liu DT, Li CL, Hoi-Fan, Lam DS Central retinal vein occlusion associated with clomiphene-induced ovulation. Fertil Steril. 2008;90(5):2011.e11-2. 17. Viola MI,  Meyer D,  Kruger T. Association between clomiphene citrate and visual disturbances with special emphasis on central retinal vein occlusion: a review. Gynecol Obstet Invest. 2011;71(2):73-6. 18. Ness RB, Cramer DW, Goodman MT, Kjaer SK, Mallin K, Mosgaard BJ, et al. Infertility, fertility drugs and ovarian cancer: A pooled analysis of case control studies. Am J Epidemiol. 2002;155:217-24. 19. Wramby H, Fredga K, Liedholm P. Chromosome analysis of human oocyte recovered from preovulatory follicles in stimulated cycles. N Engl J Med. 1987;316:121-4. 20. Seibel MM, Smith DM. The effect of clomiphene citrate on human preovulatory oocyte maturation in vivo. J In Vitro Fertil. 1989;6:3-6. 21. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E. Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database of Systematic Reviews. 2009; Issue 4. Art No.: CD002249. 22. Annapurna V, Dhaliwal LK, Gopalan S. Effects of two antiestrogens, clomiphene citrate and tamoxifen, on cervical mucus and sperm cervical mucus interaction. Int J Fertil Women’s Med. 1997;42(3):215-8.

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23. Mitwally MF, Casper RF. Aromatase inhibition improves ovarian response to FSH in poor responders. Fertil Steril. 2002;77(4):776-80. 24. Mitwally MF, Biljan MM, Casper RF. Pregnancy outcome after the use of an aromatose inhibitor for ovarian stimulation. Am J Obstet Gynecol. 2005;192:381-6. 25. Mitwally MF, Casper RF. Single dose administration of an aromatose inhibitor for ovarian stimulation. Fertil Steril. 2005;83:229-31.

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cHAPTER

3

Clomiphene Resistance— What Next? Surveen Ghumman

Many patients do not respond to clomiphene. There may be a genetic basis to clomiphene resistance and it is seen that the chance of resistance to clomiphene is almost double in women with PCOS (polycystic ovary syndrome) harboring the 680-polymorphism Ser/Ser genotype.1 It is important to define clomiphene resistance and failure.

Clomiphene Resistance Clomiphene resistance is failure to ovulate with 3 months use of clomiphene at 150 mg/day for 5 days. It occurs in 20% cases more so in PCOS patients.

Clomiphene Failure Patients who ovulate but fail to conceive after treatment with 3 cycles of clomiphene in a dose of 150 mg/day are cases of clomiphene failure. It is usually due to excess LH, androgens or insulin which leads to impaired folliculogenesis, increased

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atresia, poor oocyte quality, poor endometrial receptivity and deficient corpus luteum function. Other potential infertility factors must be ruled out. On diagnostic laparoscopy, it was seen that significant pelvic pathology was present in one third of these patients, 29.3% had minimal pathology and only 32.6% had a normal pelvis.2 Recommendation: Diagnostic laparoscopy should be done to evaluate the pelvis after failure of 3 to 6 cycles of clomiphene.

Management of Clomiphene Failure or Resistance All cases with clomiphene failure need a complete endocrinal work-up and a diagnostic laparoscopy to rule out any underlying endocrine disorder or pelvic pathology. These women may respond to additional or alternative treatment. A choice of which treatment is to be initiated is based on patient’s history, laboratory results and observation of previous unsuccessful clomiphene cycles. These are alternatives that merit consideration depending on patient’s age, goals, available resources and risk tolerance.

Weight Loss Women with central fat have high levels of LH, andros­ tenedione, estrone, insulin, triglycerides, very low-density lipoproteins and lower levels of high- density lipoprotein. These altered levels cause disturbances in hypothalamic pituitary ovarian axis. A high waist-hip ratio (more than 0.85) is associated with greater reproductive hormone and insulin derangement. Even moderate obesity with a body mass index of more than 27 kg/m2 is associated with a lesser chance of ovulation.3 Adipose tissue is an active site for

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steroid production and metabolism. It converts androgens to estrogens by aromatase activity (Table 3.1). There is defective clearance and production of androgens in central obesity. Increasing BMI is associated with an increased requirement for clomiphene. Larger doses of clomiphene up to 200 mg/day are required to ensure ovulation in obese women. Doses of gonadotropin required are also more. Weight loss improves the clinical and biochemical parameters that are disordered due to obesity. Loss of 5 to 7% of body weight is effective in restoring ovulation and leads to changes in levels of insulin, IGF and SHBG. Exercise and dietary restraint produce a favorable endocrine status of these patients and a better ovulation rate with clomiphene.4 There is a higher conception rate and a lower miscarriage rate. Even surgically induced weight loss will induce these changes.

Extended Course of Clomiphene Treatment Clomiphene can be given for up to 7 to 10 days to induce ovulation in those cases which do not respond to the 5 day regime.5 Up to 50% of women who are resistant to the standard regime respond to it.

Tamoxifen It can be tried alone or in combination with clomiphene especially in cases of poor cervical mucus score and in cases Table 3.1: Effect of adipose tissue on steroid hormone levels •  Storage of steroid hormones •  Affects insulin secretion from pancreas •  Conversion of estrogen from inactive to active form •  Peripheral conversion of androgens to estrogens •  Changes in level of sex hormone-binding globulin (SHBG)

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of poor endometrial response. Tamoxifen causes a raised estrogen levels due to multi-follicular development and a direct action on the ovaries to enhance estrogen; hence, leading to a favorable response on the cervical mucus and endometrium. It is given in a dose of 20 to 40 mg/day from day 2 to 5 days.

Aromatase Inhibitors Letrozole: Letrozole given for 5 days showed a ovulation rate of 33.3% in clomiphene resistant cases.6 However, if administered as long protocol (10 days) it can produce more mature follicles and subsequently more pregnancies than the short letrozole therapy (5 days) in clomiphene resistant women with PCOS.7 In clomiphene resistant PCOS patients, letrozole results were nearly comparable to gonadotropin therapy with an ovulation rate of 79.3% and pregnancy rate of 23.4%. It is found to be most effective when baseline estradiol level was more than 60 pg/ml.8 However, letrozole is no longer approved for use as an ovulation induction drug. Anastrazole: Anastrazole in PCOS clomiphene resistant women had an ovulation rate of 63.4% and a pregnancy rate of 15.1%, which was found to be comparable to letrozole.9

Glucocorticoids Dexamethasone 0.5 mg/day or prednisolone 5 mg/day is added either continuously or in follicular phase from day 5 to 16 to bring down raised levels of DHEAS (>200 µg/dl) in PCOS patients. It results in an ovulation rate of 80% compared to 20% in cases given placebo and a cumulative pregnancy rate which is 10-fold (40% vs 4%). This effect is seen even

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in cases where DHEAS is normal.10 The pregnancy rate in women with unexplained infertility undergoing IUI after ovulation induction with clomiphene showed a pregnancy rate of 21.4% vs 4.5% with and without  dexamethasone, respectively.11 A recent Cochrane review (2009) supported these findings.12 Glucocorticoids diminishes the androgen level in the microenvironment of the ovary by blunting the night time peak of ACTH, thus decreasing the adrenal contribution to circulating androgens. However, the mechanism involves more than androgen suppression. It may directly effect oocyte or induce indirect effects on intrafollicular growth factor and cytokines which may act synergistically with FSH. It may be continued for 3 to 6 cycles if successful and should be discontinued if not (ASRM Guidelines 2006).13 There is no evidence that glucocorticoids have any major side effect in this dose when used. It is stopped if pregnancy occurs.

Human Chorionic Gonadotropin (hCG) About 20% of cases, ovulation does not occur in clomiphene induced cycle because there is a failure of rupture of a developed follicle. hCG is given in a dose of 5,000 to 10,000 IU when follicle is 18 to 20 mm on ultrasonography, in cases where there is repeated evidence of unruptured follicle. It is also helpful in timing intrauterine insemination where midcycle LH surge may remain falsely undetected because of its brief duration. Recombinant hCG can be used in a single dose of 250 µg subcutaneously and has similar pharma­ cokinetics as the urinary formulation. All studies show that other than these two indications there is no difference in results with or without exogenous hCG.5 Midcycle hCG adminis­tration has no effect on luteal function.14

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Suppressive Therapy Suppression can be done either with oral contraceptives or GnRH agonists and is used when there are raised LH or androgen levels as in PCOS women. Oral Contraceptive Suppression with oral contraceptives decreases ovarian androgens, luteinizing hormone, FSH and 17 b-estradiol and may be responsible for the improved response in patients who previously were resistant to clomiphene citrate. It restores normal function in a patient with dysfunctional hypothalamic pituitary ovarian axis manifesting with anovulation. An ovulation rate of 70% and a cumulative pregnancy rate of 50% was achieved with such treatment in clomiphene resistant cases.15 GnRH Agonist GnRH agonists cause a down regulation of pituitary. It is given in a dose of 0.1 mg/day from day 21 of previous cycle. LH and FSH levels are brought down (E2 < 30 pg/ml, LH < 2.5 IU/l, Progesterone < 2 ng/ml). Then stimulation is begun with gonadotropins and GnRH agonist dose is reduced to half. This decreases high basal LH levels, decreases LH stimulation of ovarian androgen production and eliminates any premature LH surge. When combined with a oral contraceptive there is a dual advantage of a greater and more sustained reduction of LH, improved luteinizing hormone-to-follicle-stimulating hormone ratio and lower serum androgens, particularly dehydroepiandrosterone sulfate. It also prevents estrogen deficiency which develops on using GnRH agonist without add back therapy (Fig. 3.1).16 Results are good in clomiphene resistant cases.17,18

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Fig. 3.1: Combined suppressive action of oral contraceptive and GnRH agonist

Dopamine Agonists Bromocriptine For patients with raised serum prolactin levels bromocriptine in a dose up to 2.5 mg bd or tds is used orally or vaginally. Longacting slow release or depot preparations are also available. Ovulatory dysfunction in presence of galactorrhea responds well to bromocriptine even if prolactin level is normal.19 About 80% patients have restoration of ovulation. However, a recent study found no advantage of adding bromocriptine in clomiphene resistant patients with normal prolactin. No significant differences was seen in ovulation, and serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS), progesterone (P) between treatment and placebo group after treatment. Serum prolactin levels were reduced.20 Carbergoline Carbergoline can be used in bromocriptine resistant cases in a weekly dose of 0.5 to 3 mg orally or vaginally. It has less side effects, the most common being headache.

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Insulin Sensitizers Metformin: Patients with hyperinsulinemia (fasting insulin more than 25 IU or a fasting glucose to insulin ratio of less than 4.5) in PCOS require insulin sensitising drugs like metformin which is given in a dose of 1500 mg/day. Some recommend administration of insulin sensitizers at fasting insulin level of more than 15 IU. Now postprandial insulin levels are also taken into account and levels more than 100 IU are significant Altered GTT is considered the most reliable method of establishing insulin resistance. By reducing hyperinsulinemia metformin causes a reduction in intraovarian androgens. This also leads to reduction in E2 levels and induces an orderly follicular growth restoring ovulation. Ovulation rates are higher when combined with clomiphene (76% vs 46% when used alone).21,22 A recent meta-analysis published in 2008 showed that pregnancy rates were also increased. The live birthrate following up to 6 months of treatment with metformin given along with clomiphene was increased but not so significantly (26.8%vs 22.5% with clomiphene alone).23 Metformin combined with clomiphene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone.

Therefore, the use of metformin in improving reproductive outcomes in women with PCOS appears to be limited.24 Metformin may be added to clomiphene citrate in women with clomiphene resistance who are older and who have visceral obesity.25 Ultrashort metformin pretreatment: Women with clomiphene resistant PCOS can be started on 1500 mg metformin daily for 12 days, followed by clomiphene 150 mg daily for 5 days along with metformin. Twelve days of metformin

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pretreatment improves ovulation and pregnancy rates in women with clomiphene-resistant PCOS with 42.5% women ovulating, and 15% conceiving vs 12.5% women ovulating but none conceived in the clomiphene only group as seen in a recent study.26 A Cochrane review 2008 concluded that more randomized controlled trials are required before short treatment can be recommended.27 Pioglitazone and Rosiglitazone: Pioglitazone in a dose of 30 to 50 mg/day or Rosiglitazone in a dose of 4 to 8 mg/ day can also be used as monotherapy or in combination with metformin.28,29 A recent study showed rosiglitazone when compared to metformin has higher ovulation rates (64.3% vs 36.4%) and pregnancy rates (50% vs 38.5%) in clomipheneresistant cases when given at the start of an induced cycle. These findings suggest that short-term use of rosiglitazone with clomiphene is more efficacious than short-term use of metformin with clomiphene in these women. D-chiroinositol: Administration of D-chiroinositol makes up deficiency of D-chiroinositol containing phosphoglycan which mediates action of insulin in these patients. It is given in a dose of 1200 mg/day for 6 to 8 weeks to correct ovulatory dysfunction. N-acetyl cysteine: In clomiphene-resistant PCOS women, metformin was more effective than N-acetyl cysteine when added to clomiphene giving significantly higher ovulation and pregnancy rates (69.1% vs 20.0%, and 22.7% vs 5.3%, respectively).30

Acarbose Acarbose is an a-glucosidase inhibitor, used in the management of type 2 diabetes. Acarbose reduces the postprandial rise in both serum glucose and insulin levels

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by inhibiting a-glucosidase, an enzyme responsible for the intestinal absorption of carbohydrates. Acarbose was found to be a safe and effective agent that could be used in cases with clomiphene-resistant PCOS. It was as effective as metformin and is given in a dose of 100 mg tid. When compared with metformin both groups experienced a significant increase in ovulation and monthly mid-luteal serum progesterone levels during the 3-month treatment period compared with pretreatment scores and ovulation rates were similar between the acarbose and metformin groups. Acarbose may be an alternative to metformin for women with PCOS and clomiphene citrate resistance.31

Bezafibrate Dyslipidemia is commonly observed in PCOS patients. Bezafibrate is a drug for dyslipidemia acting through peroxisome proliferator-activated receptors. It was found to be beneficial for ovulation induction in patients with PCOS with dyslipidemia who were resistant to clomiphene citrate in a small study. It was given in a dose of 400 mg/day from day 1 of menses and clomiphene citrate 100 mg/day from day 5 of menses simultaneously until one follicle measuring at least 18 mm in diameter was found by transvaginal ultrasound. Five of seven patients successfully ovulated. Bezafibrate may be effective for ovulation induction in CC-resistant PCOS patients with dyslipidemia. However, larger studies are required.32

Naltrexone Endogenous opiates may affect various aspects of reproductive and metabolic function in patients with polycystic ovary syndrome (PCOS). Naltrexone (50 mg po daily) for 6 months caused long-term inhibition of the opioid system. In CC-resistant

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women with PCOS, there was significant reductions in BMI, fasting serum insulin, luteinizing hormone (LH), LH/folliclestimulating hormone ratio and testosterone improving a broad range of clinical, endocrine and metabolic derangements characteristic in PCOS. 10% ovulated only on natrexone. 33% patients conceived when clomiphene was added showing that it restored clomiphene sensitivity resulting in a significant number of pregnancies.33 However, larger studies need to be conducted to rule out possible teratogenicity of naltrexone.

Gonadotropins Gonadotropins may be given along with clomiphene to improve results and are specially indicated in unexplained infertility and where there is no success with clomiphene. Sequential treatment is only given if some response is seen with clomiphene. In cases where no response is seen with clomiphene, it is better to directly stimulate with gonadotropins. Treatment is individualized in the same way as traditional gonadotropin therapy based on transvaginal sonography and estradiol levels. Clomiphene citrate is given in a dose of 100 mg from day 2 to day 6. FSH is started on day 6 in a dose of 75 to 150 IU/day till adequate follicular development occurs (Fig. 3.2). Ade­­quate follicular

Fig. 3.2: Clomiphene and gonadotropin regime

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development is taken as estradiol more than 500 pg/ml or one follicle equal to or more than 14 mm mean diameter. The aim is monofollicular development and not superovulation in these anovulatory infertile women.13 Since clomiphene increases LH, FSH is preferred to hMG. Along with FSH, GnRH antagonist can be added to suppress premature LH surge. A Cochrane review however stated that in women with PCOS, no significant difference could be demonstrated between FSH and hMG, in terms of pregnancy rate. However, given similar cost, potential advantages in terms of purity and a possible reduction in OHSS risk, highly purified or recombinant FSH are likely to be widely adopted.34

GnRH Antagonists They act reversibly by competitive inhibition of GnRH receptors resulting in rapid decline in LH and FSH. There is no stimulatory phase unlike the GnRH agonists. It reduces the dose and duration of gonadotropin treatment as it does not nullify FSH or LH secretion but interrupts the premature LH surge. There are two protocols used in ovulation induction with antagonists. In both gonadotropins are started as usual. When follicle reaches 14 mm (usually Day 7), in the Lubeck Protocol antagonist, Centrorelix, is started at a dose of 0.25 mg/day (Fig. 3.3) whereas in the French protocol a single dose of 3 mg is given. Cochrane review 2002 has concluded that both protocols were equally effective in preventing premature LH surge.35

Surgical Ovulation Induction Laparoscopic ovarian drilling (LOD) is an alternative to ovulation induction with gonadotropins for polycystic ovarian

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Fig. 3.3: Clomiphene with gonadotropins and GnRH antagonist

syndrome (PCOS) patients unresponsive to clomiphene.36 Since it is as effective as FSH treatment in terms of live births, and reduces the need for ovulation induction or ART in a significantly higher proportion of women. It also increases the sensitivity to clomiphene. Laparoscopic ovarian drilling using electrocautery or laser photocoagulation can be done (Fig. 3.4). The advantage is that it is a single time treatment free of intensive monitoring with no risk of OHSS and multiple pregnancy.37 Ovulation occurs in 70–80% of patients and there is a conception rate of 60%. Complications include adhesion formation (80%) and ovarian atrophy.38 Unilateral ovarian diathermy was as effective and long lasting as bilateral ovarian diathermy in the resumption of menstruation and pregnancy rates.39 However, there are ongoing concerns about long-term effects of LOD on ovarian function.40 Patients with clomiphene resistance require further evaluation and form a challenging diagnostic problem to the infertility specialist. A step-by-step approach to rule out and treat other subclinical endocrinopathies is required.

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Fig. 3.4: Management of clomiphene resistance

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References 1. Overbeek A, Kuijper EA, Hendriks ML, Blankenstein MA, Ketel IJ, Twisk JW, et al. Clomiphene citrate resistance in relation to follicle-stimulating hormone receptor Ser680Serpolymorphism in polycystic ovary syndrome. Hum Reprod. 2009;24(8):2007-13. 2. Capelo FO, Kumar A, Steinkampf MP, Azziz R. Laparoscopic evaluation following failure to achieve pregnancy after ovulation induction with clomiphene citrate. Fertil Steril. 2003;80(6):1450-3. 3. Grodstein F, Goldman MB and Cramer DW. Body mass index and ovulatory infertility. Epidemiology. 1994;5:247-50. 4. Palomba S, Falbo A, Giallauria F, Russo T, Rocca M, Tolino A, et al. Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial. Hum Reprod. 2010;25(11):2783-91. 5. Flukar MR, Wang IY, Rowe TC. An extended 10-day course of clomiphene citrate in women with CC resistant ovulatory disorder. Fertil Steril. 1996;66:761-4. 6. Kamath MS, Aleyamma TK, Chandy A, George K. Aromatase inhibitors in women with clomiphene citrate resistance: a randomized, double-blind, placebo-controlled trial. Fertil Steril. 2010;94(7):2857-9. 7. Badawy A, Mosbah A, Tharwat A, Eid M. Extended letrozole therapy for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a novel protocol. Fertil Steril. 2009;92(1):236-9. 8. Ganesh A, Goswami SK, Chattopadhyay R, Chaudhury K, Chakravarty B Comparison of letrozole with continuous gonadotropins and clomiphene-gonadotropin combination for ovulation induction in 1387 PCOS women after clomiphene citrate failure: a randomized prospective clinical trial. J Assist Reprod Genet. 2009;26(1):19-24.

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9. Badawy A, Mosbah A, Shady M. Anastrozole or letrozole for ovulation induction in clomiphene-resistant women with polycystic ovarian syndrome: a prospective randomized trial. Fertil Steril. 2008;89(5):1209-12. 10. Parsanezhad ME, Alborzi S, Motazedian S, Omrani G. Use of dexamethasone and clomiphene citrate in the treatment of clomiphene citrate resistant patient with polycystic ovary syndrome and normal dehydroepiandrosterone sulphate levels: a prospective double blind, placebo-controlled trial. Fertil Steril. 2002;78:1001-4. 11. Moradan S, Ghorbani R. Dexamethasone in unexplained infertility. Saudi Med J. 2009;30(8):1034-6. 12. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E. Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database of Systematic Reviews. 2009, Issue 4. Art. No.: CD002249. 13. Use of clomiphene citrate in women. The Practice Committee of American Society of Assisted Reproduction. Fertil Steril. 2006;86:S187-93. 14. Agarwal SK, Buyalos RP. Corpus luteum function and pregnancy rates with clomiphene citrate therapy: comparison of human chorionic gonadotropin induced versus spontaneous ovulation. Hum Reprod. 1995;10:328-31. 15. Branigan EF, Estes MA. A randomised clinical trial of treatment of clomiphene citrate-resistant anovulation with the use of oral contraceptive pill suppression and repeat clomiphene citrate treatment. Am J Obstet Gynecol. 2003;188(6):1424-9. 16. Damario MA. Ovarian hyperstimulation syndrome prevention strategies: oral contraceptive pills-dual gonadotropin-releasing hormone agonist suppression with step-down gonadotropin protocols. Semin Reprod Med. 2010;28(6):468-74. 17. Genazzani AD, Petraglia F, Battaglia C, Gamba O, Volpe A, Gennazani AR. A long-term treatment with gonadotropins releasing hormone agonist plus low dose oral contraceptive improves the recovery of the ovulatory function in patients with polycystic ovary syndrome. Fertil Steril. 1997;67:463-8.

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18. Hughes E, Collins J, Vandekerckhove P. Gonadotrophinreleasing hormone analogue as an adjunct to gonadotropin therapy for clomiphene-resistant polycystic ovarian syndrome. Cochrane Database Syst Rev. 2000;(2):CD000097. 19. Padilla SL, Person GK, McDonough PG, Reindollar RH. The efficacy of bromocriptine in patients with ovulatory dysfunction and normoprolactinemic galactorrhoea. Fertil Steril. 1985;44:695-8. 20. Parsanezhad ME, Alborzi S, Namavar Jahromi B. A prospective, double-blind, randomized, placebo-controlled clinical trial of bromocriptin in clomiphene-resistant patients with polycystic ovary syndrome and normal prolactin level. Arch Gynecol Obstet. 2004;269(2):125-9. 21. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiroinositol) for polycystic ovary syndrome. Cochrane Database Syst Rev. 2003;3:CD003053. Comment in: ACP J Club. 2004;140(3):75. 22. Creanga AA, Bradley HM, McCormick C, Takacs Witkop C. Use of metformin in polycystic ovary syndrome: A meta-analysis. Obstet Gynecol. 2008;111:959-68. 23. 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;356:551-66. 24. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulinsensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2010;(1):CD003053. 25. Moll E, Korevaaur JC, Bossuyt PMM, van der Veen F. Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome? Human Reprod. 2008;23:1830-4. 26. Hwu YM, Lin SY, Huang WY, Lin MH, Lee RK. Ultrashort metformin pretreatment for clomiphene citrateresistant polycystic ovary syndrome. Int J Gynaecol Obstet. 2005;90(1):39-43.

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27. Sinawat S, Buppasiri P, Lumbiganon P, Pattanittum P. Long versus short course treatment with metformin and clomiphene citrate for ovulation induction in women with PCOS. Cochrane Database Syst Rev. 2008;(1):CD006226. 28. Stout DL, Fugate SE. Thiazolidinediones for treatment of polycystic ovary syndrome. Pharmacotherapy. 2005;25(2):24452. 29. Ortega-Gonzalez C, Luna S, Hernandez L, Crespo G, Aguayo P, Arteaga-Troncoso G. Responses of Serum Androgen and Insulin Resistance to Metformin and Pioglitazone in Obese, Insulin-Resistant Women With Polycystic Ovary Syndrome. J Clin Endocrin Metab. 2005;90(3):1360-5. 30. Abu Hashim H, Anwar K, El-Fatah RA. N-acetyl cysteine plus clomiphene citrate versus metformin and clomiphene citrate in treatment of clomiphene-resistant polycystic ovary syndrome: a randomized controlled trial. J Women’s Health (Larchmt). 2010;19(11):2043-8. 31. Sönmez AS, Yasar L, Savan K, KoçS, Ozcan J, Toklar A, et al. Comparison of the effects of acarbose and metformin use on ovulation rates in clomiphene citrate-resistant polycystic ovary syndrome. Hum Reprod. 2005;20(1):175-9. 32. Hara S, Takahashi T, Amita M, Igarashi H, Kurachi H. Usefulness of bezafibrate for ovulation induction in clomiphene citrateresistant polycystic ovary syndrome patients with dyslipidemia: a prospective pilot study of seven cases. Gynecol Obstet Invest. 2010;70(3):166-72. 33. Ahmed MI, Duleba AJ, El Shahat O, Ibrahim ME, Salem A. Naltrexone treatment in clomiphene resistant women with polycystic ovary syndrome. Hum Reprod. 2008 ;23(11):2564-9. 34. Hughes E, Collins J, Vandekerckhove P. Ovulation induction with urinary follicle stimulating hormone versus human menopausal gonadotropin for clomiphene-resistant polycystic ovary syndrome. Cochrane Database Syst Rev. 2000;(2):CD000087. 35. Al-Inay H, Aboulghar M. GnRH antagonist in assisted reproduction: a Cochrane review. Hum Reprod Update. 2002;17(4):874-85.

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36. Flyckt RL, Goldberg JM. Laparoscopic ovarian drilling for clomiphene-resistant polycystic ovary syndrome. Semin Reprod Med. 2011;29(2):138-46. 37. Nahuis MJ, Kose N, Bayram N, van Dessel HJ, Braat DD, Hamilton CJ, et al. Long-term outcomes in women with polycystic ovary syndrome initially randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotrophins. Hum Reprod. 2011;26(7):1899-904. 38. Campo S. Ovulatory cycles pregnancy outcome and complications after treatment of polycystic ovarian syndrome. Obstet Gynecol Survey. 1998;53:297. 39. Al-Mizyen E, Grudzinskas JG. Unilateral laparoscopic ovarian diathermy in infertile women with clomiphene citrate-resistant polycystic ovary syndrome. Fertil Steril. 2007;88(6):1678-80. 40. Farquhar C, Lilford RJ, Marjoribanks J, Vandekerckhove P. Laparoscopic ‘drilling’ by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev. 2007;(3):CD001122.

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cHAPTER

4

Gonadotropins Surveen Ghumman

The first birth after gonadotropin stimulation was reported by Alan Trounson in 1981. Since then it has become the cornerstone of ART stimulation protocols. FSH with LH separated by polyvalent antibodies was commercially available by 1987, but these still contained urinary proteins. A highly purified FSH was obtained on removing LH by monoclonal antibodies.1 Finally, the recombinant technology was used for a FSH preparation with absolutely no LH activity.

Gonadotropin Preparations 1. Human pituitary gonadotropin. 2. Human menopausal gonadotropins (75 IU of FSH, 75 IU LH). 3. Highly purified hMG (75 IU of FSH and 75 IU of LH with 60 kg). Compared with a daily dose of 200 IU of rFSH, 150 µg of corifollitropin is equivalent in safety and pregnancy outcomes in women using an antagonist protocol. In normal responder patients undergoing ovarian stimulation with GnRH antagonist co-treatment for IVF ongoing pregnancy rates of 38.9% for the corifollitropin alfa group and 38.1% for rFSH were achieved showing similar results for number of embryos transferred. Median duration of stimulation was equal (9 days) and incidence of (moderate/ severe) ovarian hyperstimulation syndrome was the same (4.1% and 2.7%, respectively).26 Fertilization rates were high, ranging from 66% to 68%. Corifollitropin alfa was generally well tolerated, with a tolerability profile similar to

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that of rFSH. There were no clinically relevant differences in pregnancy complications and the incidence of infant adverse events between the two drugs.27 Hence, compared with seven once-daily injections of rFSH, a single injection of corifollitropin alfa achieves equivalent efficacy, and provides a well tolerated and more convenient treatment option to induce multiple follicular growth prior to assisted reproduction.

Recombinant LH It is known that the follicular selection and final stages of follicular maturation are equally if not more dependent on low 28 circulating levels of LH. In addition to stimulating production of thecal androgens as substrate for estrogen synthesis, LH stimulates granulosa cells via LH receptors induced by FSH and estrogen in larger but not smaller follicles. LH then becomes the principal stimulus for final stages of follicular maturation while at the same time declining concentration of FSH starve the smaller more FSH-dependent follicles into atresia. Low dose hCG or recombinant LH can promote larger follicles to grow while hastening the regression of smaller follicles. Exogenous LH supplementation was consistently associated with higher peak estradiol concentrations. The use of hMG in long GnRH agonist cycles was associated with a 3–4% increase in live birthrate. There was insufficient evidence to make definitive conclusions on the need for exogenous LH activity in GnRH antagonist cycles or the benefit of recombinant LH and hCG protocols. Poor responders and patients 35 years of age and older benefit from exogenous LH.29 Recombinant LH can be used for inducing rupture in a single dose of 15,000 or 30,000 IU which is equivalent to reference treatment of 5000 IU hCG. It is superior with

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regard to incidence of OHSS and has a shorter half-life than hCG. Recombinant LH is also needed in hypogonadotropic hypogonadism in a dose of 75 IU daily for ovulation induction with rFSH for better results.30

Human Chorionic Gonadotropin Human chorionic gonadotropin (hCG) promotes the final stages of follicular maturation helping the oocyte reach metaphase II. Approximately 36 hours are required for completion of meiotic process and oocyte retrieval should be done within this time. It can be derived from human urine or can be recombinant. Recombinant hCG is available in syringes of 250 µg which is equivalent to 5000–6000 IU of hCG. There is no evidence of difference between rhCG or rhLH and uhCG in achieving final follicular maturation in IVF, with equivalent pregnancy rates and OHSS incidence.31 BMI affects hCG levels. The highest levels of hCG were measured in women with the lowest BMI. Patients’ body size, rather than route of hCG delivery, appears to determine circulating levels of hCG.32 Exogenous gonadotropins have been used since last 4 decades. They are highly effective in ovulation induction but are accompanied with the disadvantage of high cost, extensive monitoring and risks of ovarian hyper­stimu­lation and multiple pregnancy.

References 1. ASRM Practice Committee. Gonadotropins. Fertil Steril. 2008;90:S13-20. 2. Bellver J, Ayllón Y, Ferrando M, Melo M, Goyri E, Pellicer A, et al. Female obesity impairs in vitro fertilization outcome without affecting embryo quality. Fertil Steril. 2010;93(2):447-54.

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3. Olivennes F, Howies CM, Borini A, Germond M, Trew G, Wikland M, et al. Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study. Reprod Biomed Online. 2011;22 Suppl 1:S73-82. 4. Yates AP, Rustamov O, Roberts SA, Lim HY, Pemberton PW, Smith A, et al. Anti-Mullerian hormone-tailored stimulation protocols improve outcomes whilst reducing adverse effects and costs of IVF. Hum Reprod. 2011;26(9):2353-62. 5. Orvieto R, Meltcer S, Liberty G, Rabinson J, Anteby EY, Nahum R. Human menopausal gonadotropin versus highly purified-hMG in controlled ovarian hyperstimulation for invitro fertilisation: does purity improve outcome? Gynecol Endocrinol. 2010;26(10):733-5. 6. Orvieto R, Nahum R, Rabinson J, Ashkenazi J, Anteby EY, Meltcer S. Follitropin-alpha (Gonal-F) versus follitropin-beta (Puregon) in controlled ovarian hyperstimulation for in vitro fertilization: is there any difference? Fertil Steril. 2009;91(4 Suppl):1522-5. 7. White DM, Polson DW, Kiddy D. Induction of ovulation with low dose gonadotropins in polycystic ovary syndrome: An analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab.1996;81:3821-24. 8. Homberg R, Levy T, Ben-Rafeal Z. A comparative prospective study of conventional regimen with chronic low dose adminis­ tration of follicle stimulating hormone for anovulation associated with polycystic ovary syndrome. Fertil Steril. 1995;63:729-33. 9. Baird DT. A model for follicular selection and ovulation: Lessons from superovulation. Steroid Biochem. 1987;27:15-23. 10. van Santbrink EJP, Donderwinkel PFJ, van Dassel TJHM. Gonadotropin induction of ovulation using step-down dose regimen: Single centre clinical experience in 82 patients. Hum Reprod. 1995;10:1048-53. 11. Hugues JN, Cedrin-Dumerin I, Avril C, Bulwa S, HerveFand-Uzan M. Sequential step up and step down regimen: An alternative method for ovulation induction with FSH in polycystic ovarian syndrome. Hum Reprod. 1996;11:2581-4.

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12. Nargund J, Fauser BCJM, Macklon NS, Ombelet W, Nygren K, Frydman R. The ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod. 2007;11(14):2801-504. 13. Bruna-Catalán I, Menabrito M; Spanish Collaborative Group Ovulation induction with minimal dose of follitropin alfa: a case series study. Reprod Biol Endocrinol. 2011;24:142. 14. Karimzadeh MA, Ahmadi S, Oskouian H, Rahmani E. Comparison of mild stimulation and conventional stimulation in ART outcome. Arch Gynecol Obstet. 2010;281(4):741-6. 15. Mukherjee S, Sharma S, Chakravarty BN. Comparative evaluation of pregnancy outcome in gonadotrophinclomiphene combination vs clomiphene alone in polycystic ovarian syndrome and unexplained infertility—A prospective clinical trial. J Hum Reprod Sci. 2010;3(2):80-4. 16. Chung MT, Chan TF, Loo TC, Tang HH, Lin LY, Tsai YC. Comparison of the effect of two different doses of recombinant gonadotropin for ovarian stimulation on the outcome of intrauterine insemination. Taiwan J Obstet Gynecol. 2011;50(1):58-61. 17. Kwan I, Bhattacharya S, McNeil A, van Rumste MM. Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI). Cochrane Database Syst Rev. 2008 Apr 16;(2):CD005289. 18. Calaf Alsina J, Ruiz Balda JA, Romeo Sarrió A, Caballero Fernández V, Cano Trigo I, Gómez Parga JL, et al. Ovulation induction with a starting dose of 50 IU of recombinant follicle stimulating hormone in WHO group II anovulatory women: the 10–50 study, a prospective, obser­vational, multicentric open trial. BJOG. 2003;110-12. 19. Hugues JN, Durnerin IC. Gonadotropins-filled-by-mass versus filled-by- bioassay. Reprod Biomed Online. 2005;10(Suppl 3):11-8, 32. 20. Schats R, De Sutter P, Bassil S, Kremer JAM, Tournaye H, Donnez J. Ovarian stimulation during assisted reproduction treatment: A comparison of recombinant and highly purified urinary human FSH. Hum Reprod. 2000;15:1691-7. 21. De placido G, Alviggi C, Mollo A, Strina I, Varricchio MT, Molis M. Recombinant follicle stimulating hormone is effective in poor responders to highly purified follicle stimulating hormone. Hum Reprod. 2000;15:17-20.

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22. Brinson P, Adagios F, Gibbons L, et al. A comparison of efficacy and tolerability of two recombinant human follicle stimulating preparations in patients undergoing in vitro fertilizationembryo transfer. Fertil Steril. 2000;73:114-6. 23. van Wely M, Kwan I, Burt AL, Thomas J, Vail A, Van der Veen F, et al. Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD005354. 24. Balen AH, Mulders AG, Fauser BC, Schoot BC, Renier MA, Devroey P, et al. Pharmacodynamics of a single low dose of long-acting recombinant follicle-stimulating hormone (FSHCarboxy Terminal Peptide, Corifollitropin Alfa) in women with World Health Organization Group II Anovulatory Infertility. J Clin Endocrinol Metab. 2004;89(12):6297-304. 25. Fauser BJC, Alper MM, Ledger W, Schoolcraft WB, Zandvliet A, Mannaerts BMJM. Engage Investigators. Pharmacokinetics and follicular dynamics of corifollitropin alfa versus recombinant FSH during ovarian stimulation for IVF. Reprod Biomed Online. 2010;21(5):593-601. 26. Croxtall JD, McKeage K. Corifollitropin alfa: a review of its use in controlled ovarian stimulation for assisted reproduction. BioDrugs. 2011;25(4):243-54. 27. Rombauts L, Talmor A. Corifollitropin alfa for female infertility. Expert Opin Biol Ther. 2012;12(1):107-12s. 28. Levy DP, Navarro JM, Schattman GL, Davis OK, Rosenwaks Z. The role of LH in ovarian stimulation: Exogenous LH: Lets design the future. Hum Reprod. 2000;15:2258-65. 29. Hill MJ, Levy G, Levens ED. Does exogenous LH in ovarian stimulation improve assisted reproduction success? An appraisal of the literature. Reprod Biomed Online. 2012;24(3):261-71. 30. Schoot DC, Harlin J, Shaham Z, Mannerts BM, Lahlou N, Bouchard P, et al. Recombinant human follicle stimulating hormone and ovarian response in gonadotropin deficient women. Hum Reprod. 1994;9(7):1237-42. 31. Youssef MA, Al-Inany HG, Aboulghar M, Mansour R, AbouSetta AM. Recombinant versus urinary human chorionic gonadotropin for final oocyte maturation triggering in IVF

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and ICSI cycles. Cochrane Database Syst Rev. 2011 Apr 13;(4):CD003719. 32. Elkind-Hirsch KE, Bello S, Esparcia L, Phillips K, Sheiko A, McNichol M. Serum human chorionic gonadotropin levels are correlated with body mass index rather than route of administration in women undergoing in vitro fertilizationembryo transfer using human menopausal gonadotropin and intracytoplasmic sperm injection. Fertil Steril. 2001;75(4):700-4.

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5

Role of GnRH Agonists and Antagonists in Assisted Reproductive Technology Surveen Ghumman

The GnRH agonists and antagonists have occupied an increasingly important position in the ovulation induction protocols. GnRH analogs are able to suppress gonadotropin release and subsequently, the gonadal function. This is the basis for their clinical applications as it controls the premature endogenous luteinizing hormone (LH) surge and therefore, decreases the cycle cancelation rate.

GnRH Agonist (GnRHa) Substitutions in the GnRH molecule cause enhanced affinity for the GnRH receptors and protects against enzyme degradation increasing half-life from 8 minutes to 5 hours. Decapeptide Agonists • Triptorelin • Naferelin • Goserelin.

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Nonapeptide Agonists • Buserelin • Leuprolide • Histerelin.

Mechanism of Action The mechanism of action is a “flare effect”, followed by downregulation. Within 12 hours of administration it induces liberation of high amount of FSH and LH and also increases the number of receptors (5-fold increase in FSH, 10-fold increase in LH and 4-fold increase in estradiol receptors). This is the socalled ‘upregulation.’ A continuous adminis­tration of GnRH agonist produces the opposite effect. There is a decrease in level of FSH and LH by internalization of the receptor-agonist complex and a reduction in the number of receptors. This is called ‘downregulation’ or desensitization of the pituitary. This eliminates any premature LH surge and decreases LH stimulation of ovarian androgen production. The advantage is reduced cycle cancelation, convenient timing of treatment and higher live birthrates. Stimulation is then begun with gonadotropins. Also it can be used as an ovulation trigger to prevent ovarian hyperstimulation syndrome. Commonly used GnRH agonists are: Leuprolide sc 500–1000 µg or im depot 3.75, 7.5 mg/month Buserelin sc 200–500 µg/day or 300–400 µg intra­nasally 3–4 times/day Goserelin sc implant 3.6 mg/month Triptorelin sc 100–500 µg/day or im depot 3.75 mg/month.

Route of Administration 1. Subcutaneous injections. 2. Sustained release implants.

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3. Intramuscular depot injections. 4. Nasal spray. Subcutaneous: This route is most commonly used because of high bio­availability and low interindividual variation. It results in prolonged and delayed absorption compared to intravenous route. Intranasal route: Disadvantages of this route include a marked interindividual variation in absorption and considerable losses of peptides by proteolysis and swallowing. Initially preparation like buserelin needed frequent administration (5 times a day); however, nasal pre­parations like naferelin only require twice a day admi­nistration.1 There is an advantage of persistence of drug in the nasal mucosa for up to 24 hours consistent with depot like effects. The drug absorption varies with rhinitis and allergy. It is a more convenient route for the patient as compared to daily injections. Depot formulation: Since there is more profound suppression of the pituitary gonadal axis with continuous administration of the drug, sustained or continuous release formulations have been developed. Currently available preparations include a sus­pension of 3.75 mg triptorelin or leuprolide in micro­capsules injected intramuscularly once a month or 3.6 mg of goserelin dispersed in a biodegradable polymeric matrix of polylactide-co-glycolide as a cylindrical rod implant injected sub­cutaneously every month. The pharmacokinetics of the two differ. In both, the drug is released over 30 to 55 days. The number of follicles developed, E2 levels, oocyte quality, fertilization and pregnancy rates were same as with daily administration.2 Because of prolonged desensitization the dose of gonado­tropins needed is more and stimulation is longer.2

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Use of GnRH Agonist in COH Protocols The use of GnRH agonists decreased cancelation rates in IVF cycle from 20 to 2% and improved fertilization and implantation rates.3 Three protocols have been described: a. Long protocol. b. Short protocol. c. Ultrashort protocol.

Protocols for Administration Long Protocol

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Advantages of long Protocol 1. It prevents unwanted LH surge and hence, cancellation of cycles. 2. It helps plan the time of ovum pick-up. 3. Improves overall pregnancy rates especially in patients with raised LH levels. 4. Allows synchronization ingrowth of follicles. 5. Reduces intensive monitoring of cycles to detect premature LH surge. 6. Most studies show a better result with the long protocol than with short or ultrashort protocol. Disadvantages of Long Protocol 1. Extends or prolongs treatment cycle. 2. Higher doses of gonadotropins are needed. 3. More expensive. 4. It is associated with symptoms of depression in hypogonadal phase.4

How Long Can we Continue with GnRH Agonist if Suppression is not Achieved? In a recent study suppression was obtained after 14 GnRHa days in 75.70% and 24.30% required a mean ± SD (range) of 10 ± 4 (7–28) additional days to achieve complete suppression. In a standardized long GnRHa protocol, prolonging desensitization to achieve complete ovarian suppression does not affect the outcome in terms of pregnancy rate, oocytes retrieved, cycle cancelation, implantation rate, quality of embryos and live birthrates.5

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Oral Contraceptive Pretreatment before Suppression by GnRH Agonist Administration of a gonadotropin-releasing hormone analog (GnRHa) causes a flare effect leading to formation of ovarian cysts that can be functional and can impair downregulation and stimulation. Hence, they must be treated before commencement of stimulation. Oral contraceptives (OC) prevent the formation of ovarian cysts during GnRHa administration through a dual effect of pituitary suppression and ovarian protection. OC may be given for 14 days prior to downregulation. Pretreatment with an OC abolishes ovarian cyst formation, shortens the time required to achieve pituitary suppression, and decreases gonadotropin requirements without having a negative effect on pregnancy rates.6

Short Protocol

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Advantages of Short Protocol 1. Better for older patients and poor responders as it causes greater follicular recruitment. 2. The flare effect offers an advantage in hypogonadotropin hypogonadism. 3. Shorter protocol 4. Less expensive. 5. Less chances of ovarian hyperstimulation because of lower E2 levels. Disadvantages of Short Protocol In PCOS it causes irregular growth of follicle and is not helpful where LH levels are raised.

Ultrashort Protocol

This differs from the short protocol in discontinuing the agonist once it has stimulated the flare. This reduced the doses of both drugs. However, this protocol had poor pregnancy rates as compared to long protocol because of premature LH surge.

Which Protocol to Use? The pregnancy rate was found to be higher when GnRHa was used in a long protocol as compared to a short or ultrashort

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protocol but there was no difference in live birthrate. There was no evidence of a difference in the outcomes amongst various long protocols, nor that stopping or reducing GnRHa at the start of stimulation was associated with a reduced pregnancy rate.7 Disadvantages of GnRH Agonists 1. Increased time for stimulation in the long protocol. 2. Short protocol may add to increase in premature LH surge. 3. Luteal phase support is needed. 4. Increased cost due to increased requirement of gona­ dotropin. 5. It may cause hyperstimulation due to flare response in luteal phase in the long protocol leading to high estradiol levels and ovarian cyst.8 Advantages of GnRH Agonists 1. Decreases the need for close monitoring to detect spontaneous LH surge. 2. Less cycle cancelation. 3. Better response. 4. More flexible schedule. 5. Higher oocyte recovery and pregnancy rate. Side Effects and Risks of gnrh Agonists 1. Ovarian cyst: It is seen in 14 to 29%, more with the short protocol. 2. Ovarian hyperstimulation syndrome: The increased inci­ dence of OHSS is due to increased pregnancy rate and higher doses of gonadotropins being used. 3. Luteal phase defect. 4. Transient neurological disturbances like parasthesia or headaches occur in 5%.

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Gnrh Agonist for Ovulation Trigger In patients at risk to develop OHSS, the only option available earlier was to withhold the ovulatory dose of human chorionic gonadotropin leading to canceled cycles. GnRH agonist, when administered in a single dose, bring about the LH surge and triggers ovulation like hCG, because of its flare effect. Dose: Leuprolide acetate: 1 mg given either subcutaneously as a single, or two doses 12 hours apart can act as an ovulation trigger. Advantages a. Its short duration of action is more physiological unlike extended surge with the use of hCG. b. Decrease in multiple pregnancy. c. Prevents OHSS as it has shorter duration of action compared to hCG. Luteotropic action is prolonged in hCG administration leading to development of multiple corpora lutea and supraphysiological levels of E2. d. Can be used along with antagonist. Disadvantages a. Cannot be used in cases of hypogonadotropic hypo­ gonadism. b. Not used for cases downregulated with GnRH agonist as the flare effect of LH release by a single dose of the agonist will not occur because of pituitary downregulation, making ovulation trigger ineffective. c. It causes pituitary desensitization lead lowered pregnancy and live birth- rates. Hence, luteal support is necessary in these women. Triggering final oocyte maturation with GnRH agonist instead of hCG in IVF cycles dramatically decreases luteal levels of inhibins, reflecting significant

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inhibition of the corpus luteum function. This effect may explain, at least in part, the mechanism of ovarian hyperstimulation syndrome prevention by the use of GnRH agonist.9 A recent Cochrane review 2011 has not recommended that GnRH agonists be routinely used as a final oocyte maturation trigger in fresh autologous cycles because of lowered live birthrates and ongoing pregnancy rates. An exception could be made for women with high risk of OHSS, after appropriate counseling.10 A defective corpus luteum function resulting from the relatively short endogenous luteinizing hormone surge may be detrimental to endometrial receptivity. Adequate estradiol and progesterone supplementation in the luteal phase and the first trimester is recommended. An alternative approach is the use of adjuvant low-dose human chorionic gonadotropin, although caution should be exercised in view of the associated risk of OHSS development.11 After modified luteal support there is now a non-significant difference of 6% in delivery rate in favor of hCG triggering.12

GnRH Antagonists Antagonists act by competitive inhibition of GnRH receptors preventing the native GnRH from exerting its stimulatory effect on the pituitary cells, resulting in rapid decline in LH and FSH lasting for 10 to 100 hours. There is no stimulatory phase unlike the GnRH agonists. Due to competitive nature of action this effect is dose-dependant and depends on the equilibrium between endogenous GnRH and the antagonists. Their action is easily reversible. Antagonists neither deplete the LH and FSH stores nor inhibit their synthesis.

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Contraindications 1. Hepatic dysfunction. 2. Renal dysfunction. 3. Hypersensitivity to GnRH analogs.

Protocols Antagonist can be given in two ways: a. Lubeck protocol (Multidose protocol): Gonadotropins are started as usual. When follicle reaches 14 mm or on a fixed day of protocol, antagonist is added at a dose of 0.25 mg/day until the day before ovulation (Fig. 5.1). This protocol can be either fixed or flexible. a. Fixed Protocol – Daily injections of small doses initiated on a fixed day of stimulation till hCG administration b. Flexible Protocol – Daily injections of small doses initiated depending on the size of the dominant follicle (14 mm) or on estradiol levels till hCG administration. b. French protocol (Single dose protocol): Gonadotropins are started as usual. Antagonist is given in a single dose of 3 mg when E2 is about 150 to 200 pg/ml and follicular size is 14 mm (Fig. 5.2).

Fig. 5.1: Lubeck protocol

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Fig. 5.2: French protocol

Single Versus Multiple Dose GnRH Antagonist Protocol Advantage of single dose protocol was lesser injections but if hCG needs to be delayed additional daily doses are given. About 10% women require additional doses. Cochrane review 2002 has concluded that both protocols were equally effective in preventing premature LH surge.13 It was seen that the single dose protocol may lead to extreme suppression of LH but pregnancy rates were similar with both protocols.14

Fixed Versus Flexible Antagonist Administration In an analysis of three studies, a flexible GnRH antagonist protocol was compared to the fixed protocol. In stimulated cycles it was seen that intense ovarian response with more number of follicles led to an early rise in estradiol. Thus, threshold levels of estradiol, which initiates a LH surge, are reached earlier before follicles reach an optimum size. In these cases the flexible protocol which is dependent on the size of the follicle on ultrasound to start antagonist in order to suppress surge, may no longer be accurate to determine time of initiation of GnRH antagonist.15 This observation might explain the observed lower efficacy of the flexible protocol

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compared with a fixed protocol in a meta-analysis of four studies.16 Hence, for patients with a profound ovarian response, early initiation of the GnRH antagonist may be needed.

Which GnRH Antagonist is to be used? Cetrorelix and ganirelix both effectively prevented LH surge. However, cetrorelix required significantly fewer injections, increasing patient convenience.14

Should FSH dose be Increased in Antagonist Cycle ? Although with antagonist cycles, gonadotropin dose needed is lower as there is no pituitary suppression; however, a reduced oocyte recovery was notice. An initial higher dose of FSH gave a higher oocyte recovery but there was no difference in pregnancy rates.17 It was seen that increasing dose of FSH or hMG after starting antagonist did not increase pregnancy rates.18,19

Role of Oral Contraceptive Pill Pretreatment in Ovarian Stimulation with GnRH Antagonists for Cycle Scheduling Pretreatment with an oral contraceptive (OC) in antagonist cycle has been suggested to allow greater control over patient response rate and to avoid follicular asynchrony. Scheduling of cycle is no longer based on menstruation but on discontinuation of OCP. A meta-analysis proved that no increase in pregnancy rate was seen with OC.20 However, it has been associated with increased duration of treatment and higher doses of gonadotropin.21 In a recent study OCP (0.030 ethinyl E(2)/0.15 desogestrel) for 12–16 days, and controlled ovarian hyperstimulation with GnRH antagonist was started on day 5 after OCP treatment. On comparison with long

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protocol no differences were observed in the fertilization rates (68.1% vs 64.8%), total number of embryos obtained (5.9 vs 6.2), mean number of embryos transferred (1.8 vs 1.8), implantation rate (36% vs 39%), miscarriage rate (8.9% vs 17%), ongoing pregnancy rate (47.8% vs 53.9%), or live birthrate (44.3% vs 47%).22

LH Supplementation with GnRH Antagonist An abrupt suppression of endogenous LH by GnRH antagonist occurs in the mid-follicular phase, at a critical stage for follicular development. However, studies have shown no increase in pregnancy rate with LH supplementation or increase of hMG dose on initiation of antagonist.19,23 The decision to add LH must be individualized. It has been seen that the direction and rate of change in LH concentrations are the important factors governing the follicular unit development, not the LH concentration itself.24 It was found in a study that in 12–14% of downregulated patients the initial response to FSH is suboptimal (in terms of follicular growth and estradiol rise) and their day 8 LH concentration decreased from 1.2 to 0.7. It was suggested that these patients are the candidates for LH supplementation. Normal responders increased their mean LH concentrations from 1.5 to 4.3 after 8 days of stimulation. It was suggested that the follicular unit is sensitive not necessarily to the current concentration of LH, but rather to the dynamics of the change in these concentrations and hence, LH supplementation must be individualized.25 In women on antagonist-based cycles for the first time, it is preferable to add recombinant LH or partly switch to hMG on the day of antagonist administration.26

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Luteal Support It is seen that pituitary suppression may continue into luteal phase with poor development of endometrium. Hence, luteal support is a must and has shown to improve pregnancy rates.

Advantages of GnRH Antagonists over GnRH-agonist in ART 1. Short, simple and convenient method of stimulation, which is well tolerated by the patient. 2. There is immediate suppression with no stimulatory phase. So no ovarian cyst formation takes place as in agonist cycle. 3. There are no symptoms of estrogen deprivation. 4. Minimal local reactions. 5. Decreased risk of OHSS: A recent Cochrane (2011) showed a decreased risk of OHSS but similar live birthrates compared to GnRH agonists.27 6. Clinical results of IVF cycles are comparable in both (Cochrane 2011)27 7. Decrease in the overall cost of treatment. 8. Immediate reversibility. 9. Reduced dose of gonadotropins. 10. Effect on endometrium: Simón et al (2005) observed that the endometrial development after GnRH antagonist mimics the natural endometrium more closely than after GnRH agonist.28 11. LH levels and embryo quality: GnRH antagonists administration during the late follicular phase resulted in lower serum LH levels and better embryo quality in comparison to GnRH agonists.29

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Studies have concluded that antagonists should be the first choice in IVF treatment, with less of the complications and risks of controlled ovarian hyperstimulation and an acceptable success rate.29 Recommendation: For GnRH antagonist use in IVF cycle:30 1. Increase in the starting dose of gonadotropins or to increase gonadotropin dose at antagonist initiation is not necessary. 2. OCP pretreatment can be used for scheduling IVF cycles. 3. Addition of LH with initiation of antagonist not necessary. 4. Fixed protocol appears to be superior to flexible initiation by a follicle of 14–16 mm. 5. Results with single dose and multiple dose protocols were similar but single dose led to more profound LH suppression although convenience of a single injection administration was there.

Disadvantages of Antagonists 1. Easy patient scheduling is lacking, because of the reliance on spon­taneous menstrual cycles. 2. Lack of stimulatory effects on folliculogenesis typical of GnRH agonist regimens. 3. Need to replace LH if recombinant FSH is used.

Gonadotropin-Releasing Hormone It is mainly used in WHO group I anovulatory women but can be used in PCOS patients. The advantages are that significant follicular monitoring is not needed and it has less risk for OHSS and multiple pregnancy. It can be given either subcutaneously in a dose of 20 µg or intravenously 5 µg at 90 min interval through a portable programmable mini pump worn by the patient throughout. If there is no response in weekly estradiol level the dose is increased by increments of 5 µg. Luteal phase

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support can be given by continuation of the pump. Problems encountered are malfunction of the pump and local effects like thrombophlebitis, cellulitis, urticaria or anaphylaxis. Ovulation rates of 90%, conception rates of 20 to 30% per cycle and cumulative pregnancy rate of 80 to 90% after 12 months are seen in WHO group 1 women.31 In PCOS cumulative pregnancy rate is 30 to 40%. Abortion occurs in 20% cases and multiple preg­nancies in 5%. Thus, to conclude the GnRH antagonist reduces the dose and duration of gonadotropin treatment as it does not nullify FSH or LH secretion but interrupts the premature LH surge. It has the disadvantage of loss of easy patient rescheduling because of reliance on natural recruitment of follicles, lack of stimulatory effect on folliculogenesis unlike GnRH agonists and need for replacement of LH if recombinant FSH is used.

References 1. Anik ST, McRae G, Narenberg C, Worden A, Foreman J, Hwang JY, et al. Nasal absorption of naferelin acetate, the decapeptide (D-Nal{2}6) LHRH, in rhesus monkeys. J Pharm Sci. 1984;73:684-5. 2. Albuquerque LE, Saconato H, Maciel MC. Depot versus daily administration of gonadotrophin releasing hormone agonist protocols for pituitary desensitization in assisted reproduction cycles. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD002808. 3. Akagbosu FT. The use of GnRH agonists in infertility. In: Brinsden R (Ed). A Textbook of In Vitro Fertilization and Assisted Reproduction (2nd ed): London: Parthenon Publishing; 1999:83-9. 4. Bloch M, Azem F, Aharonov I, Ben Avi I, Yagil Y, Schreiber S, et al. GnRH-agonist induced depressive and anxiety symptoms during in vitro fertilization-embryo transfer cycles. Fertil Steril. 2011;95(1):307-9. 5. Dessolle L, Ferrier D, Colombel A, Fréour T, Jean M, Barrière P. Prolonging GnRH-agonist to achieve ovarian suppression

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does not compromise the results of a long protocol. Eur J Obstet Gynecol Reprod Biol. 2011;159(1):111-4. 6. Biljan MM, Mahutte NG, Dean N, Hemmings R, Bissonnette F, Tan SL. Effects of pretreatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotropin-releasing hormone analogues and on subsequent implantation and pregnancy rates. Fertil Steril. 1998;70(6):1063-9. 7. Maheshwari A, Gibreel A, Siristatidis CS, Bhattacharya S. Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction. Cochrane Database Syst Rev. 2011 Aug 10;(8):CD006919. 8. Depenbusch M, Diedrich K, Griesinger G. Ovarian hyperresponse to luteal phase GnRH-agonist administration. Arch Gynecol Obstet. 2010;281(6):1071-2. 9. Nevo O, Eldar-Geva T, Kol S, Itskovitz-Eldor J. Lower levels of inhibin A and pro-alpha C during the luteal phase after triggering oocyte maturation with a gonadotropin-releasing hormone agonist versus human chorionic gonadotropin. Fertil Steril. 2003 ;79(5):1123-8. 10. Youssef MA, Van der Veen F, Al-Inany HG, Griesinger G, Mochtar MH, Aboulfoutouh I, et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD008046. 11. Engmann L, Benadiva C. Ovarian hyperstimulation syndrome prevention strategies: Luteal support strategies to optimize pregnancy success in cycles with gonadotropin-releasing hormone agonist ovulatory trigger. Semin Reprod Med. 2010;28(6):506-12. 12. Humaidan P, Kol S, Papanikolaou EG. Copenhagen GnRH Agonist Triggering Workshop Group. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update. 2011;17(4):510-24. 13. Al-Inay H, Aboulghar M. GnRH antagonist in assisted reproduction: a Cochrane review. Hum Reprod Update. 2002;17(4):874-85.

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14. Wilcox J, Potter D, Moore M, Ferrande L, Kelly E. CAP IV Investigator Group. Prospective, randomized trial comparing cetrorelix acetate and ganirelix acetate in a programmed, flexible protocol for premature luteinizing hormone surge prevention in assisted reproductive technologies. Fertil Steril. 2005;84(1):108-17. 15. Al-Inany HG, Aboulghar M, Mansour R, Serour GI. Optimizing GnRH antagonist administration: meta-analysis of fixed vs flexible protocol. Reprod Biomed Online. 2005;10:567-70. 16. Tarlatzis BC, Fauser BC, Kolibianakis EM, Diedrich K, Rombauts L, Devroey P. GnRH antagonists in ovarian stimulation for IVF. Hum Reprod Update. 2006;12:333-40. 17. Out HJ, Rutherford A, Fleming R, Tay CCK, Trew G, Ledger W, et al. A randomized, double-blind, multicentre clinical trial comparing starting doses of 150 and 200 IU of recombinant FSH in women treated with the GnRH antagonist ganirelix for assisted reproduction. Hum Reprod. 2004;19:90-5. 18. Propst AM, Bates GW, Robinson RD, Arthur NJ, Martin JE, Neal GS. A randomized controlled trial of increasing recombinant follicle-stimulating hormone after initiating a gonadotropinreleasing hormone antagonist for in vitro fertilization-embryo transfer. Fertil Steril. 2006;86(1):58-63. 19. Aboulghar MA, Mansour RT, Serour GI, Al-Inany HG, Amin YM, Aboulghar MM. Increasing the dose of human menopausal gonadotropins on day of GnRH antagonist administration: randomized controlled trial. Reprod Biomed Online. 2004;8:524-7. 20. Griesinger G, Venetis CA, Marx T, Diedrich K, Tarlatzis BC, Kolibianakis EM. Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF: a systematic review and meta-analysis. Fertil Steril. 2008;90(4):1055-63. 21. Bendikson K, Milki A, Speck-Zulak A, Westphal L. Comparison of GnRH antagonist cycles with and without oral contraceptive pill pretreatment in poor responders. Fertil Steril. 2003;80(Suppl. 3):s188. 22. Garcia-Velasco JA, Bermejo A, Ruiz F, Martinez-Salazar J, Requena A, Pellicer A. Cycle scheduling with oral contraceptive

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23.

24.

25.

26. 27.

28.

29.

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Step by Step Ovulation Induction pills in the GnRH antagonist protocol vs the long protocol: a randomized, controlled trial. Fertil Steril. 2011;96(3):590-3. Griesinger G, Schultze-Mosgau A, Dafopoulos K, Schroeder A, Schroer A, von Otte S, Hornung D, et al. Recombinant luteinizing hormone supplementation to recombinant follicle stimulating hormone induced ovarian hyperstimulation in the GnRH antagonist multiple-dose protocol. Hum Reprod. 2005a;20:1200-06. Huirne JA, van Loenen ACD, Schats R, McDonnell J, Hompes PGA, Schoemaker Joop, et al. Dose-finding study of daily GnRH antagonist for the prevention of premature LH surges in IVF/ICSI patients: optimal changes in LH and progesterone for clinical pregnancy. Hum Reprod. 2005;20:359-67. De Placido G, Alviggi C, Perino A, et al. Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum Reprod. 2005;20:390-6. Kol S. To add or not to add LH: consideration of LH concentration changes in individual patients. Reprod BioMed Online. 2005;11:664-6. Al-Inany HG, Youssef MAFM, Aboulghar M, Broekmans FJ, Sterrenburg MD, Smit JG, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews. 2011, Issue 5. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub3 Simon C, Oberye J, Bellver J, Vidal C, Bosch E, Horcajadas JA, et al. Similar endometrial development in oocyte donors treated with either high- or standard-dose GnRH antagonist compared to treatment with a GnRH agonist or in natural cycles. Hum Reprod. 2005;20(12):3318-27. Xavier P, Gamboa C, Calejo L, Silva J, Stevenson D, Nunes A, et al. A randomised study of GnRH antagonist (cetrorelix) versus agonist (buserelin) for controlled ovarian stimulation: effect on safety and efficacy. Eur J Obstet Gynecol Reprod Biol. 2005;120:185-9.

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30. Tarlatzis BC, Kolibianakis EM, Griesinger G, et al. GnRH antagonists in ovarian stimulation for IVF. Hum Reprod Update. 2006;12:333-40. 31. Ghosh C, Buck G, Priore R, Wende JW, Severino M. Follicular response and pregnancy among infertile women undergoing ovulation induction and intrauterine insemination. Fertil Steril. 2003;80:328-35.

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cHAPTER

6

Mild Ovarian Stimulation Surveen Ghumman

The basis of successful assisted reproduction is appropriate ovarian stimulation. Since IVF procedures have not produced a 100% result, ovarian stimulation has become the compensatory mechanism to improve results by increasing the number of oocytes retrieved; thus, providing the choice of the best quality embryos for transfer. In the conventional protocol downregulation is started in the luteal phase and continued into next cycle, involving high doses and prolonged administration of FSH. It has high chances of complications like ovarian hyperstimulation syndrome (OHSS). The prolonged treatment with high cost results in larger dropout rates. In the recent years, mild protocols have been introduced that aim at a low stimulation that gives acceptable results with minimal risks. International Society of Mild Approaches in Assisted Reproduction (ISMAAR) defines a “mild” IVF cycle either as (a) a stimulation regimen in which gonadotropins are administered at a lower-than-usual dose and/or for a shorter duration throughout a cycle in which GnRH antagonist

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is given as co-treatment, or (b) a stimulation in which oral compounds (e.g. antiestrogens) are used either alone or in combination with gonadotropins and GnRH - antagonists.1

Role of GnRH Antagonist in Mild Stimulation With use of antagonists downregulation is not needed. The IVF cycle can start with an undisturbed early follicular phase recruitment of follicles by an endogenous FSH rise that occurs in a natural menstrual cycle. The endogenous inter-cycle FSH rise is taken advantage of rather than suppressed. FSH is added on day 5 to continue FSH elevation and extend the FSH window, for many follicles to develop. This limits the duration and dose of FSH administration. A premature LH surge may occur with rising estradiol levels that act through positive feedback loop. GnRH, antagonist has an immediate action blocking the pituitary when estradiol levels start rising and approach threshold levels at which an LH surge can occur. The action of GnRH antagonists is immediate suppression of the pituitary release of gonadotropins and a rapid reversibility of normal gonadotropin secretion when the drug is withdrawn.

Protocols Antagonist can be given in three ways: a. Single large dose on, usually sixth day of stimulation with gonadotropins b. Fixed Protocol: Daily injections of small doses initiated on a fixed day of stimulation till hCG administration. c. Flexible Protocol: Daily injections of small doses initiated depending on the size of the dominant follicle or on estradiol levels till hCG administration. In an analysis of three studies, a flexible GnRH antagonist protocol was compared to the fixed protocol. In stimulated

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cycles it was seen that intense ovarian response with more number of follicles led to an early rise in estradiol. Thus, threshold levels of estradiol that initiates a LH surge are reached earlier before follicles reach an optimum size. In these cases the flexible protocol, which is dependent on the size of the follicle on ultrasound to start antagonist to suppress surge, may no longer be accurate to determine time of initiation of GnRH antagonist.2 This observation might explain the observed lower efficacy of the flexible protocol compared with a fixed protocol in a meta-analysis of four studies.3 Hence, for patients with a profound ovarian response, early initiation of the GnRH antagonist may be needed.

Clomiphene, Gonadotropins and GnRH Antagonist The second mild regime includes using clomiphene 100 mg, delayed low dose gonadotropin and a flexible GnRH antagonist administration for ovarian stimulation protocol. Pregnancy rates comparable to the standard stimulation regimens were obtained, with a significant reduction in the total dose of gonadotropin and hence, the cost. The number of recovered oocytes, obtained embryos, transferred embryos, peak of estradiol on the day hCG administration and OHSS were significantly higher in conventional group but there were no significant difference in clinical pregnancy rate and ongoing pregnancy rate between two groups.4,5

Mild vs Conventional Protocols Dose of FSH The mild form used lower dose FSH for a shorter period. Mean dose of FSH used was 1183 IU in the mild group versus 1836 IU for the conventional group (Table 6.1).6

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Table 6.1: Comparison of mild and conventional protocols Low oocyte recovery Optimal outcomes Poor outcome

Mild Pregnancy rate per embryo transfer – Good 5 oocyte recovery

Conventional Pregnancy rate per embryo transfer – Poor

> 8 oocytes recovered

> 18 and < 4 oocytes recovered 55%

Proportion of 73% abnormal and mosaic embryos Dose of FSH used 1836

10 oocyte recovery

1183

Correlation of Number of Oocytes Recovered with Pregnancy Rate A higher pregnancy rate is achieved when there is a moderate ovarian response. The highest ongoing pregnancy rate per embryo transfer of 30.7% in mild stimulation is observed where five oocytes were obtained but a 28.5% ongoing pregnancy rate with a median of 10 oocytes is seen in the conventional protocol. A sharp decline in implantation rates was seen with retrieval of more than 8 oocytes in the mild stimulation protocol. These differences between the two stimulation regimens were statistically significant (P = 0.045).6 Excessive follicles do not lead to a higher pregnancy rate. In both protocols, the number of pregnancies following the retrieval of 18 oocytes or more was very low (Table 6.1). Hence, when a few oocytes are recruited they are better quality oocytes from a homogenous group that lead to a higher pregnancy rate. Mild stimulation protocol simulates

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a natural cycle where the natural selection of good quality oocytes remains. It decreases detrimental effect of ovarian stimulation on the growing follicle. By delaying the initiation of ovarian stimulation to the mid-follicular phase, exogenous FSH may only stimulate the naturally selected most mature follicles giving rise to the best quality oocytes. A second study reinforced this, showing that those patients where stimulation was started on day 5, fewer cycles were characterized by a total fertilization failure or by abnormal embryo development. After stronger ovarian stimulation, only 7% of the patients who retrieved less than 5 oocytes conceived, whereas after “mild” stimulation 67% of these patients conceived. 7 The retrieval of a less number of oocytes gives higher chance of ongoing pregnancy per embryo transferred in mild stimulation but poor results in conventional protocols. The implication of a poor ovarian response in the conventional protocol usually means a low ovarian reserve resulting in poor IVF outcomes whereas a poor response in mild ovarian stimulation is probably a normal response with natural selection of follicle with best receptor endowment. Overall, no differences were found among the two stimulation protocols as far as the pregnancy rate per started cycle was concerned because of the higher number of oocytes retrieved in the conventional group, more number of embryos were available to select the best. No significant difference in the quality of the best transferred embryo was observed among the two groups.7 The higher pregnancy rate per oocyte retrieved seen with mild protocol may be due to better development of embryo that has been naturally selected with higher chance of being chromosomally normal. Secondly, detrimental effects seen with very high levels of hormones on endometrium are absent, as ostradiol levels are lower than the conventional protocol.

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Endometrial Factor The conventional regime has supra-physiological circulating estradiol levels that have a well-documented negative impact on the developmental and implantation potential of human embryos.8 A higher endometrial receptivity is seen in the natural cycle and since the “mild” stimulation regimen, like the natural cycle has a lower peak estradiol levels, implantation is thought to be better.9,10

Chromosomal Abnormality with Mild Ovarian Stimulation In a recent study, embryos were biopsied on day 3 when at least six blastomeres were present after stimulation with both regimes. One or two cells were removed for a fluorescence in situ hybridization procedure. Both regimens finally generated the same number (1.8/cycle) of chromosomally normal embryos. As the conventional protocol had higher number of oocytes per cycle, overall abnormality rates (abnormal and mosaic embryos) were 55% following mild and 73% following conventional ovarian stimulation (Table 6.1). However, the proportion of mosaic embryos per patient was more significantly increased following conventional ovarian stimulation (65% vs 37%; P = 0.004). This observation indicates that the increase in abnormal embryos is mainly due to an increase in mitotic segregation errors in early embryonic cleavage divisions.11 Ovarian stimulation might disrupt mechanisms involved in maintaining accurate chromosome segregation leading to differences in rates of mosaic embryos.12 Hence, a lower embryo aneuploidy rate was present following mild stimulation. Several animal studies have supported this. Increased incidences of morphological and chromosomal abnormalities have been observed in mouse oocytes after exposure to high doses of gonadotropins during in vitro maturation of oocytes.13

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Ovarian stimulation strategies should avoid maximizing oocyte yield, but aim at generating a sufficient number of chromosomally normal better quality embryos by reduced interference with ovarian physiology.

Cumulative Pregnancy Rate In another study of the “mild” treatment group the pregnancy rate per cycle was significantly lower in the “mild” stimulation group vs the conventional group (17.6% vs 28.6%, p < 0.0001). However less dose of FSH was used since it was cheaper, patient discomfort was less resulting in higher acceptance of patient for a second IVF. The one year cumulative live birthrate was 43.4% with the mild protocol, 44.7% with the standard regimen.14 Hence, there was not much difference in the cumulative pregnancy rate.

Multiple Pregnancy The second advantage was that twin pregnancy was 0.5% in comparison to conventional protocol which had a rate of 13.1%.14 This also contributed to the cost effectivity of the regime as multiple pregnancy requires a more intensive monitoring and subsequent neonatal care.

Cryopreservation The pooled data from a meta-analysis shows that the ongoing pregnancy rate per started cycle sorts out to be 15% in the “mild” group and 29% in the classical group clearly showing conventional protocol to be more effective. Also, the conventional protocol will give excess embryos for a subsequent frozen embryo transfer that will get down both the cost and patient discomfort and increase the overall IVF pregnancy chance per oocyte pick-up by approximately 10–15%.15

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Cancelation The other factor that decreases the effectiveness of “mild” strategy is the relatively high rate of cycle cancelation due to mono- or bifollicular response (around 15–20%). It is recommended that next cycle stimulation should be started earlier on day 2. Ovarian aging and high BMI have been identified as relevant variables to predict the risk of insufficient response to “mild” stimulation, and a predictive model has been developed in order to minimize the need of canceling the cycle.16

Poor Ovarian Reserve and Mild Ovarian Stimulation The standard approach to women who are poor responders is based on starting with high doses of stimulation of 300 FSH IU and going up to 600 FSH IU. However, IVF outcomes in terms of pregnancy rates with 225 FSH UI/day and those receiving 450 UI/day was shown to be similar, despite the latter obtained more oocytes.17,18 High gonadotropin doses lower the cycle cancelation rate, but the likelihood of clinical pregnancy and live birthrate have been observed to reduce and to increase the risk of spontaneous miscarriage because of its adverse effects on endometrium and oocyte and embryo quality generated from follicles that were rescued from atresia if a natural cycle had taken place.19 In patients with poor ovarian reserve, the choice of a mild stimulation protocol instead of a classical, high dose regimen could be particularly indicated. Although these patients have a very low risk of OHSS, the quality of both their oocytes and their endometrium may be better when a smoother stimulation approach is used. A combination of clomiphene citrate (CC) plus gonadotropins and GnRH antagonists has been proposed

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as a “mild” stimulation alternative for poor responders. The treatment protocol consisted of a daily dose of clomiphene citrate 100 mg for 5 days and gonadotropin injections daily from cycle day 4 onward. Cetrorelix, 0.25 mg/day, was started when the leading follicle reached 14 mm. Induction of ovulation was triggered with human chorionic gonadotropin. The combination of clomiphene with gonadotropins may counterbalance its undesired antiestrogenic effect on the endometrium and clomiphene; at the same time their effects may reduce the amount of gonadotropins required, because of the combined synergistic effect on the ovary. A significantly higher blastocyst development rate and a very good (41.2%) ongoing pregnancy rate was found with this regimen.20 In CC/Gn/GnRH antagonist cycles, it was seen that in some cases LH was profoundly suppressed by GnRH antagonist and the circulating level of LH were less than one third at the time of hCG than it was at the beginning of stimulation. In these cases, both the pregnancy (18% vs 39%) and implantation rates are significantly reduced. This suggests that in these patients medications containing LH or hCG rather than FSH alone should be associated with CC in this kind of protocol.21

Risk of Ovarian Hyperstimulation Syndrome (OHSS) Severe OHSS has an incidence of 1–3% in IVF programs involving standard ovarian stimulation regimens. The incidence of severe OHSS is significantly lower when GnRH antagonists are used instead of agonists probably due to the smaller cohort of recruited follicles and to the lower circulating estradiol levels during ovarian stimulation.22 The risk of developing severe OHSS is further significantly reduced using “mild” stimulation regimens. In one study, the incidence of OHSS was 1.4% with the mild protocol and 3.7% with the long protocol.11 While in another study,

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there was no case of OHSS in the group treated with “mild” stimulation versus 6% in the group treated with conventional stimulation.4 Further, the risk of severe OHSS is reduced if ovulation trigger is elicited using a single dose of GnRH agonist instead on hCG; this is possible if a stimulation with GnRH antagonists has been applied.23

Emotional Stress Emotional stress represents a well-known negative side effects associated with IVF treatment, and probably one of the most important reasons for dropping out of the program. In the mild stimulation, a lower incidence of side effect faced with a conventional protocol; maybe the reason for a lower dropout rate and patients going in for a repeat IVF sooner as the psychological burden is lower. This leads to a higher cumulative success rate.24 However, a lower pregnancy chance with mild stimulation may itself cause psychological problems associated with failure. Also, the increased number of repeat oocyte retrievals with this protocol is a stressing event.

Economical Costs A milder ovarian stimulation is associated with a lower medication consumption per cycle thus lowering the cost. The balance between lower costs and lower “per cycle” results must be kept in mind when taking a decision. Also, the frequent need to repeat treatment actually increases cost as amount of FSH required to achieve one pregnancy goes up. However, in a recent study it was seen that although there is a significantly increased average number of IVF cycles (2.3 versus 1.7), lower average total costs over a 12-month period (8333 euro versus 10,745 euro) were observed using the mild strategy. Despite an increased mean number of IVF

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cycles within 1 year, from an economic perspective, the mild treatment strategy is more advantageous per term live birth.25

Lower Effectiveness The lower effectiveness of IVF procedure can also become a problem for IVF clinics choosing the mild strategy, who will compete on the market with clinics following classical stimulation concepts. If the clinic loses patients for the lower “per cycle” effectiveness of its IVF program, it could be forced to go back to classical stimulations, or alternatively, to increase prices, finally weighting on patients’ budget. In conclusion, lower number of oocytes retrieved during mild stimulation is associated with favorable pregnancy outcomes as there may be natural selection. As the mild stimulation did not show better pregnancy rates compared with a conventional stimulation protocol with GnRH agonist co-treatment, the benefits of low cost should be balanced with the decrease in pregnancy rate per cycle. With current recommendation of maximum two embryo transfer, there seems to be no need of aggressive stimulation to obtain large number of oocytes at the cost of good quality oocyte selection and adequately primed endometrium.

References 1. Nargund J, Fauser BCJM, Macklon NS, Ombelet W, Nygren K, Frydman R. The ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod. 2007;11(14):2801-04. 2. Al-Inany HG, Aboulghar M, Mansour R, Serour GI. Optimizing GnRH antagonist administration: meta-analysis of fixed vs flexible protocol. Reprod Biomed Online. 2005;10:567-70. 3. Tarlatzis BC, Fauser BC, Kolibianakis EM, Diedrich K, Rombauts L, Devroey P. GnRH antagonists in ovarian stimulation for IVF. Hum Reprod Update. 2006;12:333-40.

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4. Karimzadeh MA, Ahmadi S, Oskouian H, Rahmani E. Comparison of mild stimulation and conventional stimulation in ART outcome. Arch Gynecol Obstet. 2010;281(4):741-6. 5. Williams SC, Gibbons WE, Muasher SJ, Oehninger S. Minimal ovarian hyperstimulation for in vitro fertilization using sequential clomiphene citrate and gonadotropin with or without the addition of a gonadotropin-releasing hormone antagonist. Fertil Steril. 2002;78(5):1068-72. 6. Verberg MFG, Eijkemans MJC, Macklon NS, Heijnen EMEW, Baart EB, Hohmann FP, et al. The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Hum Reprod Update. 2009;15:5-12. 7. Hohmann FP, Macklon NS, Fauser BC. A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist co-treatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab. 2003;88(1):166-73. 8. Valbuena D, Jasper M, Remohi J, Pellicer A, Simon C. Ovarian stimulation and endometrial receptivity. Hum Reprod. 1999;14(2):107-11. 9. Check JH, Choe JK, Nazari A, Summers-Chase D. Ovarian hyperstimulation can reduce uterine receptivity. A case report. Clin Exp Obstet Gynecol. 2000;27(2):89-91. 10. Check JH, Check ML. A case report demonstrating that follicle maturing drugs may create an adverse uterine environment even when not used for controlled ovarian hyperstimulation. Clin Exp Obstet Gynecol. 2001;28(4):217-8. 11. Baart EB, Martini E, Eijkemans MJ, Van Ostal D, Beckers NG, Verhoeff A, et al. Milder Ovarian stimulation for in vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomised controlled trial. Hum Reprod. 2007;22(4):980-8. 12. Hodges CA, Ilagan A, Jennings D, Keri R, Nilson J, Hunt PA. Experimental evidence that changes in oocyte growth influence meiotic chromosome segregation. Hum Reprod. 2002;17:1171-80.

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13. Roberts R, Iatropoulou A, Ciantar D, Stark J, Becker DL, Franks S, Hardy K. Follicle-stimulating hormone affects metaphase I chromosome alignment and increases aneuploidy in mouse oocytes matured in vitro. Biol Reprod. 2005;72:107-18. 14. Hejinen EMEW, Eijkemans MJC, De Klerk C, Polinder S, Beckers NGM, Klinkert ER, et al. A mild treatment strategy for in vitro fertilization: a randomised non inferiority trial. Lancet. 2007;369(9563):743-9. 15. Revelli A, Casano S, Salvagno F, Piane LD. Milder is better? advantages and disadvantages of “mild” ovarian stimulation for human in vitro fertilization. Reprod Biol Endocrinol. 2011;9:25-30. 16. Verberg MF, Eijkemans MJ, Macklon NS, Heijnen EM, Fauser BC, Broekmans F. Predictors of low response to mild ovarian stimulation initiated on cycle day 5 for IVF. Hum Reprod. 2007;22(7):1919-24. 17. Land JA, Yarmolinskaya MI, Dumoulin JC, Evers JL. Highdose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome. Fertil Steril. 1996;65(5):961-5. 18. Lekamge DN, Lane M, Gilchrist RB, Tremellen KP. Increased gonadotrophin stimulation does not improve IVF outcomes in patients with predicted poor ovarian reserve. J Assist Reprod Genet. 2008;25(11-12):515-21. 19. Pal L, Jindal S, Witt BR, Santoro N. Less is more: increased gonadotropin use for ovarian stimulation adversely influences clinical pregnancy and live birth after in vitro fertilization. Fertil Steril. 2008;89(6):1694-701. 20. Takahashi K, Mukaida T, Tomiyama T, Goto T, Oka C. GnRH antagonist improved blastocyst quality and pregnancy outcome after multiple failures of IVF/ICSI-ET with a GnRH agonist protocol. J Assist Reprod Genet. 2004;21(9):317-22. 21. Yanaihara A, Yorimitsu T, Motoyama H, Ohara M, Kawamura T. The decrease of serum luteinizing hormone level by a gonadotropin-releasing hormone antagonist following the mild IVF stimulation protocol for IVF and its clinical outcome. J Assist Reprod Genet. 2008;25(4):115-8.

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22. Kolibianakis EM, Collins I, Tarlatzis BC, Devroey P, Griesinger G. Among patients treated for IVF with gonadotrophins and GnRH analogues is the probability of live birth dependent on the type of analogue used? A systematic review and metaanalysis. Hum Reprod Update. 2006;12a(6):651-71. 23. Humaidan P, Papanikolaou EG, Tarlatzis BC. GnRHa to trigger final oocyte maturation: a time to reconsider. Hum Reprod. 2009;24(10):2389-94. 24. de Klerk C, Heijnen EM, Macklon NS, Duivenvoorden HJ, Fauser BC, Passchier J, et al. The psychological impact of mild ovarian stimulation combined with single embryo transfer compared with conventional IVF. Hum Reprod. 2006;21(3):721-7. 25. Polinder S, Heijnen EM, Macklon NS, Habbema JD, Fauser BJ, Eijkemans MJ. Cost-effectiveness of a mild compared with a standard strategy for IVF: a randomized comparison using cumulative term live birth as the primary end point. Hum Reprod. 2008;23(2):316-23.

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7

Premature luteinization Surveen Ghumman, Monika Gupta

Premature luteinization (PL) has been defined as the rise of progesterone on the day hCG is given. It is an important entity in women who are undergoing ovulation induction. There is no strict criterion of diagnosis and no definite etiology has been identified.

Diagnosis Serum Progesterone on Day of hCG Various studies have quoted a cut-off of 0.8 to 2 ng/ml.1 As more number of follicles produce more progesterone, it may be important to link ovarian response to estrogen and progesterone levels rather than absolute progesterone values. Hence, P/E2 ratio may be better in detecting PL. A level of more than 1 is thought to differentiate between progesterone secretion from a dysmature follicle as occurs in PCOS from that of a mature healthy follicle.2 A study showed that PL seems unrelated to preovulatory luteinizing hormone (LH) elevation and LH/hCG content of gonadotropins and could be associated with poor ovarian response and the presence of dysmature follicles.3

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Progesterone/Estradiol Ratio on Day of hCG Cycles with elevated P/E2 ratios are associated with lower clinical pregnancy and live birth rates, which decrease further as the P/E2 ratio rises. P/E2 ratio improves the prediction of IVF outcome when compared to serum P levels alone.4

Ultrasound Appearance Collaborative ultrasound appearance of the follicle shows a thickened follicular wall and appearance of irregular echogenic structures within the follicle.

Incidence It varies in various studies from 13 to 71%, using P only to define PL. It was found that 41% had a P/E2 ratio.2 The incidence varies with different stimulation protocols. It is maximum with flare protocol being 85%.5 It is 54.7% in women undergoing COH with CC hMG and a single 2.5 mg dose of the GnRH antagonist, cetrorelix.6 With GnRH agonist protocol incidence varied from 5 to 35% and with antagonist from 20 to 35%.7,8

Causes Increased Levels of hCG Accumulated with hMG Administration It has been seen that there are higher levels of hCG in women with PL suggesting that the LH activity in hMG is responsible for PL. Hence, in these cases recombinant or highly purified FSH may be given.9

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Increased LH Levels Although GnRH agonists suppress LH, it has been seen that in some cases suppression may be incomplete. LH levels may be enough to stimulate granulose cells to produce progesterone but not enough to cause rupture of follicle.

Increased LH Sensitivity of Granulose Cells to FSH It is postulated that there is a higher sensitivity of LH receptors of granulose cells to FSH, which may be due to increased estradiol levels.

Increased LH Sensitivity in Poor Responders PL is seen more often in poor responders and raised progesterone may be because of adversely developing cumulus oocyte complex and not because of a raised LH.

Effect on Reproductive Outcomes Adverse Effects on Oocyte Maturation, Fertilization or Early Cleavage A study showed that the mean number of retrieved oocytes, recovered mature oocytes, embryos and top quality embryos were significantly higher in the non-prematurely luteinized group than in the prematurely luteinized group. Although fertilization rates and implantation rates were similar between the two groups, the clinical pregnancy rate was higher in the non-prematurely luteinized group than in the prematurely luteinized group.3 However, many authors have not found a negative impact of PL.10

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Effect on Endometrium Since many studies did not find an adverse oocyte quality, it was suggested that PL has an adverse effect on endometrium. There is an abnormally accelerated endometrial maturation leading to impaired endometrial receptivity.11

Pregnancy Rate A systemic review and meta-analysis stated that no statistically significant association between progesterone elevation and the probability of clinical pregnancy was detected in women undergoing ovarian stimulation with GnRH analogs and gonadotropins for IVF.12 With COH cycles using GnRH antagonists and where serum P is measured by ELISA there does not seem to be any disadvantage of higher serum P levels up to 2 ng/ml at the time of hCG in IVF-ET cycles.13

Prevention Flexible Antagonist Protocol In flexible antagonist protocol, antagonist is initiated when follicle size is more than 14 mm or estradiol is more than 600 pg whereas in the fixed protocol it is administered on day 6. In stimulated cycles, it was seen that intense ovarian response with more number of follicles led to an early rise in estradiol. Thus, threshold levels of estradiol that initiates a LH surge are reached earlier before follicles reach an optimum size. In these cases the flexible protocol, which is dependent on the size of the follicle on ultrasound to start antagonist to suppress surge, may no longer be accurate to determine time of initiation of GnRH antagonist.2 This observation might explain the observed lower efficacy of the flexible protocol compared

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with a fixed protocol in a meta-analysis of four studies.3 Hence, for patients with a profound ovarian response, early initiation of the GnRH antagonist may be needed.14 Treatment with ganirelix effectively prevents premature LH rises; luteinization in subjects undergoing stimulated IUI. Low-dose rFSH regimen combined with a GnRH antagonist may be an alternative treatment option for subjects with previous proven luteinization.15

Low-dose hCG Alone in the Late Follicular Stage Women who were undergoing COS with recombinant FSH/ hMG followed by low-dose hCG (200 IU/day) alone [66]. This regimen did not cause PL.16

Mifepristone Mifepristone was started in a daily dose of 40 mg along with stimulation. 50 mg progesterone was given along with hCG to counteract the antiprogesterone effect of mifepristone. No PL was seen in any case. However, endometrial receptivity status requires additional evaluation after decreasing RU486 doses.17

hCG Administration Preponed to day of Progesterone Rise Progesterone was monitored from day 7 and hCG was given when a rise was detected >1.0 ng/ml. It was seen that the quality of embryos and implantation rate was better than when hCG was delayed in cases of PL.18

Aspiration of Single Lead Follicle Better pregnancy rates were seen if a single lead follicle was aspirated and other follicles continued to grow and were aspirated later. No premature LH surge was seen.19

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Premature luteinization is a diagnostic and therapeutic challenge for the infertility specialist. Its impact on ART results is controversial and more randomized studies are required before one can be definite about it.

References 1. Hofmann GE, Bentzien F, Bergh PA, Garrisi GJ, Williams MC, Guzman I, et al. Premature luteinization in controlled ovarian hyperstimulation has no adverse effect on oocyte and embryo quality. Fertil Steril. 1993;60:675-9. 2. Younis JS, Simon A, Laufer N. Endometrial preparation: lessons from oocyte donation. Fertil Steril.1996;66:873-84. 3. Ou YC, Lan KC, Chang SY, Kung FT, Huang FJ. Increased progesterone/estradiol ratio on the day of hcg administration adversely affects success of in vitro fertilization–embryo transfer in patients stimulated with gonadotropin-releasing hormone agonist and recombinant follicle-stimulating hormone Taiwan. J Obstet Gynecol. 2008;47:168-74. 4. Keltz MD, Stein DE, Berin I, Skorupski J. Elevated progesteroneto-estradiol ratio versus serum progesterone alone for predicting poor cycle outcome with in vitro fertilization. J Reprod Med. 2012;57(1-2):9-12. 5. Sims A, Seltman HJ, Muasher SJ. Early follicular rise of serum progesterone concentration in response to a flare-up effect of gonadotrophin-releasing hormone agonist impairs follicular recruitment for in-vitro fertilization. Hum Reprod. 1994;9:235-40. 6. Seow KM, Lin YH, Huang LW, Hsieh BC, Huang SC, Chen CY, et al. Subtle progesterone rise in the single-dose gonadotropinreleasing hormone antagonist (cetrorelix) stimulation protocol in patients undergoing in vitro fertilization or intracytoplasmic sperm injection cycles. Gynecol Endocrinol. 2007;23:338-42. 7. Edelstein MC, Seltman HJ, Cox BJ, Robinson SM, Shaw RA, Muasher SJ. Progesterone levels on the day of human chorionic gonadotropin administration in cycles with gonadotropinreleasing hormone agonist suppression are not predictive of pregnancy outcome. Fertil Steril. 1990;54:853-7.

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8. Bosch E, Valencia I, Escudero E, Crespo J, Simon C, Remohi J, et al. Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome. Fertil Steril. 2003;80:1444-9. 9. Copperman AB, Horowitz GM, Kaplan P, Scott RT, Navot D, Hofmann GE. Relationship between circulating human chorionic gonadotropin levels and premature luteinization in cycles of controlled ovarian hyperstimulation. Fertil Steril. 1995;63:1267-71. 10. Martinez F, Coroleu B, Clua E, Tur R, Buxaderas R, Parera, et al. Serum progesterone concentrations on the day of hCG administration cannot predict pregnancy in assisted reproduction cycles. Reprod Biomed Online. 2004;8:183-90. 11. Yovel I, Yaron Y, Amit A, Peyser MR, David MP, Kogosowski A, et al. High progesterone levels adversely affect embryo quality and pregnancy rates in vitro fertilization and oocyte donation programs. Fertil Steril. 1995;64:128-31. 12. Bosch E. Comment on: is progesterone elevation on the day of human chorionic gonadotrophin administration associated with the probability of pregnancy in vitro fertilization? A systematic review and meta-analysis. By Venetis et al (2007). Hum Reprod Update. 2008;14:194-5. 13. Katsoff B, Check JH, Wilson C, Choe JK. Effect of serum progesterone level on the day of human chorionic gonadotropin injection on outcome following in vitro fertilization-embryo transfer in women using gonadotropin releasing hormone antagonists. Clin Exp Obstet Gynecol. 2011;38(4):322-3. 14. Al-Inany HG, Aboulghar M, Mansour R, Serour GI. Optimizing GnRH antagonist administration: meta-analysis of fixed vs flexible protocol. Reprod Biomed Online. 2005;10:567-70. 15. Lambalk CB, Leader A, Olivennes F, Fluker MR, Andersen AN, Ingerslev J, et al. Treatment with the GnRH antagonist ganirelix prevents premature LH rises and luteinization in stimulated intrauterine insemination: results of a double-blind, placebocontrolled, multicentre trial. Hum Reprod. 2006;21(3):632-9.

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16. Filicori M, Cognigni GE, Gamberini E, Parmegiani L, Troilo E, Roset B. Efficacy of low-dose human chorionic gonadotropin alone to complete controlled ovarian stimulation. Fertil Steril. 2005;84:394-401. 17. Escudero EL, Boerrigter PJ, Bennink HJ, Epifanio R, Horcajadas JA, Olivennes F, et al. Mifepristone is an effective oral alternative for the prevention of premature luteinizing hormone surges and/or premature luteinization in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab. 2005;90:2081-8. 18. Harada T, Katagiri C, Takao N, Toda T, Mio Y, Terakawa N. Altering the timing of human chorionic gonadotropin injection according to serum progesterone concentrations improves embryo quality in cycles with subtle P rise. Fertil Steril. 1996;65:594-7. 19. Barash A, Shoham Z, Lunenfeld B, Segal I, Insler V, Borenstein R. Can premature luteinization in superovulation protocols be prevented by aspiration of an ill-timed leading follicle? Fertil Steril. 1990;53:865-9.

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8

Polycystic Ovarian Syndrome and Insulin Sensitizers Surveen Ghumman

Polycystic ovarian syndrome (PCOS) is a heterogeneous collection of signs and symptoms that form a spectrum of mild to severe disturbance of reproductive, endocrine and metabolic functions. It was first described by Stein and Leventhal in 1935.1 The disorder is multifactorial in origin. It is thought to have a genetic etiology but the severity and course is determined by lifestyle, especially body mass index. 80 to 90% of women suffering from anovulation have PCOS. Prevalence of PCOS has been studied in several populations and it appears that it affects as many as 5–10% of women of reproductive age.

Diagnosis Presence of two out of the following three criteria are essential for diagnosis.1 1. Oligo and/or anovulation. 2. Hyperandrogenism (clinical and/or biochemical). 3. Polycystic ovaries with exclusion of other etiologies.

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Histopathological Criteria 1. Atretic follicles and/or degenerating granulosa cells. 2. Hypertrophy and luteinization of the inner theca cell layer. 3. Thickened ovarian tunica.

Transvaginal Sonography Diagnosis is on the basis of these criteria:2 1. Presence of 12 or more cysts of 2 to 9 mm 2. Ovarian volume equal to or more than 12 cm3 3. Bright echogenic stroma. Degree of insulin resistance is correlated well with the ovarian volume and stromal echogenicity whereas serum LH and testosterone is related well with ovarian volume, stromal echogenicity and follicle number. Ovarian volume was found to be the best predictor for hyperandrogenism.3

Insulin Resistance Insulin resistance is defined as reduced glucose response to a given amount of insulin. It occurs in 80% of obese women and 30 to 40% of women with normal weight with PCOS. Hyperinsulinemia is more common in patients with more than 10 follicles in the ovary, enlarged ovarian volume or elevated day 10 LH. Peripheral target tissue insulin resistance can be due to decreased number of peripheral insulin receptors, decreased insulin binding or a post receptor failure. In PCOS it is caused by the post-receptor defect because of excessive serine phos­ phorylation of beta chain of insulin receptor and of adrenal and ovarian cytochrome P450c17 enzyme. This enzyme catalyzes 17 hydroxylase and the 17, 20 lyase activities

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that is a rate limiting step in androgen biosynthesis thus leading to hyperandrogenemia. There is evidence of adrenal hyperandrogenemia in 15% of PCOS women (Fig. 8.1). Peripheral target tissue resistance leads to hyper­insulinemia as a compensatory mechanism. When the beta cells of pancreas fail to meet this challenge there are declining insulin levels and an impaired GTT finally leading to type 2 NIDDM. Hyperinsulinemia leads to adverse lipid effects (Increased triglycerides and VLDL cholesterol and a decreased HDL) (Fig. 8.2). Insulin when in excess binds to IGF-I receptors and also decreases insulin-like growth factor binding protein I (IGFBP-I) production in liver thus, increasing levels of IGF-I. IGF-I augments theca androgen response to LH. Another theory states that insulin binds to its own receptors causing steroidogenesis. Increased IGF-I activity in endometrium may also be responsible for the endometrial growth and increased risk of endometrial cancer in these patients. Plasminogen activator inhibitor-I is increased causing impaired fibrinolysis. In PCOS the ovary does not secrete increased amount of estrogen. Levels of estrone are increased because of peripheral conversion of increased amount of androstenedione to

Fig. 8.1:  Mechanism of hyperinsulinemia and hyperandrogenemia4

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Fig. 8.2:  Effect of hyperinsulinemia in polycystic ovarian syndrome

estrone. Serum prolactin levels may be high in 30 to 40% of PCOS women because of increased estrogen levels. Sex hormone binding globulin are decreased because raised insulin levels inhibit hepatic synthesis of SHBG (Fig. 8.2). Also the increased testosterone level suppresses SHBG. This further increases levels of estradiol and testosterone. High levels of estradiol cause increased LH secretion and suppress FSH secretion 40% of cases will have an increased level of LH. As FSH secretion is not totally suppressed follicular growth is continuously stimulated but not to the point of full maturation and ovulation. Small follicles 2 to 10 mm in diameter are present that may last for months. These are surrounded by hyperplastic theca cells that under the influence of LH get luteinized. The tissue derived from follicular atresia contributes to stromal compart­ ment that secretes androstenedione and testos­terone. High androgens

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prevent normal follicular development and premature atresia of follicles. All anovulatory women who are androgenic should be assessed for glucose tolerance and insulin resistance with measurement of 2 hour glucose and insulin value after 75 g load.4

Clinical Presentation 1. Hyperandrogenism (acne, hirsutism, alopecia—not virilization). 2. Menstrual disturbance. 3. Infertility. 4. Obesity. 5. Clinical evidence of insulin resistance – Acanthosis nigricans.

Late Sequelae 1. Diabetes mellitus. 2. Dyslipidemia. 3. Hypertension and cardiovascular disease. 4. Endometrial carcinoma. 5. Breast cancer.

Serum Endocrinology 1. Fasting insulin levels (Normal < 25 IU/L) in glucose tolerance test preferred (Tables 8.1 and 8.2). 2. Postprandial insulin >100 ug/ml 3. Fasting blood sugar:insulin ratio (> 4.5) 4. Glucose tolerance test (Table 8.1) 5. Total and free testosterone (Normal total testosterone 20–80 ng/dl) 6. DHEAS (Normal–Less than 350 µg/dl)

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Polycystic Ovarian Syndrome and Insulin Sensitizers  Table 8.1: Blood glucose value after 75 g load4 Normal

Impaired

Diabetes mellitus

Fasting (mg/dl)

< 100

100–126

> 126

2 hour value (mg/dl)

< 140

140–199

> 200

Table 8.2: Hour insulin value after 75 g load4

Value (µg/ml)

Likely insulin resistance

Insulin resistance

Severe insulin resistance

100–150

150–300

> 300

7. LH raised (2–10 IU/l) Measured on day 2–3 or on any day if amenorrheic 8. FSH normal (2-8 IU/L) 9. Decreased SHBG (normal 16–119 nmol/L) 10. Free androgen index (FAI) T × 100/SHBG (Normal 100 ng/ml.10 ii. Presence of headaches and visual field defects. iii. Abnormal X-ray cone down view of the sella turcica. With increasing use of these modalities, incidental discovery of pituitary microadenomas is seen in 10% of individuals having normal prolactin levels. These tumors are called pituitary incidentalomas.7 Macroadenoma by definition is more than 1 cm and imaging techniques now identify suprasellar extensions, compression of optic chiasma and invasion of cavernous sinus.

Treatment of Hyperprolactinemia (Fig. 11.2) Aim • Elimination of symptoms like galactorrhea and amenorrhea • Induction of ovulation • Treatment of prolactin secreting macroadenomas. The management options for hyperprolactinemia are: • Expectant • Medical • Surgical • Radiation. Management of Hyperprolactinemia due to Antipsychotic Drugs The pituitary is imaged to rule out prolactinoma. The drug is changed to an alternative drug such as an atypical neuroleptic or be discontinued. Serum prolactin levels are monitored to ensure they are not rising further. Low dose contraceptive pill may be given if estrogen deficiency is present. The use of dopamine agonist along with an antipsychotic drug may

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Fig. 11.2: Management of hyperprolactinemia

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lower the prolactin levels but would antagonize the effect of the anti-psycotic drug. Dopaminergic agents can occasionally induce or worsen psychotic symptoms.

Expectant Management Where no tumor is seen on imaging and there is absence of symptoms like galactorrhea, infertility, menstrual disturbance or hypoestrogenism one can use the expectant line of management with serial monitoring of prolactin levels and a CT scan every 2 years.

Medical Management Bromocriptine It is a derivative of lysergic acid substituted with bromine at position 2. It is a dopamine agonist that binds to dopamine receptors and therefore, induces inhibition of pituitary prolactin secretion. Dosage 1. Orally a. Tablet of 2.5 mg given in a twice daily dose as half-life is 8 to 12 hours. It can be increased to 10 mg/day. b. Slow release oral preparation is also available to be given once a day in a dose of 5 to 15 mg/day and is equally effective. 2. Long-acting depot intramuscular injection: They are made by embedding glucose initiated polygycolide micro­ spherules and have a maximum degradation time of 3 months. They are given in a dose of 50 to 75 mg/month. Since response to these injections is rapid, they are useful in large tumors with visual field impairment.10 It has the same severity of side effects as the oral preparation.

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3. Intravaginal: It is given in a similar dose of 5 to 10 mg/day. Since it avoids direct contact with the intestinal mucosa, it has lesser side effects than oral administration. The levels are sustained for a longer time as it escapes the liver first pass effect when given vaginally and therapeutic results are achieved at a lower dose. Side effects 10% patients show intolerable side effects (Table 11.1). Measures to reduce side effects are: • Building tolerance by slowly increasing the dose at weekly intervals. • Taking the drug at bedtime as peak levels are achieved after 2 hours. • Individualizing the dosage schedule • Using intravaginal route. Table 11.1: Side effect of bromocriptine Immediate effects •  Nausea •  Headache •  Fatigue •  Dizziness •  Orthostatic hypotension •  Nasal congestion •  Vomiting •  Abdominal cramps •  Hallucinations Long-term effects11 •  Raynaud’s phenomenon •  Constipation •  Psychiatric changes specially aggression

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Efficacy 1. Amenorrhea and galactorrhea: 80% of patients with amenorrhea and galactorrhea improved.12 There was 75% reduction in breast secretion by 6 weeks and galactorrhea was suppressed in 60% of patients by 12 weeks. 2. Infertility: Ovulation was restored within 5 to 6 weeks. Studies have shown successful ovulation induction and pregnancy with bromocriptine in the absence of galactorrhea or hyperprolactinemia in previous nonresponders to clomiphine.13 3. Pituitary tumor: Bromocriptine causes regression of macroadenomas. In some shrinkage is seen even with low dose (5–7.5 mg/day) whereas in others larger doses and prolonged duration may be required. Usually a dose of more than 10 mg is ineffective. Visual improvement occurs within days and tumor shrinkage occurs rapidly in first 3 months of therapy. Locally invasive tumors with levels of bromocriptine more than 1000 ng/ml show a good response to medical treatment. Problem with treatment of the tumor with this drug is that it has to be taken indefinitely. No adverse effect of bromocriptine has yet been seen as in early pregnancy.14 After 2 years therapy, 75% of microadenomas and 80 to 90% of macroadenomas regress. On discontinuation of drug after 5 years only 25% patients remained normoprolactinemic.15 Problems 1. Recurrence: Recurrence of symptoms occurred in 75% of patients with prolactinomas within 4 to 6 weeks on stopping of the drug. Hence, these drugs are used only for short-term purpose of achieving pregnancy, curing galactorrhea or reducing tumor mass.16 2. Resistance: 5 to 18% of patients do not tolerate bromo­ criptine or are resistant to it because of decreased

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dopamine receptor on lactotroph cell membrane. In these cases other drugs can be tried. 3. Perivascular fibrosis: It may cause perivascular fibrosis in tumors if given for a long time making surgery difficult. Other Dopamine Agonists a. Pergolide: It is more potent, longer-acting, better tolerated and useful in bromocriptine resistant patients. It is given in a dose of 50 to 150 mg/day and is increased slowly to avoid side effects. b. Quinagolide: It is a long-acting non-ergot derivative, with higher affinity for dopamine receptors and lesser side effects. It is useful in bromocriptine resistant tumors. It also has antidepressant properties and is given in a dose of 75 to 300 mg/day at bedtime. c. Cabergoline: It is useful in bromocriptine resistant cases. It has less side effects compared to bromocriptine, the most common being headache. It is more effective in reducing tumor size and prolactin levels than bromocriptine or quinagolide.17 It is given in a dose of 0.5 to 3 mg once a week orally or vaginally, usually starting with a lower dose. Fetal safety is not yet completely established as there is limited experience. A recent study showed that cabergoline achieved a high pregnancy rate with uneventful outcomes in infertile women with prolactinoma, independent of tumor size and bromocriptine resistance or intolerance. Cabergoline monotherapy could substitute for the conventional combination therapy of pregestational surgery or irradiation plus bromocriptine in macroprolactinomas.18 d. Hydergine: It is a mixed ergot alkaloid effective only if serum prolactin levels are less than 100 ng/ml. It is well tolerated by patients and should be used in cases where bromocriptine fails.

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Cabergoline vs Bromocriptine in ART A recent study showed that the cost of treatment was significantly higher with cabergoline than with bromocriptine. However, side effect rate was significantly higher with bromocriptine than with cabergoline (15.3% vs 2.5%). Cabergoline and bromocriptine showed no differences in IVF outcomes and pregnancy results.19 Patients who show resistance to one dopamine agonist may respond to another.

Estrogen Replacement Therapy Where tumor is small but is producing a significant hypo­ estrogenism estrogen replacement therapy should be given for protection of the bones and vascular system. When contraception is needed, they can be put on low dose contraceptive pills. There is no risk of tumor expansion due to estrogens since the level given is only enough to raise levels up to those in a natural cycle.20

Surgical Removal Indications 1. Patient unwilling for long-term drug therapy. 2. Drug resistance. 3. Intolerable side effects of drugs. 4. Nonfunctioning tumors where prolactin levels are not very high. These tumors may expand with invasion into cavernous sinus, compression of optic chiasma and hemorrhage causing pituitary apoplexy. 5. Suprasellar extension not regressing with drug therapy.

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Surgical techniques have advanced to microsurgery using the trans-sphenoidal approach to expose the sella turcica. Normal yellow tissue of the pituitary gland can be distinguished from tumor tissue in small tumors. However, this tumor does not have a capsule and it may be difficult to distinguish from normal tissue in large tumors. Once it grows beyond the sella turcica it cannot be removed totally. Preoperative medical therapy: This decreases the tumor size in 50 to 70% of cases making tumor more amenable for sur­ gery. However, prolonged administration of drug may cause fibrosis and difficulty in dissecting. Results: Serum prolactin comes to normal with resumption of normal menstrual cycles in 30% of cases with macro­ ade­ noma and 70% with microadenoma. The best results are obtai­ ned in patients with serum prolactin less than 500 ng/ml. Cure rate decreases if levels of prolactin are high. Results are better in intrasellar tumors.21 Pregnancy was achieved in 88% of those desiring conception following surgery.22 Recurrence: It may occur for 10% of cases with macro­ade­ noma and 70% of those with microadenoma.23 Reason for recurrence being: 1. Partial resection of tumor, since it may be difficult to differentiate from normal tissue. 2. Multifocal origin of prolactinoma. 3. Persistant abnormal stimulus to lactotrophs. Follow-up in cases where symptoms persist includes moni­toring of serum prolactin every 6 months and imaging of pituitary every year for 2 years. Imaging is thereafter done every year. Dopamine agonists are used for tumor recurrence or when ovulation induction is required. Repeat surgery has a success rate of 33% only. Irradiation after surgery may cause stroke and other brain tumors.

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Complications 1. Panhypopituitarism: It is seen in up to 10 to 30% of patients. 2. Cerebrospinal fluid leak. 3. Meningitis. 4. Diabetes insipidus: It manifests in 10 to 40% of patients and lasts for about 6 months. 5. Mortality: Mortality occurs in less than 1% of the total surgeries.

Radiation It is not the primary choice of treatment and may be tried if medical management or surgery fail. It is given using linear cobalt or proton mode. Disadvantage 1. Results are less satisfactory than with surgery. 2. Slow response with radiotherapy prolactin levels years to come to normal. 3. Panhypopituitarism can occur even after many years and may need hormone replacement. 4. Multiple endocrinopathies.24 5. Damage to optic nerve. 6. Diabetes insipidus. Hyperprolactinemia is a frequent cause of anovulatory infertility and luteal phase defect. Dopaminergic treatment is the first line of treatment and is very effective in both idiopathic hyperprolactinemia and prolactinoma, with a 60 to 80% pregnancy rate.

References 1. Ben-David M, Schenker JG. Transient hyperprolactinemia. A correctable cause of female idiopathic infertility. J Clin Endocrinol Metab. 1983;57:442-4.

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2. Cunha-Filho JS, Gross JL, Lemos NA, Brandelli A, Castillos M, Passos EP. Hyperprolactinemia and luteal insufficiency in infertile patients with mild and minimal endometriosis. Horm Metab Res. 2001;33(4):216-20. 3. Padilla SL, Person GK, McDonough PG, Reindollar RH. The efficacy of bromocriptine patients with ovulatory dysfunction and normoprolactinemic galactorrhea. 1985;44:695-8. 4. Strachan MW, Teoh WL, Don-Wauchope AC, Seth J, Stoddart M, Beckett GJ. Clinical and radiological features of patients with macroprolactinaemia. Clin Endocrinol. 2003;59(3):339-46. 5. Sadideen H, Swaminathan R. Macroprolactin: what is it and what is its importance? Int J Clin Pract. 2006;60(4):457-61. 6. Cattaneo F, Kappeler D, Müller B. Macroprolactinaemia, the major unknown in the differential diagnosis of hyperprolactinaemia. Swiss Med Wkly. 2001;131(9-10):122-6. 7. Elster AD. Modern imaging of the pituitary. Radiology. 1993;187:1-14. 8. Bayrak A, Saadat P, Mor E, Chong L, Paulson RJ, Sokol RZ. Pituitary imaging is indicated for the evaluation of hyperprolactinemia. Fertil Steril. 2005;84(1):181-5. 9. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH. Pituitary MRI in normal human volunteers: Occult adenomas in general populations. Ann Intern Med. 1994;120:817-20. 10. Beckers A, Petrossians P, Abs R, Flandroy P, Stadnik T, de Longueville M, et al. Treatment of macroprolactinomas with long acting and repeatable form of bromocriptine: a report of 29 cases. J Clin Endocrinol Metab. 1992;75:275-80. 11. Soule SG, Jacob HS. Prolactinoma: Present day management. Br J Obstet Gynecol. 1995;102:178-81. 12. Cuellar FG. Bromocriptine mesylate (Parlodel) in the management of amenorrhea/galactorrhea associated with hyperprolactinemia. Obstet Gynecol. 1980;55:278-84. 13. Porcile A, Gallardo E, Venegas E. Normoprolactinemic anovulation nonresponsive to clomiphene citrate: Ovulation induction with bromocriptine. Fertil Steril. 1990;53:50-5. 14. Turkalj I, Braun P, Krupp P. Surveillance of bromocriptine in pregnancy. JAMA. 1982;247:1589-91.

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15. Webster J. Carbogoline and qunagolidine therapy for prolacti­ nomas. Clin Endocrinol. 2000;53:549-50. 16. Passos VQ, Souza JJ, Musolino NR, Bronstein MD. Long-term follow-up of prolactinomas: normoprolactinemia after bromo­ criptine withdrawal. Clin Endocrinol Metab. 2002;87:3578-82. 17. Di Sarno A, Landi ML, Cappabianca P, Di Salle F, Rossi FW, Pivonello R, et al. Resistance to cabergoline as compared to bromocriptine in hyperprolactinemia: prevalence clinical definition and therapeutic strategy. J Clin Endocrinol Metab. 2001;86:5256-61. 18. Ono M,  Miki N,  Amano K,  Kawamata T,  Seki T,  Makino R, et al. Individualized high-dose cabergoline therapy for hyperprolactinemic infertility in women with micro- and macroprolactinomas. J Clin Endocrinol Metab. 2010;95(6):26729. 19. Bahceci M,  Sismanoglu A,  Ulug U. Comparison of cabergoline and bromocriptine in patients with asymptomatic incidental hyperprolactinemia undergoing ICSI-ET. Gynecol Endocrinol. 2010;26(7):505-8. 20. Correnblum B, Donovan L. The safety of physiological estrogen plus progestin replacement therapy and oral contraceptive therapy in women with pathological hyperprolactinemia. Fertil Steril. 1993;59:671. 21. Losa M, Mortini P, Barzaghi R, Gioia L, Giovanelli M. Surgical treatment in prolactin secreting adenoma: Early results and long-term outcome. J Clinical Metab. 2002;87:3180-6. 22. Feigenbaum SL, Downey DE, Wilson CB, Jaffe RB. Transs­ phenoidal pituitary resection for preoperative diagnosis of prolactin secreting adenoma in women: Long-term follow-up. J Clin Endocrinol Metab. 1996;81:1711-9. 23. Schlechte JA, Sherman BM, Chapler FK, Van Gilder J. Longterm follow-up of women with surgically treated prolactin secreting tumors. J Clin Endocrinol Metab. 1986;62:1296-301. 24. Hoybye C, Grenback E, Rahn T, Degerblad M, Thorén M, Hulting AL. Adrenocorticotropic hormone producing pituitary tumor: 12 to 22 year follow up after treatment with sterotactic radiosurgery. Neurosurg. 2001;49:284-91.

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cHAPTER

12

Role of Androgens in Ovulation Induction Shashi Prateek, Surveen Ghumman

Androgens are intermediates in estrogen biosynthesis and local regulators of ovarian function. The atherogenic nature of androgens has been questioned. It is believed that androgens may amplify the FSH effects on the ovary improving ovarian response and that granulosa cell stimulation by FSH is actually an androgen-modulated process. Androgens contribute to the paracrine regulation of follicular maturation and atresia. Ovarian stroma and granulosa cells of primordial follicles and follicles at more advanced stages of folliculogenesis have androgen receptors. During intermediate stages of follicular development, locally produced androgen acts via granulosa cell androgen receptors (AR) to promote follicle-stimulating hormone (FSH)-induced granulosa cell differentiation through amplifying cAMP-mediated post-receptor signaling.1 Granulosa cell-specific androgen receptors, promote preantral follicle growth and prevent follicle atresia, thus enhancing ovarian function.2 In a recent study, the physiological significance of androgens in female reproduction became clear when female mice with

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global knockout of androgen receptor (AR) expression were found to have reduced fertility with abnormal ovarian function.3 It was concluded that androgen receptors and androgens are essential for follicular recruitment, and normal follicle development and play a critical role in regulating ovarian function and fertility. This theory is supported by the fact that very low levels of testosterone on day 3 decrease success rate of IVF.4 Decreased ovarian reserve is becoming a common entity as more women are postponing childbearing. Many protocols are followed for these poor responders. Therapeutic benefits from supplementation with dehydroepiandrosterone (DHEA) and testosterone in women with diminished ovarian reserve (DOR) have been noted in the form of improved response to ovarian stimulation. Supplemental treatment with these drugs during ovarian stimulation may represent a novel way to maximize ovarian response.5

Impact of Androgens on Reproductive Outcome Improvement in Number of Oocytes and Embryo It was suggested that DHEA supplementation appears to augment ovarian stimulation with gonadotropins in poor responders, resulting in improved oocyte yields. Cumulative DHEA effects may have possible effects on follicle recruitment. In a study after DHEA, a significant decrease in cycle day-3 estradiol levels was found. There was an increased number of >17 mm follicles (3 versus 1.9) and MII oocytes (4 versus 2.1).6 In a recent study, it was observed that transdermal testosterone increased the number of recruited follicles in previously poor responders by over fivefold. The total amount of gonadotropin needed to achieve such improved response

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with testosterone was significantly lower. The antral follicle count increased during testosterone treatment, and the number of follicles available for recruitment and development at the time of starting FSH therapy was higher.7 Androgen treatment promoted FSH action in those recruitable follicles as suggested by increased serum levels of androstenedione and IGF-I (both considered as markers of ovarian responsiveness to gonadotropin stimulation), thus yielding higher numbers of oocytes.8 80% of patients underwent oocyte retrieval and embryo transfer in the testosterone supplemented IVF cycle.7

Improvements in Oocytes and Embryo Quality It has been observed that with DHEA and testosterone, not only significant increase in oocytes and embryo numbers are seen, but also improved embryo quality is available.9 After DHEA supplementation, a significant increase in number of top quality day 2 (2.2 versus 1.3) and day 3 embryos (1.9 versus 0.7) were achieved. Cycle cancelation rates were reduced (5.3% versus 42.1%), and pregnancy rates per patients (47.4% vs 10.5%, P < 0.001) and per embryo transfer (44.4% vs 0.0%, P < 0.01) were improved.6 A randomized, prospective, controlled study showed higher live birthrate compared with controls (23.1% versus 4.0%).5 Pretreatment with transdermal testosterone gel (TTG) was also shown to improve number of mature oocytes, fertilized oocytes, good-quality embryos, embryo implantation rate and clinical pregnancy rate per cycle initiated.8 Premature Versus Physiologic Diminished Ovarian Reserve (DOR) DHEA supplementation was effective in both age dependent DOR and premature ovarian aging (POA), though POA patients did mildly better.10 The beneficial effects of DHEA increased with length of DHEA supplementation.11

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Premature ovarian failure (POF)/primary ovarian insufficiency (POI) patients have conceived spontaneously whereas 50–75 mg of dehydroepiandrosterone supplementation for at least 4 months. It also considerably improved intrauterine insemination and IVF outcome and pregnancy rates in these women. FSH levels in these patients decrease with DHEAS administration. Positive effect has been reported with oocyte and embryo quality, with number of euploid embryos increasing and miscarriage rate decreasing.12



Effects on Embryoploidy, Miscarriage Risk and live Birthrates It is assumed that ovarian aging is related to aneuploidy and a higher incidence is seen in older women and those with DOR. Hence, miscarriage rate, which is dependent on aneuploidy, is much more in these women. Pregnancy loss rates in women with DOR were 57.1% in women 40 years old. These rates of pregnancy loss were significantly higher compared to age-matched patients with normal ovarian reserve.13 Anti-Mullerian hormone (AMH) levels are a direct reflection of ovarian aging. Significantly improved live birthrates at AMH ≥1.06 ng/mL were seen. The chance of live birth per treatment cycle is only 5% if AMH was less than 1.05 ng/mL. Above that, chances are significantly improved. Thus, AMH 1.05 ng/mL represents a distinct point of separation between poorer and better live birth chances.14 In a recent study on carrying out preimplantation genetic screening (PGS), short term DHEAS supplementation of 4–12 weeks resulted in reduction in aneuploidy. Beneficial DHEA effects on DOR patients, at least partially, are the likely consequence of lower embryo aneuploidy.15 Increasing

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aneuploidy with advancing female age occurs and it is difficult to have adequate numbers of PGS to check for embryoploidy. Alternatively, miscarriage rates may be taken as a surrogate for aneuploidy risk. Since at least 60% of spontaneous pregnancy loss is attributable to chromosomal abnormalities, it can be hypothesized that significant reductions in aneuploidy after DHEA supplementation should be reflected in lower miscarriage rates. After DHEA supplementation the miscarriage rate was found to be 15.1%, being significantly lower at all ages but most pronounced above age of 35 years. Miscarriage rates after DHEA not only were lower than in an average IVF population but were also comparable to rates reported in normally fertile populations. This supports the assumption of a DHEA effect on embryoploidy. It was suggested that preconception DHEA supplementation in normal fertile populations above age 35 years may have a positive role.16

How Does DHEA Affect Ovarian Reserve? Many mechanisms have been suggested explaining the beneficial effects of DHEAS and testosterone on ovarian reserve. DHEA may be able to decrease aneuploidy rate by reversing damage to oocytes. Second mechanism may be that oocytes in unrecruited stage do not age but changes start taking place once follicle starts maturing after recruitment. The ovarian environment then varies with age and may provide substandard conditions for the oocyte. As proposed by Hodges et al, the environment affects segregation processes during meiosis, giving rise to increased aneuploidy at older ages. He suggested major disturbances in chromosome alignments on the meiotic spindle of oocytes (congression failure), responsible for aneuploidy, result from the complex interplay of signals regulating folliculogenesis. These changes subtly alter the late stages of oocyte growth,

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increasing the risk of a nondisjunction error. These findings have important implications for human aneuploidy, since they suggest that it may be possible to develop prophylactic treatments for reducing the risk of age-related aneuploidy. This pharmacological maneuvering to reduce aneuploidy and miscarriage rate has been tried with DHEAS.17 DHEA levels peak in humans between ages 20 and 30 years, and then decline by approximately 2% per year, to reach nadirs of 10 to 20% around age 80 years.18 Age-related aneuploidy may actually be a reversible DHEA deficiency. Since follicles are still present in menopausal ovaries if ovarian environment can be reconstituted to that present at young age fertility could be preserved for much longer. DHEA may, therefore, represent a first compound in a new category of pharamacological agents with potential to rejuvenate ovarian environments. Following a similar concept, Bentov et al based on the known loss of mitochondrial functions with advancing age, recently suggested the use of mitochondrial nutrients, like coenzyme Q10 (CoQ10), after demonstrating that CoQ10 increases oocyte numbers in older mice.19 Androgens also positively affect mitochondrial function.20 DHEA was seen to increase IGF-1 and since growth hormone had been suggested to improve oocytes yields via IGF-1, it is hypothesized that DHEA may be able to achieve similar effects.21 Predicting the Effectiveness of DHEA It was seen in a study that AMH concentrations significantly improved after DHEA supplementation longitudinally by 60% over time (P=0.002). Younger women (under age 38 years) demonstrated improved AMH concentrations more than older females.22

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DHEA supplementation significantly improved ovarian reserve in parallel with longer DHEA use and was more pronounced in younger women.

AMH levels are predictable of treatment outcomes after DHEA utilization. Spontaneous pregnancies were, of course, conceived after shorter exposure to DHEA as they conceived spontaneously on DHEA during waiting period for IVF. So, it was concluded that shorter exposure sometimes may be enough to raise fecundity but may not suffice to positively affect ploidy and miscarriage rates.23 Improvements in AMH are statistically highly predictive of pregnancy success.22

Treatment Protocols, Side Effects and Complications Pretreatment with 12.5 mg transdermal testosterone gel (TTG) has been applied daily for 21 days in the cycle preceding COS with GnRH antagonist protocol for IVF in poor responders. It may be given as transdermal 20 µg/kg per day during the 5 days preceding gonadotropin treatment. It takes about three months for a given primordial follicle to reach the preovulatory stage. However, the time of exposure to testosterone in the above studies that showed a positive result was relatively reduced. It can be hypothesized that it affects late events involved in follicular maturation rather than earlier stages. At present, since it has not been determined whether androgens are rescuing follicles or simply increasing the number of recruited ones, further research is needed in this respect. Therefore, the daily dose, timing and duration of androgen supplementation may be critical to adequately stimulate folliculogenesis mainly considering a recent study in rhesus monkeys showing that chronic administration

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(for five days before and continuing throughout FSH and LH treatment) of high dose of androgens is antagonistic to gonadotropin-stimulated ovarian function in primates. It has been postulated that there is a threshold effect of androgens on follicular function such that antagonistic actions of androgens may be manifested at elevated concentrations.24 Dose DHEAS is given as 25 mg of micronized tablet tid, for at least four weeks prior to IVF cycle.11 Short-term supplementation is up to 4 to 12 weeks of DHEA prior to IVF and PGS.11 Preparation and Route Distinct advantages from micronized and orally delivered DHEA was demonstrated in a single-dose study comparing three dehydroepiandrosterone delivery methods (oral crystalline steroid, micronized steroid, and vaginal administration) to ascertain whether physiologic levels of circulating dehydroepiandrosterone can be obtained while increases in testosterone are minimized. Micronization of oral dehydroepiandrosterone diminishes bioconversion to testosterone. Vaginal dehydroepiandrosterone delivers equivalent dehydroepiandrosterone but substantially diminishes dehydroepiandrosterone bioconversion.25 Side Effects Side effects at these dosages are small and rare, and primarily relate to androgen effects. They include oily skin, acne vulgaris and hair loss. More frequently, patients comment on improved energy levels and better sex drive.

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A recent systemic review and meta-analysis in 2012 on the use of androgens or androgen-modulating agents in poor responders undergoing IVF concluded that transdermal testosterone pretreatment seems to increase clinical pregnancy and live birthrates in poor responders undergoing ovarian stimulation for IVF. However, there is insufficient data to support a beneficial role of rLH,  hCG, DHEA or letrozole administration in the probability of pregnancy in poor responders undergoing ovarian stimulation for IVF.26 In conclusion, ovarian environments, but not resting oocytes, age as women grow older. Hence, pretreatment with transdermal testosterone may be a useful approach for women known to be low responders on the basis of a poor response to controlled ovarian stimulation but having normal basal FSH concentrations.  DHEA supplementation apparently significantly reduces these age-related increases in aneuploidy, and, therefore, also reduces age-associated increases in miscarriages. A definite beneficial effect of androgens is seen in poor responders but needs further research to determine the best dose and period of administration.

References 1. Hillier SG, Tetsuka M. Role of androgens in follicle maturation and atresia. Baillieres Clin Obstet Gynaecol. 1997;11(2):249-60. 2. Ware VC. The role of androgens in follicular development in the ovary. I. A quantitative analysis oocytes ovulation. J Exp Zoology. 1982;222:155-67. 3. Sen A, Hammes SR. Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Mol Endocrinol. 2010;24(7):1393-403. 4. Frattarelli JL, Peterson EH. Effect of androgen levels on in vitro fertilization cycles. Fertil Steril. 2004;81(6):1713-4.

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5. Casson PR,  Lindsay MS,  Pisarska MD,  Carson SA,  Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod. 2000;15(10):2129-32. 6. Sönmezer M, Ozmen B, Cil AP, Ozkavukçu S, Taşçi T, Olmuş H, et al. Dehydroepiandrosterone supplementation improves ovarian response and cycle outcome in poor responders. Reprod Biomed Online. 2009;19(4):508-13. 7. Balasch J, Fábregues F, Peñarrubia J, Carmona F, Casamitjana R, Creus M, et al. Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poorresponder IVF patients with normal basal concentrations of FSH. Hum Reprod. 2006;21(7):1884-93. 8. Kim CH,  Howles CM,  Lee HA. The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders. Fertil Steril. 2011;95(2):679-83. 9. Barad D, Gleicher N. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod. 2006;21(11):2845-9. 10. Wiser A, Gonen O, Ghetler Y, Shavit T, Berkovitz A, Shulman A. Addition of dehydroepiandrosterone (DHEA) for poorresponder patients before and during IVF treatment improves the pregnancy rate: a randomized prospective study. Hum Reprod. 2010;25(10):2496-500. 11. Barad D, Brill H, Gleicher N. Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function. J Assist Reprod Genet. 2007;24(12):629-34. 12. Mamas L, Mamas E. Dehydroepiandrosterone supplementation in assisted reproduction: rationale and results. Curr Opin Obstet Gynecol. 2009;21(4):306-8. 13. Levi AJ, Raynault MF, Bergh PA, Drews MR, Miller BT, Scott RT Jr. Reproductive outcome in patients with diminished ovarian reserve. Fertil Steril. 2001;76(4):666-9. 14. Gleicher N, Weghofer A, Barad DH. Anti-Müllerian hormone (AMH) defines, independent of age, low versus good live-birth

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chances in women with severely diminished ovarian reserve. Fertil Steril. 2010;94(7):2824-7. 15. Gleicher N, Weghofer A, Barad DH. Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS). Reprod Biol Endocrinol. 2010;8:140. 16. Gleicher N, Ryan E, Weghofer A, Blanco-Mejia S, Barad DH. Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study. Reprod Biol Endocrinol. 2009;7:108. 17. Hodges CA, Ilagan A, Jennings D, Keri R, Nilson J, Hunt PA. Experimental evidence that changes in oocyte growth influence meiotic chromosome segregation. Hum Reprod. 2002;17(5):117180. 18. Walker ML,  Anderson DC,  Herndon JG,  Walker LC. Ovarian aging in squirrel monkeys (Saimiri sciureus). Reproduction. 2009;138(5):793-9. 19. Bentov Y, Esfandiari N, Burstein E, Casper RF. The use of mitochondrial nutrients to improve the outcome of infertility treatment in older patients. Fertil Steril. 2010;93(1):272-5. 20. Pitteloud N, Mootha VK, Dwyer AA, Hardin M, Lee H, Eriksson KF, et al. Relationship between testosterone levels, insulin sensitivity, and mitochondrial function in men. Diabetes Care. 2005;28(7):1636-42. 21. Casson PR, Santoro N, Elkind-Hirsch K, Carson SA, Hornsby PJ, Abraham G, et al. Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: a six-month trial. Fertil Steril. 1998;70(1):107-10. 22. Gleicher N, Weghofer A, Barad DH. Improvement in diminished ovarian reserve after dehydroepiandrosterone supplementation. Reprod Biomed Online. 2010;21(3):360-5. 23. Gleicher N, Barad DH. Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). Reprod Biol Endocrinol. 2011;9:67. 24. Zeleznik AJ, Littler-Ihrig L, Ramasawamy S. Administration of dihydrotestosterone to rhesus monkeys inhibits gonadotropin-

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stimulated ovarian steroidogenesis. J Clin Endocrinol Metab. 2004;89:860-6. 25. Casson PR, Straughn AB, Umstot ES, Abraham GE, Carson SA, Buster JE. Delivery of dehydroepiandrosterone to premenopausal women: effects of micronization and nonoral administration. Am J Obstet Gynecol. 1996;174(2):649-53. 26. Bosdou JK, Venetis CA, Kolibianakis EM, Toulis KA, Goulis DG,  Zepiridis L,  et al. The use of androgens or androgenmodulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update. 2012;18(2):127-45.

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cHAPTER

13

Ovarian Reserve and Fertility in Older Women Neerja Goel, Surveen Ghumman

In the modern era, women are increasingly delaying childbirth till their thirties and forties when fertility declines and risk of congenital anomalies and miscarriage increases. This is the section of population that is becoming a challenge for the infertility expert. A woman’s advancing age is directly related to poor ovarian response to simulation. This situation arises from the natural process of aging and the depletion of the primordial follicular pool and consequent failure in recruitment of follicles. When superovulated these women produce few eggs and are known as poor responders. This may be because of interference with FSH action due to proteins. An autoimmune basis where there could be presence of antibodies against granulosa cells, or defective angiogenesis, autocrine or paracrine alterations leading to decreased quantities of certain intraovarian peptides could be the cause. There could be a genetic basis with FSH-receptor polymorphism. Low diffusion of exogenous gonadotropins has also been proposed. Evaluation of the ovarian reserve forms an integral part of workup of these women.

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Age and Fertility Effect of age is seen on all the reproductive organs affecting fertility.

Ovary 1. Decreasing population of follicles in the ovary that are responsive to stimulation are seen. During embryonic development, the number of oogonia peak by 20 weeks of gestation to approximately 7 million oocytes. At birth this number declines to 1–2 million germ cells and by 20 years only 250,000 to 300,000 remain, decreasing to about 25,000 by age of 30–35 years, and 6,000 by age of 40 years.1 2. Oocytes show high incidence of chromosomal abnor­ malities because of advancing maternal age. During IVF the fertilization rate declines with advancing age and an increasing proportion of the residual unfertilized eggs showed abnormal chromosomes. It is this decline in the number and quality of oocytes that hampers fertility.

Uterus Uterine senescence may be partially responsible for the decrease in fertility associated with increasing age. It is clear that uterine factor plays only a small part in this decline. With surrogacy it has been proven that even an older uterus is capable of reproductive functions when stimulated. There are various theories put forward for poor reproductive perfor­ mance of the uterus with age. 1. Number of pinopodes in the uterine endothelium may be drastically decreased, thus hindering implantation. 2. Uterus may become fibrous with poor blood supply and has decreased ability to synthesize prostaglandins.

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3. Reactive oxidative species produced in the reproductive tract of older women is thought to decrease implantation. 4. There is an increase in the incidence of fibroids and endometriosis in older women.

Tube 1. Deciliation of the Fallopian tube endothelium occurs leading to decreased efficiency of tubal transport. 2. Increased incidence of pelvic inflammatory disease in older women may lead to damaged tubes.

Management of Older Women with a Fertility Problem It is advisable to initiate investigations at an early stage. It is important to exclude factors such as fibroids, incipient ovarian failure, and endometrial polyps, which are less likely to affect younger women. Fibroids of significant size or location should generally be removed prior to any form of assisted conception. Smoking appears to expedite the ovarian aging process. More recent molecular research has indicated a genetic etiology for the age diminished ovarian reserve. There is evidence to show a decline in oocyte quality with increasing maternal age. With DNA fragmentation, the rates of chromosomal abnormalities were found to be significantly higher in older women when their unfertilized oocytes were analyzed following IVF. A significantly higher amount of disassociated chromatids was found in older women. For women less than 34, the rate of genetic aberrations was 24%, between 35 and 39 years the rate was 52%, and women 40 years and above had a rate of 95.8%.2

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Assessment of the Ovarian Reserve With intensified research on reproductive aging, methods to measure the number, quality and reproductive potential of the remaining ovarian follicle pool have evolved and been given the name of ‘Ovarian Reserve Tests’. These tests are indicated in those groups of patients at high risk of ovarian failure (Table 13.1). No single test for assessment of ovarian reserve is adequate, so a combination of following tests is recommended (Table 13.2). Basal Follicle Stimulating Hormone Levels Raised early follicular FSH level is one of the earliest indi­ cations of reproductive aging (Table 13.3). It has been shown that women with elevated FSH levels have a higher minimum

Table 13.1: Indications for testing ovarian reserve 1.  Age more than 35 years 2.  Unexplained infertility regardless of age 3.  Family history of early menopause 4.  Previous ovarian surgery   •  Cystectomy   •  Ovarian drilling   •  Unilateral oophorectomy   •  Chemotherapy   •  Radiation 5. Smoking 6.  Demonstrated poor response to exogenous gonadotropin stimulation

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threshold level of FSH required to initiate sustained follicular development.3 Table 13.2: Ovarian reserve tests 1. Clinical variables--age, history of canceled cycles 2. Blood tests

• Basal FSH



• Day 2 or 3 serum estradiol



• Basal inhibin B



• Mullarian inhibiting substance

3. Dynamic tests

• Clomiphene citrate challenge test



• D  ynamic assay of estradiol and inhibin B after GnRHa stimulation test (GAST)



• Exogenous FSH ovarian reserve test (EFORT)

4. Ultrasound

• Antral follicle count



• Ovarian volume



• Ovarian stromal peak systolic velocity, including waveform and pulsatility index

Table 13.3: Basal follicle stimulating hormone level FSH levels IU/L 20

No pregnancy

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Early Follicular Phase Estradiol Levels Elevated estradiol level in early follicular phase is an indicator of diminished ovarian reserve and has been associated with poor results. Early elevation of serum estradiol level reflects advanced follicular development and early selection of dominant follicle seen in older women due to rising FSH levels. A premature elevation of estradiol may suppress FSH causing masking of an elevated day 3 FSH. Hence, it is better if both FSH and estradiol are measured, to eliminate false negative results. Basal E2 level of more than 80 pg/ml is associated with poor follicular response and development. Early Follicular Phase Inhibin B Levels Inhibin A is secreted predominantly in the luteal phase and inhibin B in the follicular phase by granulosa cells. Inhibin B may, therefore, be a direct marker of ovarian reserve.4 Inhibin B levels decline with increasing age due to decreased number of follicles and decreased secretion by the granulosa cells. Since inhibin is decreased, there is poor negative feedback and FSH level is increased. Low levels of inhibin B on day 3 are associated with a poor outcome of IVF. Its role is limited because of less reliability and difficult serum estimation. A value of more than 45 pg/ml is taken as normal. Anti-Müllerian Hormone Like inhibin levels of anti-Müllerian hormone reflect the health of the granulosa cell. The anti-Müllerian hormone and antral follicle count correlates well with age even in women under 40 years whereas FSH and inhibin B predominantly changes in women more than 40 years of age.5 It has been seen that 35)

Fewer follicles (48% 6. Potassium level >5.0 mg/L 7. Serum creatinine >1.2 mg II. All cases of grade IV and V should be hospitalized. Severe OHSS Aim of therapy after admission: 1. Correction of circulatory volume electrolyte imbalance 2. Maintenance of renal function 3. Prevention of thrombosis. 1. Maintenance of intravascular volume and electrolyte imbalance: The aim must be to restore normal intravascular volume and preserve adequate renal function. Colloid expander may be used for this purpose, but they have the disadvantage that after a short while they redistribute into the extravascular space worsening the ascitis. Low salt albumin is the expander of choice and is given in a dose

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of 50–100 gram every 2 to12 hours. It reverses hematocrit changes, improves renal function and is safe from viral contamination. Other options tried are mannitol, dextran and fresh frozen plasma. Dextran can cause ARDS. Only if there is hyponatremia, normal saline with or without glucose is the crystalloid used for replacement. Up to 1.5 to 3 liters may be needed. Other electrolyte imbalances like hyperkalemia are corrected. Prevention of thrombosis: Low dose heparin should be given, as prophylaxis, in cases where there is an altered coagulation profile. Diuretics: These drugs are usually not used but can be given after hemodilution is achieved if oliguria is persisting or in cases of pulmonary edema. Dopamine: Dopamine may help to avoid fluid and salt retention by improving the renal blood flow in oliguric patient. Management of ascitis: Paracentesis under ultrasound guidance is done where there is severe discomfort, compromise of venous return leading to a decreased cardiac output and hypotension, renal compromise, respiratory distress or hemoconcentration unresponsive to medical therapy. Repeat aspiration may be required. Paracentesis of hydrothorax: This should be done if dyspnea is present because of severe pleural effusion.

Critical OHSS Critical OHSS causes multisystem failure and requires multidisciplinary intensive care. 1. Renal failure: Dopamine central venous pressure line and hemodialysis may be required in severe cases. 2. Pulmonary compromise: Arterial blood gas monitoring, thoracocentesis or assisted ventilation is required if they do not respond to basic treatment.

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3. Thromboembolic events: Patients with thromboembolic episodes require therapeutic anticoagulation with heparin. 4. Termination of pregnancy: If critical condition does not improve one may consider termination of pregnancy. 5. Laparotomy: Laparotomy is required if the cysts undergo torsion, hemorrhage or rupture. Laparoscopic unwinding can be done in cases of torsion. OHSS is an iatrogenic complication of controlled ovarian stimulation and may sometimes lead to life-threatening complications. Prevention is the best way to manage OHSS. Proper monitoring is essential and a balance between a conservative and aggressive approach is ideal to prevent unnecessary cycle cancelation.

Multiple Pregnancy Multiple pregnancy may occur when ovulation induction is done with clomiphene, GnRH agonists and gonadotropins with an incidence of 5 to 10%, 7 to 10% and 16 to 40%, respectively. The greater relative increase in incidence is more with triplets and quadruplets (58%) compared to twins (18%).29 Multiple pregnancy causes increased incidence of preterm delivery, preeclampsia and abnormal bleeding. Cerebral palsy rates are 0.2% in singleton, 1.2% in twins and 4.5% in triplets. Besides this there may be a social burden on the family in bringing up twins. Fetal reduction is offered if there are triplets or more. Transvaginal sonography guided reduction is done at 8–9 weeks and transabdominally at 11 to 12 weeks with aspiration of the gestational sac or injection of cardiotoxic drug (KCl) into fetus. (see Chapter 13). The contribution of superovulation and ovulation induction to the multiple pregnancy epidemic is substantial.30 Strict guidelines should be followed so as to minimize these multiple births. Close monitoring is essential and presence of no more than 3 mature

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follicles should be there for administration of hCG. Transfer of more than 3 embryos in IVF cycle should be discouraged.

Ovarian Cancer and Ovulation Induction Earlier studies suggested a three times increased risk of ovarian cancer in women who had used ovulation inducing drugs.31 There were reports of increased incidence of ovarian epithelial dysplasia in relation to intake of ovulation induction drugs in women who had later undergone hysterectomy and bilateral oophorectomy.32 It is thought that epithelial inclusion cysts formed at each ovulation are stimulated to undergo malignant transformation by gonadotropins that normally become elevated at menopause. This predicts that agents which provoke multiple ovulation by gonadotropin stimulation will increase the risk of ovarian cancer. An alternative theory is that gonadotropins may not be mutagenic but mitogenic (provoke a pre-existing tumor). It need not be a causal relationship but a stimulation of an already existing lesion. However, reports of large increases in ovarian cancer risk associated with fertility medications have not been replicated by more recent investigations.33 Some studies do report an increased incidence of borderline ovarian tumors.34 This was seen particularly with hMG. The association was not demonstrated with invasive tumors. No significant excess risk was associated with treatment with ovulation induction.35 It should also be kept in mind that cancers are over diagnosed in infertile women because of the close medical surveillance, which may also contribute to the early detection of cancers. However, it has been recommended that these drugs should not be used for more than 6 cycles consecutively and not more than a total of 12 cycles. It is therefore appropriate to use the smallest doses of ovarian stimulation for the shortest duration needed for clinical effectiveness.

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Ovulation induction should be individualized to prevent problems of OHSS and multiple pregnancy. High-risk women should be kept under close surveillance. Women should be counseled about these problems before starting treatment.

References 1. Schenker IG, Weinsyein D. Ovarian overstimulation syndrome: a current survey. Fertil Steril. 1978;30:255-68. 2. Golan A, Ron-elR, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Survey. 1989;44:430-40. 3. Navot D, Bergh PA, Lanfer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril. 1992;58:249-61. 4. Lee TH, Liu CH, Huang CC, Wu YL, Shih YT, Ho HN, et al. Serum anti-mullerian hormone and estradiol levels as predictors of ovarian hyperstimulation syndrome in assisted reproduction technology cycles. Hum Reprod. 2008;23:160-7. 5. Levy T, Orvieto R, Homberg R, Dekel A, Peleg D, Ben-Rafael Z. Severe hyperstimulation syndrome despite low plasma estrogen levels in hypogonadotropic hypogonadal patient. Hum Reprod. 1996;11:1177-9. 6. Cheema P, Gelbaya TA, Horne G, Fitzgerald CT, Pease EH, Brison DR, et al. The optimal length of ‘coasting protocol’ in women at risk of ovarian hyperstimulation syndrome undergoing in vitro fertilization. Hum Fertil (Camb). 2006;9(3):175-80. 7. Moon HS, Joo BS, Moon SE, Lee SK, Kim KS, Koo JS. Short coasting of 1 or 2 days by withholding both gonadotropins and gonadotropinreleasing hormone agonist prevents ovarian hyperstimulation syndrome without compromising the outcome. Fertil Steril. 2008;90(6):2172-8. 8. D’Angelo A,  Brown J,  Amso NN. Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2011;(6):CD002811.

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9. Martínez F, Rodríguez DB, Buxaderas R, Tur R, Mancini F, Coroleu B. GnRH antagonist rescue of a long-protocol IVF cycle and GnRH agonist trigger to avoid ovarian hyperstimulation syndrome: three case reports. Fertil Steril. 2011;95(7):2432.e17-9. 10. Aboulghar M. Agonist and antagonist coast. Fertil Steril. 2012 Mar;97(3):523-6. 11. Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Ross R. Comparison of human chorionic gonadotropin and gonadotropinreleasing hormone agonist for final oocyte maturation in oocyte donor cycles. Fertil Steril. 2007;88(1):237-9. 12. Griesinger G, Diedrich K, Devroey P, Kolibianakis EM. GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. Hum Reprod Update. 2006;12(2):159-68. 13. Engmann L,  Benadiva C. Ovarian hyperstimulation syndrome prevention strategies: Luteal support strategies to optimize pregnancy success in cycles with gonadotropin-releasing hormone agonist ovulatory trigger. Semin Reprod Med. 2010;28(6):506-12. 14. Humaidan P, Kol S, Papanikolaou EG. Copenhagen GnRH Agonist Triggering Workshop Group. Collaborators (14). GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update. 2011;17(4):510-24. 15. Youssef MA,  Van der Veen F,  Al-Inany HG,  Griesinger G, Mochtar MH, Aboulfoutouh I, et al. Gonadotropin-releasing hormone agonist versus hCG for oocyte triggering in antagonist assisted reproductive technology cycles. Cochrane Database Syst Rev. 2011;(1):CD008046. 16. Zhu WJ, Li XM, Chen XM, Zhang L. Follicular aspiration during the selection phase prevents severe ovarian hyperstimulation in patients with polycystic ovary syndrome who are undergoing in vitro fertilization. Eur J Obstet Gynecol Reprod Biol. 2005;122(1):79-84. 17. Youssef MA, Al-Inany HG, Evers JL, Aboulghar M. Intravenous fluids for the prevention of severe ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2011;(2):CD001302. 18. D’Angelo A, Amso N. Embryo freezing for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2007;(3):CD002806.

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19. Lainas T, Petsas G, Stavropoulou G, Alexopoulou E, lliadis G, Minaretzis D. Administration of methylprednisolone to prevent severe ovarian hyperstimulation syndrome in patients undergoing in vitro fertilization. Fertil Steril. 2002;78:529-33. 20. Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Freitas V. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane  Database Syst Rev. 2009;(2):CD006105. 21. Youssef MA, van Wely M, Hassan MA, Al-Inany HG, Mochtar M, Khattab S, et al. Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis. Hum Reprod Update. 2010;16(5):45966. 22. Sherwal V, Malik S, Bhatia V. Effect of bromocriptine on the severity of ovarian hyperstimulation syndrome and outcome in high responders undergoing assisted reproduction. J Hum Reprod Sci. 2010;3(2):85-90. 23. Busso C,  Fernández-Sánchez M,  García-Velasco JA,  Landeras J,  Ballesteros A,  Muñoz E,  et al. The non-ergot derived dopamine agonist quinagolide in prevention of early ovarian hyperstimulation syndrome in IVF patients: a randomized, doubleblind, placebo-controlled trial. Hum Reprod.  2010;25(4):9951004. 24. Olivennes F. Ovarian hyperstimulation syndrome prevention strategies: individualizing  gonadotropin  dose. Semin Reprod Med. 2010;28(6):463-7. 25. Huang JY,  Chian RC,  Tan SL. Ovarian hyperstimulation syndrome prevention strategies: in vitro maturation. Semin Reprod Med. 2010;28(6):519-31. 26. Lainas TG,  Sfontouris IA,  Zorzovilis IZ,  Petsas GK,  Lainas GT,  Alexopoulou E,  et al. Live births after management of severe OHSS by GnRH antagonist administration in the luteal phase. Reprod Biomed Online. 2009;19(6):789-95. 27. Lainas TG,  Sfontouris IA,  Zorzovilis IZ,  Petsas GK,  Lainas GT,  Kolibianakis EM. Management of severe early ovarian hyperstimulation syndrome by re-initiation of GnRH antagonist. Reprod Biomed Online. 2007;15(4):408-12.

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28. Alvarez C, Martí-Bonmatí L, Novella-Maestre E, Sanz R, Gómez R, Fernández-Sánchez M, et al. Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction. J Clin Endocrinol Metab. 2007;92(8):2931-7. 29. Hecht BR. The impact of assisted reproductive technology on incidence of multiple gestation. In Keith LG, Papiernik E’Keith DM, Luke B (Eds). Multiple Pregnancy London: Parthenon. 1995;175-90. 30. Legro RS. Superovulation and  multiple  birth: in search of kryptonite. Fertil Steril. 2012;97(4):793-4. 31. Whittemore AS, Harris R, Itnyre J, Halpern J. Characteristics related to ovarian cancer risk: collaborative analysis of 12 US case controlled studies. I Methods. Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992;136:1175-83. 32. Nieto JJ, Crow J, Sundaresan M, Constantinovici N, Perrett CW, MacLean AB, et al. Ovarian epithelial dysplasia in relation to ovulation induction and nulliparity. Gynecol Oncol. 2001;82(2):344-9. 33. Brinton LA, Moghissi KS, Scoccia B, Westhoff CL, Lamb EJ. Ovulation induction and cancer risk. Fertil Steril. 2005;83(2):26174. 34. Ayhan A, Salman MC, Celik H, Dursun P, Ozyuncu O, Gultekin M. Association between fertility drugs and gynaecologic cancers, breast cancer, and childhood cancers. Acta Obstet Gynecol Scand. 2004;83(12):1104-11. 35. Calderon-Margalit R,  Friedlander Y,  Yanetz R,  Kleinhaus K,  Perrin MC,  Manor O,  et al. Cancer  risk after exposure to treatments for  ovulation induction. Am J Epidemiol. 2009;169(3):365-75.

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cHAPTER

18

Selective Multifetal Pregnancy Reduction Shweta Mittal, Deepak Chawla, Abha Majumdar

The incidence of multifetal pregnancies has increased dramatically over the past two decades, mainly because of the widespread use of ovulation induction agents and assisted reproduction techniques.1 These techniques have been a matter of concern since twin and higher order pregnancies have long been associated with an increased risk of maternal complications as well as a high prevalence of perinatal and neonatal morbidity and mortality. The most common complication is preterm delivery, with twins having an average gestational age at delivery of 36 to 37 weeks; triplets, 34 weeks; quadruplets, 29 to 31 weeks, and quintuplets, even earlier. In addition, researchers have shown an increased incidence of low birth weight, gestational diabetes mellitus, pregnancy-induced hypertension and greater requirement of neonatal hospital admission with multifetal pregnancy. A couple has several options when faced with a multifetal pregnancy.

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1. They can electively terminate the multifetal pregnancy with the intent to conceive again. Since the pregnancy is most likely wanted, achieved at great psychological and economic cost and with no guarantee of future con­ ceptions, this option is usually the least desirable. 2. The couple can attempt to proceed with the pregnancy. Even though there are reports of survival of some or all quadruplets and quintuplets, there is still significant risk of long-term morbidity. Survival with six or seven fetuses, although reported, is extremely rare. There are no reports of any fetal survivals with eight or more fetuses. 3. The couple can choose multifetal pregnancy reduction. Selective fetal reduction in triplets is still controversial. The procedure of multifetal pregnancy reduction (MFPR) has, in recent years, become both clinically and ethically accepted as a therapeutic option in pregnancies with four or more fetuses, and in multifetal pregnancies in which one or more of the fetuses has congenital abnormalities.2 MFPR results in better pregnancy outcome, regardless of the initial number of fetuses.3 In a study of IVF-conceived triplets, selective reduction of the pair to a singleton pregnancy  was associated with a significantly greater likelihood of delivery at ≥34 weeks. On average, reduction of the pair was associated with 52 days longer gestation.4 The pregnancy loss subsequent to fetal reduction has been reported as ranging from 0 to 40%.

Methods of Multifetal Pregnancy Reduction5 • Transcervical aspiration of the gestational sac • Transvaginal puncture and embryo aspiration • Intrathoracic injection of potassium chloride, by both transabdominal and transvaginal approaches.

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Transcervical Aspiration Some authors have used transcervical aspiration of the gestational sac. This method, however, was thought to be associated with an increased incidence of fetal loss due to infection caused by introduction of bacteria from the cervix, or due to cervical incompetence brought about by cervical dilatation.

Transvaginal Puncture and Embryo Aspiration Fetal reduction very early in gestation (6 to 8 weeks) by the transvaginal puncture and embryo aspiration has also been reported with fairly good pregnancy outcome.6 However, this method might have some theoretical limitations, such as: a. Use of general anesthesia. b. Possibility of spontaneous fetal reduction at this stage of gestation. c. Inability to perform early fetal screening, such as nuchal translucency test which is done at 10 to 12 weeks of gestation. d. Possibility of introducing infections. Intrathoracic Injection of Potassium Chloride by Transabdominal and Transvaginal Approach Multifetal pregnancy reduction using intrathoracic injection of potassium chloride, by both the transabdominal and the transvaginal approaches, has been reported. No method has yet been proven to be superior to the others. Although several techniques of multifetal pregnancy reduction have been reported, the most popular is however the intrathoracic injection of potassium chloride by the transabdominal approach at 10 to 12 weeks gestation. It is logical to perform a detailed ultrasonographic fetal anomaly

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scan prior to the reduction (Fig. 18.1). This will allow the reduction to be performed more selectively and will decrease the chance of delivery of a chromosomal or structurally abnormal fetus. Intracranial Injection of Potassium Chloride In certain cases of MFPR, where difficulty is encountered in reaching the thorax due to the fetal position as well as the location of membranes and placenta, an alternative approach may be the insertion of the needle to the fetal cranium. This approach enables a technically easier procedure than the intrathoracic approach. However, the use of this technique should be reserved for selected cases of MFPR only by experienced operators and centers.7

Pre-procedural Preparation 1. Counseling of the couple regarding the procedure and its possible complications. 2. Informed written consent. 3. Prophylactic antibiotic administration. 4. Patient may be admitted for a day in the hospital.

Fig. 18.1: USG showing triplets

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Transvaginal Procedure of Fetal Reduction8 This procedure is done between 8 and 9 weeks of gestational age under general anesthesia. Strict aseptic conditions should be maintained throughout the procedure. Patient is placed in dorsal lithotomy position. Cleaning of vagina is done with povidone iodine solution. Needle guide is attached to the transvaginal probe. Begin with transvaginal ultrasound examination of all the fetuses. Choose the correct path of the needle avoiding the path of the blood vessels. A 35 cm 18 gauge needle with a stylet is introduced through a guide and advanced through the vaginal wall, uterine wall into the fetal sac. The stylet is removed and a 21 gauge needle 40 cm long is introduced into the fetal thorax. 2 ml of 2 mEq of potassium chloride is injected. Fetal asystole is observed and needle is removed.

Transabdominal Procedure of Fetal Reduction5 This procedure is performed between 10 and 12 weeks of gestational age, under local anesthesia. Prior to the procedure ultrasound examination of all the fetuses is performed (Figs 18.2 and 18.3; See accompanying interactive CD-Rom).

Fig. 18.2: Ultrasound machine

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Fig. 18.3: Ultrasound showing triplets before the procedure

Abdomen is prepared with povidone iodine solution. Fetus nearest to the ultrasound probe is selected (Fig. 18.4). Spinal needle no. 21 with stylet is advanced through the abdominal and uterine wall into the fetal sac. Stylet is removed (Fig. 18.5). Syringe is loaded with 2 ml of 2 mEq potassium chloride (Fig. 18.6).

Fig. 18.4: Selection of fetus nearest the ultrasound probe

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Fig. 18.5: Insertion of needle

Fig. 18.6: Loading of syringe

The needle is visualizing on ultrasound and advanced into the fetal thorax (Fig. 18.7). After the needle is advanced in the fetal thorax potassium chloride is injected. Needle is removed after confirming fetal cardiac asystole (Fig. 18.8). Cardiac activity of other fetus is confirmed. Post-procedural second look ultrasound is done after few hours and another scan a few days later.

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Fig. 18.7: Visualization of needle tip

Fig. 18.8: Injection of intrathoracic potassium chloride

Complications 1. Leaking per vaginum. 2. Bleeding per vaginum. 3. Abortion or loss of remaining fetuses. 4. Infection.

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Advantages of Transvaginal Procedure Feasibility of the procedure at an earlier gestational age. However, the physician should be familiar with the procedure before applying it for routine use. Advantages of Transabdominal Route 1. A more detailed USG of the fetuses can be performed and nuchal thickness can be assessd as it is measured between 10 and 12 week gestational age. 2. Chances of spontaneous reduction of multifetal pregnancy is ruled out. 3. Lower risk of infection. No decision in a high-order-multiple pregnancy is easy, and parents may under­standably review their choices for years afterward, wondering if they should have chosen differently.

References 1. Gonen R, Heyman E, Asztalos EV, Ohlsson A, Pitson LC, Shennan AT, et al. The outcome of triplet, quadruplet and quintuplet pregnancies managed in a perinatal unit: obstetric neonatal and follow-up data. Am J Obstet Gynecol. 1990;162:454-9. 2. Berkowitz RL, Lynch, L, Chitkara U, Wilkins IA, Mehalek KE, Alvarez E. Selective reduction of multifetal pregnancies in the first trimester. N Engl J Med. 1988;318:1043-7. 3. Antsaklis A, Anastasakis E. Selective reduction in twins and multiple pregnancies. J Perinat Med. 2011;39(1):15-21. 4. Skiadas CC, Missmer SA, Benson CB, Acker D, Racowsky C. Impact of selective reduction of the monochorionic pair in in vitro fertilization triplet pregnancies on gestational length. Fertil Steril. 2010;94(7):2930-1. 5. Wapner RJ, Davis GH, Johnson A, Weinblatt VJ, Fischer RL, Jackson LG, et al. Selective reduction of multifetal pregnancies. Lancet. 1990;335:90-3.

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6. Mansour RT, Aboulghar MA, Serour GI, Sattar MA, Kamal A, Amin YM. Multifetal pregnancy reduction: modification of the technique and analysis of the outcome. Fertil Steril. 1999;71(2):380-4. 7. Lembet A, Selam B, Bodur H, Ergin T, Demirel C. Intracranial injection with KCl: an alternative method in selected cases of multifetal pregnancy reduction. Fetal Diagn Ther. 2009;26(3):134-6. 8. Shalev J, Frenkel Y, Goldenberg M, Shalev E, Lipitz S, Barkai G, et al. Selective reduction in multiple gestations: pregnancy outcome after transvaginal and transabdominal needle-guided procedures. Fertil Steril. 1989;52:416-20.

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cHAPTER

19

Ultrasonography and Color Doppler Imaging in Ovulation Induction Reeti Sahani

Reproductive organs of a woman during her fertile years shows daily changes which are very diverse. They can easily be viewed and assessed with modern imaging techniques such as sonography and color Doppler imaging.

Examination Technique Sonographic examination of the female pelvic organs is the most commonly performed using the following approaches: 1. Transabdominal (TAS). 2. Transvaginal (TVS). 3. Transperineal (less frequently). A thorough ultrasound examination of the pelvis should include both complete transabdominal and transvaginal studies. The techniques are complementary, not mutually exclusive unless limited information is needed (e.g. follicle size) or extenuating circumstances dictate otherwise (e.g. patient refusal).

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Ovaries The ovaries are generally situated on either side of the uterus. A search along the internal iliac artery would most often find the ovary located anterior to the vascular bifurcation into anterior and posterior branches. The blood supply is from the ovarian artery and branches of uterine artery (Figs 19.1A and B).

Figs 19.1A and B: Ovarian artery

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Uterus Uterus receives its supply via the uterine artery, a branch of the internal iliac artery. From the uterine artery arise perforating branches, which extend through the serosa. Endometrium in midcycle has a triple layered appearance (Figs 19.2A and B). It derives its supply from arcuate branches of the uterine arteries. Radial arteries, branch of arcuate arteries, extend through the myometrium to just outside the endometrium (Fig. 19.3) where they form terminal branches of two types: straight and coiled. The straight branches (basal arteries) supply the basalis layer of the endometrium. The coiled bran­ ches (spiral arteries) traverse the endometrium and supply the functionalis layer.

Figs 19.2A and B: Typical triple layer endometrium

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Fig. 19.3: Endometrial vascularity

Color Doppler Imaging (CDI) Purpose of CDI • • •

Identify cyclical endometrial and follicular neovascularity followed by regression in neovascularity. Determine changes in vascularity. Quantify blood flow.

Indices used for Quantifying in CDI • • •

Resistive index. Pulsatility index. SD ratio.

CDI in Ovarian Physiology and Cycle Changes The ovarian arterial supply exhibits different flow characteristics during the different phases of a normal menstrual cycle (Fig. 19.4). These phases are: • Early follicular phase index values of arteries are relatively high (days 5–7).

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Fig. 19.4: Resistance ovarian waveform pattern

• • •

Late follicular phase index values (days 11–13) are high. Early luteal phase index values (days 15–17) are low. Late luteal phase index values (days 26–28) rise. The variations are believed to be hormone related and reflect changes in vascular compliance.1 Ovarian artery blood flow is detectable when the dominant follicle reaches a size of 12 to 15 mm. The resistance index (RI) is 0.54 ± 0.04 and declines the day before ovulation (Fig. 19.5). Moderate RI value of 0.55 and increased flow velocity in subendometrial vessels indicate favorable uterine receptivity (Fig. 19.6).

Fig. 19.5: Low resistance pattern

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Fig. 19.6: Blood flow velocity waveforms of the sub-endometrial vessels on the day of ET

During ovarian stimulation, the waveform and index value differences normally noted between the two ovaries may be absent. Bilaterally, the ovarian arterial blood supply may demonstrate pulsatility waveforms typical of low impedance. During the stimulation process, ultrasound has its greatest contribution in monitoring follicular development and guiding the oocyte harvesting procedure. Gray­scale evaluation of ovarian follicles can help distinguish physiologic from insufficient or abnormal cycles according to the growth of the follicle. Transvaginal color Doppler can be employed to assess the physiologic development of the follicles through depiction of flow parameters2 (Figs 19.7 to 19.9). Four grades of perifollicular flow on color Doppler are seen (Table 19.1). a. Normal blood flow surrounding a corpus luteum around entire periphery. In real­time imaging, virtually the entire corpus luteum displayed color flow (Fig. 19.7A). b. Normal blood flow surrounding a corpus luteum (90%) (Fig. 19.7B). c. Moderate 50% perifollicular flow (Fig. 19.7C). d. More than 75% perifollicular flow (Fig. 19.7D).

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Figs 19.7A to D: Corpus luteal flow

Fig. 19.8: Normal robust flow

Optimal stromal artery flow in the ovary has also been assessed. The peak systolic velocity should be more than 10 cm/sec for a good pregnancy rate (Table 19.2). 3D ultrasound is much more accurate for volume assessment of the follicle. Presence of cumulus increases the surety of the presence of a mature ovum in the follicle.

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Fig. 19.9: Abnormal anemic flow

Table 19.1: Optimal perifollicular flow CDI/power Doppler to assess follicle circumference vascularization 1.

Grade 1

< 25%

2.

Grade 2

25–50%

3.

Grade 3

50–75%

4.

Grade 4

> 75%

•

Peak systolic velocity > 10 cm/sec

•

Pulsatility index—is not indicative

•

Resistive index is not indicative except for hyperstimulation (RI < 0.48)

Table 19.2: Optimal stromal artery flow

3D US and 3D PD when used with 2D US and color Doppler for pre-hCG follicular assessment would definitely improve pregnancy rates in IUI cycles.3

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CDI in Uterine Physiology The uterine vessels examined during the cycle are the uterine artery, spiral artery and vessels at the endomyometrial junction to note the following:4 • Proliferation of spiral arteries • Growth of spiral arteries toward the endometrium • Increased vascularity in the endometrium • Increased flow in the main uterine arteries. Uterine Artery The general pattern of uterine blood flow throughout the menstrual cycle is that perfusion increases in response to rising plasma estrogen and progesterone and decreases with the periovulatory fall in estrogen.5 The lowest pulsatility index (PI) values are seen around days 8 and 21, while the highest values are seen around days 1, 14 and 17. Significant changes in diastolic blood flow at the different times of the cycle may not be noted. In general; the index values for the uterine artery ipsilateral to the ovary containing the dominant follicle are lower than the contralateral artery (Figs 19.10 and 19.11). Other patterns of uterine artery blood flow have been described. When the uterine arteries were interrogated at the level of the uterine cornua, the PI reached its peak by day 11 and remained relatively constant until day 16. The lowest values were generally seen around days 1 and 21. At this anatomic level, end-diastolic flow was commonly absent during the early follicular phase (Fig. 19.12) but it was demonstrable by the luteal phase. The cyclical changes reflected by the flow velocity waveforms and index values appear to be mediated by the reproductive hormones. The baseline evaluation (pre­ treatment) demonstrated a narrow systolic spectral flow pattern with a mean PI of 5.2 ± 0.4. Evaluations performed

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Fig. 19.10: Doppler waveform of uterine artery ipsilateral to dominant follicle ovary

Fig. 19.11: Doppler waveform of uterine artery contralateral to dominant follicle ovary

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Fig. 19.12: Near absent end-diastolic flow during follicular phase

on days 13–14, showed a spectral tracing that was broader with an uninterrupted diastolic component. The mean PI was 1.5 ± 0.2. On days 26 to 27, no significant differences were noted (mean PI = 1.7 ± 0.3).6,7 Uterine artery RI is given a score of 0–48 (Table 19.3). Endometrium Endometrial morphology: In preparation for implantation, the endometrium undergoes transformations by increased blood Table 19.3: Optimal uterine artery RI score RI

Score

< 0.7

4

0.7–0.8

2

> 0.8

0

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flow and uterine oxygen consumption. The cells in the stroma and epithelium increase and there is a generalized edema. The endometrium and periendometrial area is divided into 4 zones (Table 19.4). These zones give it the typical preovulatory triple line appearance that is an indicator of good uterine receptivity (Fig. 19.13). Endometrial vascularity: Endometrial zonal neovascularity is of prime importance for embryo transfer and is determined at the following levels: • Subendometrial • Basal • Mid zone • Inner layer. The spiral arteries, like the endometrium, are remarkably responsive to the hormonal changes occurring in the menstrual cycle. These include:9 Table 19.4: The endometrial and periendometrial areas have the following four zones •

Zone 1

2 mm thick area surrounding the hyperechoic outer layer of the endometrium

•

Zone 2

The hyperechoic outer layer of the endometrium

•

Zone 3

The hypoechoic inner layer of the endometrium

•

Zone 4

The endometrial cavity

Fig. 19.13: Triple layer endometrial thickness

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• •

Endothelial proliferation Wall thickening and coiling. These vessels play an important role in implantation. The chances for a normal implantation may be reduced if the spiral arterioles are inadequately developed. It is possible to see variations in the depth of vascular penetration before, during and after the mid­cycle. In patients with uterine artery PIs of more than 3.0, preliminary results have not revealed any successful pregnancies in IVF patients unless there is vascularity demonstrated either within zone 3 or within zones 3 and 4 prior to transfer10 (Figs 19.14A and B, and 19.15).

Figs 19.14A and B: Normal zone 3 blood flow is demonstrated on this endovaginal image

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Fig. 19.15: Vascular penetration on power Doppler to zone 4

An optimal score based on imaging vascularity taking into consideration number of vessels and endometrial power Doppler area, is used for assessment (Table 19.5 and Fig. 19.16). The color Doppler findings in unsuccessful cycles may relate to the histologic findings. A majority demonstrated an immature endometrium at the time of embryo transfer. The abnormalities included a variety of patterns, all indicating a lack of secretory transformation, suggesting poor endometrial receptivity for implantation.11 Endometrial thickness (ET): Thickness of endometrium is also important for implantation. Less than 7 mm gives a poor pregnancy rate (Table 19.6). Table 19.5: Optimal endometrial score and vascularity quantification Characteristic •

•

Scoring

Number of vessels 3 and above

Score of 3

1–3

Score of 2

Absent

Score of 0

Endometrial power

Score of 4

Doppler area of > 5 mm sq •

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Fig. 19.16: Imaging in optimal endometrial score

Table 19.6: Optimal endometrial score ET

Score

•

< 7 mm

0

•

10–11 mm

2

•

12 mm and above

3

In cycles resulting in pregnancy, mean endometrial thickness was higher compared to cycles with negative outcomes. Higher serum estradiol is associated with higher endometrial thickness and pregnancy rates. Women achieving pregnancy and pregnant women with endometrium thicker than 9 mm were younger. Follicle stimulation was better with higher endometrial thickness. After adjustments for age, no statistical difference was found in endometrial thickness between agonist and antagonist protocols.12 Endometrial volume on 3D ultrasound: With the 3D ultrasound being used to assess endometrial receptivity, the volume estimation of endometrium is done. The endometrial volume was measured by area tracing from the fundus to the internal cervical os in a number of parallel slices 1 to 2 mm apart. An ideal volume is 2–7 mL (Fig. 19.17).13

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Fig. 19.17: Endometrial volume on 3D ultrasound

Ultrasonographic Scoring of Uterine Receptivity A scoring system for endometrial receptivity has been done taking into account endometrial thickness, pattern and vascularity. It also includes the appearance of myometrium (Table 19.7). Another score was devised for patients undergoing IVF to assess the uterine receptivity (Table 19.8). The maximum score was 7 and the cut­off value was 5. Table 19.7: Scoring system for uterine receptibity Uterus

Nature

Score

Nature

Score

ET

>7

4

3

0

End-diastolic flow

Present

4

Absent

0

Endometrial vascularity

Present

3

Absent

0

Total score

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20

0

0

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Table 19.8: Two-dimensional ultrasonographic scoring system for evaluation of uterine receptivity in patients undergoing IVF-ET procedures11 Characteristic

Score

Endometrial thickness, mm 6–8

0

9–14

2

>15

1

Endometrial morphology Triple line

0

Homogenous hyperechoic

2

Hypoechogenic with hyperechogenic borders

1

Sub-endometrial blood flow (RI) Absent

0

>0.55

1

=0.55

3

Maximum score*

7

*The cut­off value was 5.

Scoring on evaluation of 3D ultrasonography of endometrium included endometrial volume, vascularity and morphology. The maximum score was 7 with a cut­off score of 5 (Table 19.9).

Comparison of 3D and 2D Ultrasonography for Assessment of Endometrial Receptivity On comparing the sensitivity, specificity, positive predictive value, negative predictive value and efficiency of the 2D and 3D ultrasound assessment of endometrial receptivity no significant difference was found (Table 19.10).

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Table 19.9: Three-dimensional ultrasonographic scoring system for evaluation of uterine receptivity in patients undergoing IVF-ET procedures11 Characteristic

Score

Endometrial volume, mL 7

1

Endometrial morphology Triple line

0

Homogenous hyperechogenic

2

Hypoechogenic with hyperechogenic borders

1

Sub-endometrial blood flow (FI) 15

1

Maximum score*

7

*The cut­off value was 5

Table 19.10: Comparison between 2D and 3D ultrasonographic scoring systems in the assessment of endometrial receptivity in patients undergoing IVF-ET procedures11 Ultrasonographic

Sensitivity%

Specificity%

PPV%

NPV%

Efficiency%

2D cD

97.0

41.0

64.0

92.6

70.1

3D PD

97.0

39.3

63.7

92.3

69.5

NPV indicates negative predictive value; PPV, positive predictive value; 2D cD, 2D color Doppler ultrasonography; 3D PD, 3D power Doppler ultrasonography.

Ultrasonography and color Doppler imaging can help to predict the success rates in assisted reproduction (Table 19.11).

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•

Endometrium—Triple layer appearance and 12 mm thickness

•

Endometrial power Doppler area > 5 mm sq

•

Myometrium appears homogenous

•

Uterine artery PI < 3

•

Uterine artery end-diastolic flow present

•

Perifollicular circumfrential vascularity > 75%

•

Ovarian stromal arteries—PSV > 10 cm/sec

Ultrasound imaging of the female pelvis has helped us to understand, identify, diagnose, treat and manage the infertile patient. The endovaginal scanning and Doppler imaging has enabled us to extend our evaluation further. It is now possible to perform a sonographic physiologic assessment of the structures we visualize.

References 1. Fleischer Ac, Kepple DM, Vasquez J. conventional and color Doppler transvaginal sonography in gynecologic infertility. Radiol Clin North Am. 1992;30:693-702. 2. Fleischer AC, Daniell JF, Rodier J, Lindsay AM, James AE Jr. Sonographic monitoring of ovarian follicular development. J Clin Ultrasound. 1981;9:275-80. 3. Panchal S, Nagori cB. Pre­hcG 3D and 3D power Doppler assessment of the follicle for improving pregnancy rates in intrauterine insemination cycles. J Hum Reprod Sci. 2009 Jul;2(2):62-7. 4. Kurjak A, Kupesic-Urek S, Schulman H, Zalud I. Transvaginal color flow Doppler in the assessment of ovarian and uterine blood flow in infertile women. Fertil Steril. 1991;56:870-73. 5. Steer cV, campbell S, Pampiglione JS, Kingsland cR, Mason BA, Collins WP. Transvaginal color flow imaging of the uterine

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6.

7.

8.

9.

10. 11. 12.

13.

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arteries during the ovarian and menstrual cycles. Hum Reprod. 1990;5:391­5. Steer CV, Campbell S, Tan SL, Crayford T, Mills C, Mason BA, et al. The use of transvaginal color flow imaging after in vitro fertilization to identify optimum uterine conditions before embryo transfer. Fertil Steril. 1992;57:372-6. Sterzik K, Grab D, Sasse V, Hütter W, Rosenbusch B, Terinde R. Doppler sonographic findings and their correlation with implantation and in an in­vitro fertilization program. Fertil Steril. 1989;52:825-28. Friedler S, Shenker JG, Herman A, Lewin A. The role of ultrasonography in the evaluation of endometrial receptivity following assisted reproductive treatments: a critical review. Hum Reprod. 1996;2:323-35. Fleischer AC. Ultrasound imaging—2000: Assessment of utero-ovarian blood flow with transvaginal color Doppler sonography; potential clinical applications in infertility. Fertil Steril. 1991;55:684-91. Applebaum M, Cadkin AV. Decidual flow—an early sign of pregnancy. Ultrasound Obstet Gynecol. 1992;2:65. Fleischer Ac, Gordon AN, Entman SS, Kepple DM. Transvaginal scanning of the endometrium. J Clin Ultrasound. 1990;18:33749. Giannaris D, Zourla A, chrelias c, Loghis C, Kassanos D.Ultrasound assessment of endometrial thickness: correlation with ovarian stimulation and pregnancy rates in IVF cycles. clin Exp Obstet Gynecol. 2008;35(3):190-3. Kurjak A, Zalud I. Transvaginal color Doppler in the study of uterine perfusion. In: Mashiach S, Ben-Rafael Z, Laufer N, Schenker JG (Eds). Advances in Assisted Reproductive Technologies. New York: Plenum Press. 1990;541­4.

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Index Page numbers followed by f refer to figure and t refer to table

A Abdominal cramps 180 distension 279 girth measurement 289 Abdominopelvic discomfort 25 Abnormal anemic flow 317f Abortion 152, 306 Absence of corpus luteum 263 Acanthosis nigricans 118 Acarbose 39, 125 Accuracy of test 8 Acid-base balance 289 Acne 118 Addison’s disease 159 Adenoma with stalk compression 172 Adjunctive use of nitric oxide 217, 224 Adnexal torsion 281 Adrenal function assessment 17 Advantages of GnRH agonists 78 antagonists over GnRH agonist in ART 85 pulsatile therapy 165 ovarian reserve testing 209 recombinant FSH 63 transabdominal route 307

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transvaginal procedure 307 vaginal administration 267 Amenorrhea 4, 158, 163, 173, 177, 181 Amitryptilene 172 Amount of ascites 289 Amoxapine 172 Anastrazole 34 Androgen receptor expression 189 Anovulation and tests for ovulation 1 Antagonizing androgens 119 Anti-Müllerian hormone 191, 205 tailored protocols 53 Antiphospholipid syndrome 234 Antipsychotic drugs 177 Antral follicle count 204, 207, 207t, 216 Appearance of ovary after drilling 147f Aromatase inhibitors 34 Ascitis 291 Aspiration of single lead follicle 110 Aspirin 217, 225, 250 Assessment of ovarian reserve 203 Atresia 12

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hypogonadotropic hypogonadism 156f poor ovarian response 215t Basal anti-Müllerian hormone 283 CC challenge test 216 Central retinal vein occlusion 23 body temperature 4, 263 follicle stimulating hormone Cerebral radiotherapy 2 levels 203, 204, 204t Cervical mucus 22 ovarian stromal blood Chemotherapy 203 flow 207 Chest Bilateral polycystic ovaries 145f wall stimulation 171 Bleeding per vaginum 306 X-ray 289 Blood Choice and dose of gases 289 gonadotropin 52t tests 204 Chromohysteroscopy 245 Blunting of hepatic Chronic gluconeogenesis 122 endometritis 242, 243, 243f Body mass index 4 nonspecific endometritis 242 Bone mineral density 158 renal failure 172 Breast Cimetidine 172 cancer 62, 118 Cirrhosis 172 discomfort and bloating 23 Clomiphene 14, 20, 21, 27, Bright echogenic stroma 115 128, 266 Bromocriptine 37, 128, 129, and gonadotropin regime 41f 179, 183, 287 challenge test 208 Buserelin 72 citrate 9, 14, 127, 128, 271 Butyrophenones 172 challenge test 204 failure 31 C in mild stimulation protocol 60 Cabergoline 182, 183 resistance 31, 52 Calcium channel blockers 172 therapy 16 CAM therapy 217 with gonadotropins and Causes of GnRH antagonist 43f anovulation 282 suitable for ovulation with single dose FSH 60 induction treatment 2t Colony-stimulating factor 237

B

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Index  Color and pulsed Doppler ultrasound 264 Doppler imaging 312 Combined oral contraceptive pills 225 Complications of ovulation induction 276 Congenital adrenal hyperplasia 2 malformations 24 uterine abnormalities 234 Constipation 180 Corpus luteal flow 316f Correction of circulatory volume electrolyte imbalance 291 Correlation of number of oocytes recovered with pregnancy rate 95 Corticotropin releasing hormone 238 stimulation test 159 Craniopharyngioma 2, 171 Creatinine 279 Cryopreservation 98 of embryo 211, 226, 286 of oocyte 211, 226 Cumulative conception rate 20 pregnancy rate 98 Cushing’s syndrome 135, 159 Cyproterone acetate 135 Cystectomy 203 Cytokines 236

Index.indd 333

333

D Danazol 9 D-chiroinositol 39, 126 Decidual prolactin measurement 263 Decreased renal function 279 SHBG 119 Dehydroepiandrosterone 189 sulfate 135 Dehydrogesterone 268 Delayed puberty 173 Dendritic cells 239 Determination of ovarian tissue 17 Development of GnRH antibodies 165 Dexamethasone suppression test 159 Diabetes insipidus 185 mellitus 118 Diminished ovarian reserve 189, 190, 215 Dizziness 25, 180 Dominant follicle ovary 319f Donor oocytes 217 Dopamine 292 agonists 37, 182, 287 receptor blockers 172 synthesis inhibitors 172 Dose of clomiphene 20 FSH 94

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334 

Step by Step Ovulation Induction

Drainage of hydrosalpinx 252 Drug-induced hypersecretion 172 Dynamic tests 204 Dysgerminoma 171 Dyslipidemia 118 Dysparenia 173

E Early follicular phase estradiol levels 205 inhibin B levels 205 Elevated circulating androgens 262 Emotional stress 101 Empty sella syndrome 172 Endometrial aspiration 246 biopsy 9, 126, 246, 263 carcinoma 118 growth 22 hyperplasia 25 lymphocytes 242 morphology 326, 327 polyps 25 power 323 thickness 27, 247, 323, 326 vascularity 312f, 321 volume 324, 327 Endometriosis 234, 262 Endometritis 234 Endometrium 320, 328 Endothelial proliferation 322 Epidermal growth factor 236 Epileptic seizures 172

Index.indd 334

Estrogen 249 deficiency 173 replacement therapy 183 Evaluation of male partner 16 Exogenous FSH ovarian reserve test 204, 209 gonadotropin stimulation 203 hCG 9 Extended lithotomy position 145f

F Failure of medical therapy for ovulation induction 142 Fasting blood sugar 118 insulin levels 118 serum insulin 41 Fatigue 180 Flexible antagonist protocol 109 Fluid in cul-de-sac 11 Flutamide 136 Focal or diffuse hyperemia 244 Follicle aspiration 286 stimulating hormone 3, 51, 159, 188 Free androgen index 119 Functional hypothalamic chronic anovulation 159

G Galactorrhea 173, 177, 181 Glucocorticoids 34, 128, 129, 217, 224

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Index  Glucose tolerance test 118 GnRH agonist 36, 42, 71, 80, 128, 131, 133, 136, 221 for ovulation trigger 79 in luteal phase 270 pulsatile therapy 164f therapy 163 GnRHa stimulation test 208 Golan’s classification 277 of OHSS 278t Goldmann’s perimetry 176 Gonadotropin 41, 50, 130, 217, 250 releasing hormone 86 analog 76 challenge test 158 stimulation 288 therapy 128, 159 Grades of severity of hypothalamic amenorrhea 157t Granulomas 172 Granulosa cells 215 of primordial follicles and follicles 188 Grasping of ovarian ligament 146f Growth hormone 223 replacement 163

H Hair loss and dryness 23 Hallucinations 180

Index.indd 335

335

Hashimoto’s thyroiditis 234 Headache 23, 25, 180 Hematoma 165 Hepatic dysfunction 81 High dose of gonadotropins 210, 218 Highly purified human menopausal gonadotropin 53 Hormonal control of endometrial preparation 234 evaluation 246 Hormones 172 Hot flushes 23, 25 Human chorionic gonadotropin 35, 51, 66, 268 menopausal gonadotropin 219, 50, 266, 272 pituitary gonadotropin 50 Hydrothorax 289 Hydroxyethyl starch administration 286 Hypergonadotropic hypogonadism 1 Hyperinsulinemia 133 in polycystic ovarian syndrome 117f Hyperplasia of lactotrophs 172 Hyperprolactinemia 2, 170, 173, 174f, 177, 262 Hyperstimulation syndrome 62 Hypertension and cardiovascular disease 118 Hypoglycemia 123

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336 

Step by Step Ovulation Induction

Hypogonadotropic hypogonadism 1, 2, 52, 53, 155, 156, 158, 159t, 161, 166 and ovulation induction 155 Hypophysectomy 2 Hypotension 291 Hypothalamic pituitary dysfunction 1 failure 1, 16 stalk damage 171 Hypothalmic disorders 155 Hypothyroidism 2, 159, 172 Hysteroscopy 246, 249

Intravenous immunoglobulins 251 Invasive hemodynamic monitoring 289 Irregularity of follicle 11

K Kallmann syndrome 2 Ketoconazole 136 Kidney function tests 289

L

Laparoscopic evaluation of pelvis 142 ovarian drilling 42, 128, 131 I Laparotomy 293 Idiopathic hyperprolactinemia 173 Large granular lymphocytes 239 L-arginine 251 Imipramines 172 Late Induction of ovulation 177 follicular phase index Infertility 118 values 313 Injection of intrathoracic luteal phase index values 313 potassium chloride 306f Leaking per vaginum 306 Insertion of needle 305f Letrozole 25, 27, 34, 217, Insulin 226, 250 resistance 115 Leukemia inhibitory factor 237 sensitizers 38, 121, 128 Leukocyte immunotherapy 251 sensitizing drugs 128 Leuprolide 72 Intolerable nausea and Liver vomiting 291 disease 16 Intracranial injection of dysfunction 281 potassium chloride 302 enzymes 279 Intramuscular depot function tests 17, 289 injections 73 toxicity 25 Intranasal route 73 Loading of syringe 305f Intrathoracic injection of Long-acting depot intramuscular potassium chloride injection 179 300, 301

Index.indd 336

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Index 

337

Loss of remaining fetuses 306 Low dose of gonadotropin 59 oral contraceptive pills 133 estradiol levels 157 gonadotropins 157 ovarian stimulation protocols 288 progesterone levels in luteal phase 264 resistance pattern 313f Lubeck protocol 81, 81f Lupus erythematosis 234 Luteal estradiol 217, 225 initiation of FSH 219 phase defect 16, 260 support 252, 286 serum progesterone levels 6 supplementation 282 support 85, 283 Lutein cyst formation 263 Luteinized unruptured follicle 12, 263 Luteinizing hormone 3, 41, 106 Lymphocytic hypophysitis 172

Management of ascitis 292 clomiphene failure 32 resistance 44f hyperprolactinemia 177, 178f luteal phase defect 265f OHSS 282 PCOS 134f Mechanism of hyperinsulinemia and hyperandrogenemia 116f Medical treatment of endometritis 253 Meningioma 171 Menstrual disturbance 118 irregularities 173 Metalloproteases 236 Metformin 38, 121, 124, 128, 133, 136, 287 Methods of endometrial evaluation 246t multifetal pregnancy reduction 300 Metoclopromide 172 Micro-adenoma 172 Micronized progesterone 266 Micropolyps 244 Mifepristone 110 M Mild ovarian stimulation 92, 97 Macro-adenoma 172 Mild stimulation protocol 58, 222 Macroprolactin 175 Miscarriage 62 Maintaining normal Modes of ovulation induction in endometrium 119 PCOS 127f Maintenance of Monitoring of thyroid activity 166 intravascular volume and Mucosal edema 244 electrolyte imbalance 291 Mullarian inhibiting renal function 291 substance 204

Index.indd 337

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338 

Step by Step Ovulation Induction

perifollicular flow 317t stromal artery flow 317t uterine artery RI score 320t Oral contraceptive 36, 76, 83, 210, 217 N pill 9, 135, 172 N-acetyl cysteine 39 Orthostatic hypotension 180 Naltrexone 40, 128 Osteopontin 233 Nasal Osteoporosis 173 congestion 180 Ovarian spray 73 artery 310f Natural cancer 62, 276 cycle 217 and ovulation killer cells 239 induction 294 Nausea 23, 25, 180 cyst 16 Navot’s classification 278 drilling 203 Nitric oxide 251 enlargement 279 Nitroglycerin 250 failure 1, 16, 151 Nonapeptide agonists 72 hyperstimulation syndrome Nonspecific chronic 53, 92, 100, 276, 277 endometritis 241 reserve tests 203, 204t Number of sensitivity index 206 follicles 282, 284 size 289 mature follicles 27 stimulation 83 stroma 188 stromal O arteries 328 Obesity 118 peak systolic velocity 204 Oligomenorrhea 4, 173 suppressive agents 262 Oligo-ovulation 262 transplant 211 Oocyte volume 204, 207, 216 donation 211, 226 Ovaries 201, 310 pick-up 254 irrigated with normal Optic nerve 185 saline 147f Optimal Overnight dexamethasone endometrial score 324f, 324t suppression test 135 and vascularity Ovulation 27, 152 quantification 323t documentation 4 Multiple endocrinopathies 185 pregnancy 61, 98, 276, 293

Index.indd 338

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Index 

339

ovaries 2, 114 syndrome 31, 40 Poor hormonal environment 232 ovarian reserve and mild ovarian stimulation 99 P uterine artery blood flow 234 Panhypopituitarism 159, 185 Post-oocyte retrieval Paracentesis of hydrothorax 292 albumin 286 Pathophysiology of Postpartum hemorrhage 166 luteal phase defect 261f Postprandial insulin 118 ovarian hyperstimulation Pouch of Douglas 151 syndrome 279, 280f Pregnancy 27, 283, 289 Peak systolic velocity 317 and lactation 171 Perifollicular circumfrential complications 166 vascularity 328 monitoring 166 Perivascular fibrosis 182 rate 109, 152 Persistent Premature hypersecretion of LH 142 luteinization 106 perifollicular reaction 263 menopause 4 Phenothiazines 172 ovarian aging 190 Pioglitazone 39 Prevention of Piroxicam 252 endometrial hyperplasia 133 Pituitary thrombosis 291, 292 capacity test 158 Previous ovarian surgery 203 dynamic testing 158 Primary amenorrhea 4 failure 2 Principle of ELISA test 7 function assessment 17 Procedure of multifetal gland 164f pregnancy reduction 300 hypersecretion 172 Progesterone 3 stimulation test 159 supplementation 264, 266 Prolactin tumor 181 and ovarian function 171 Plenty of fluids 290 secreting adenoma 159 Polycystic Prolactinoma 172 ovarian Proliferation of spiral disease 141 arteries 318 syndrome 42, 114 induction 126 protocol 282 treatment 2t with clomiphene 19f

Index.indd 339

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340 

Step by Step Ovulation Induction

Protocol of ovarian stimulation 283 Pulmonary compromise 292 Pulsatility index 204, 317, 312 Pulse frequency and dose 163 Purified urinary FSH 50

Q Quantify blood flow 312 Quinagolide 182, 287

R Radioimaging of sella turcica 176 Ranitidine 172 Raynaud’s phenomenon 180 Recombinant FSH 50, 62, 63, 219 hCG 51 LH 50, 65 Recurrent abortion 262 Reducing uterine contractility 252 Regularization of cycles 133 Renal dysfunction 81 failure 279, 292 Resistance ovarian waveform pattern 313f Resistive index 312, 317 Results of gonadotropin therapy 162 laparoscopic treatment 152 Rheumatoid arthritis 234 Ritodrine 252

Index.indd 340

Role of androgens in ovulation induction 188 chronic endometritis in endometrial receptivity 241 GnRH agonists 290 and antagonists in assisted reproductive technology 71 GnRH antagonist 290 in mild stimulation 59, 93 LH supplementation 159 metformin after conception 124 natural killer cells 239 oral contraceptive pill 83 Rosiglitazone 39

S Scanning electron microscopy 246 Selective multifetal pregnancy reduction 299 Sella turcica 176 Serum estradiol 283 levels 61 prolactin estimation 175 measurement 263 Severe OHSS 291 Sex hormone-binding globulin 33 Sheehan’s syndrome 2 Sibutramine 120

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Index  Side effect of bromocriptine 180t Signs of ovulation on ultrasonography 11t Sildenafil 250 Simple needle puncture 149 office procedure 11 Slide test 7 Small for gestational age 166 Spindle damage 234 Spiral arteries 311 Spironolactone 136 Standard flare protocol 220 Steroid 287 hormone receptor analysis 263 Stimulation of folliculogenesis 271 Storage of steroid hormones 33 Strenuous exercise 262 Stress 2, 171 Strict intake output chart 289 Study of pinopodes 246 Subcutaneous injections 72 Sub-endometrial blood flow 326, 327 Suppressive therapy 36 Supraseller pituitary mass extension 171 Surgical ovulation induction 42, 128, 131, 141 Systemic disorders 172

Index.indd 341

341

T T regulatory cells 240 Tamoxifen 24, 33, 250 Termination of pregnancy 293 Testosterone 3 Tests for ovulation 4 Thiazolidinediones 125 Thioxanthenes 172 Thyroid stimulating hormone 3, 119 Transabdominal procedure of fetal reduction 303 Transcervical aspiration 301 of gestational sac 300 Transdermal testosterone gel 190, 194, 223 Transient hyperprolactinemia 173 Transvaginal procedure of fetal reduction 303 puncture and embryo aspiration 300, 301 sonography 115 ultrasound scan 4 Treating anovulation 119 Treatment of hyperprolactinemia 177 luteal phase defect 264 poor uterine receptivity 249 prolactin secreting macroadenomas 177 Triple layer endometrial thickness 321f

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342 

Step by Step Ovulation Induction

Triptorelin 71, 236 Tube 202 Tubercular endometritis 241, 242 Tuberculosis and chronic nonspecific endometritis 241 Tumor 171 necrosis factor alpha 237 Turner’s syndrome 2 Typical triple layer endometrium 311f

U Ultrasonographic scoring of uterine receptivity 325 Ultrasonography of ovary 282 Ultrasound machine 303f Unexplained infertility 16, 52, 203 Unilateral oophorectomy 203 Use of general anesthesia 301

Index.indd 342

LH 217 recombinant FSH 219 Uterine artery 318, 328 dysfunction 166 Uterus 201, 311

V Vaginal dehydroepiandrosterone 195 dryness 173 Visual disturbances 23 Visualization of needle tip 306f Vomiting 23, 25, 180

W Wall thickening and coiling 322 WBC count 279 Weight charts 289 loss 32, 120, 127, 128

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