aypee Brothers - Jaypee Apps

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocols

prelims.indd 1 10-10-2015 09:42:39

Jayp

ee B

rothe

rsEditorsGautam N Allahbadia

MD DNB FNAMS FCPS DGO DFP FICMU FICOG

Medical DirectorDepartment of Assisted Reproduction

Rotunda—The Center for Human Reproduction, BandraRotunda Blue Fertility Clinic and Keyhole Surgery Center, Parel

Mumbai, Maharashtra India

Rubina Merchant PhDEmbryologist

Department of Assisted ReproductionRotunda—The Center for Human Reproduction, Bandra

Mumbai, Maharashtra India

ForewordHassan N Sallam

MD FRCOG PhD (London)

Manual of Ovulation Induction and Ovarian Stimulation Protocols

New Delhi | London | Philadelphia | Panama

The Health Sciences Publisher

Third Edition

prelims.indd 3 10-10-2015 09:42:40

Jayp

ee B

rothe

rs

Jaypee Brothers Medical Publishers (P) Ltd.

HeadquartersJaypee Brothers Medical Publishers (P) Ltd.4838/24, Ansari Road, DaryaganjNew Delhi 110 002, IndiaPhone: +91-11-43574357Fax: +91-11-43574314E-mail: [email protected]

Overseas OfficesJ.P. Medical Ltd.83, Victoria Street, LondonSW1H 0HW (UK)Phone: +44-20 3170 8910Fax: +44(0)20 3008 6180E-mail: [email protected]

Jaypee-Highlights Medical Publishers Inc.City of Knowledge, Bld. 237, ClaytonPanama City, PanamaPhone: +1 507-301-0496Fax: +1 507-301-0499E-mail: [email protected]

Jaypee Medical Inc.325, Chestnut StreetSuite 412, Philadelphia, PA 19106, USAPhone: +1 267-519-9789E-mail: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd.17/1-B, Babar Road, Block-B, ShaymaliMohammadpur, Dhaka-1207BangladeshMobile: +08801912003485E-mail: [email protected]

Jaypee Brothers Medical Publishers (P) Ltd.Bhotahity, Kathmandu, NepalPhone: +977-9741283608E-mail: [email protected]

Website: www.jaypeebrothers.comWebsite: www.jaypeedigital.com

© 2016, 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, photo copying, 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 contra indications. 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]

Manual of Ovulation Induction and Ovarian Stimulation ProtocolsFirst Edition: 2001

Second Edition: 2005

Third Edition: 2016

ISBN: 978-93-5090-958-4

Printed at

prelims.indd 4 10-10-2015 09:42:40

Jayp

ee B

rothe

rsDedicated to Our Children

Akanksha and Ranveerand

Mustafa and Insiya

There are only two lasting bequests we can hope to give our children.One of these is roots, the other, wings.

—Johann Wolfgang von Goethe

prelims.indd 5 10-10-2015 09:42:40

Jayp

ee B

rothe

rs

viiContributors

Contributors

Akanksha G Allahbadia MBBS Clinical Assistant Department of Assisted Reproduction Rotunda Blue Fertility Clinic and Keyhole Surgery Center Mumbai, Maharashtra India

Akmal El-Mazny MD FICS Assistant Professor Consultant of Reproductive and Endoscopic Surgery Department of Obstetrics and Gynecology Faculty of Medicine Cairo University, Cairo Egypt

Alan B Copperman MD Director Division of Reproductive Medicine Vice-Chairman Department of Obstetrics and Gynecology Mount Sinai Medical Center New York USA

Albert Opoku MRCOG Consultant Obstetrician and Gynecologist Special Interest in Reproductive Medicine Homerton Fertility Center Homerton University Hospital NHS Foundation Trust London UK

Alejandra Bermúdez MD Scientific Director CONCIBE Reproducción Asistida México City México

Alessandra Gambineri MD Division of Endocrinology Department of Clinical Medicine University Alma Mater Studiorum S. Orsola-Malpighi Hospital Bologna Italy

Alfonso Gutierrez Nájar MD Medical Director Reproduction and Genetics Clinic Angeles del Pedregal Hospital Mexico City Mexico

Ameya B Padmawar MD DGO FCPS DNB

Dip in Advanced Laparoscopy {Austria} Gynecological Endoscopic Surgeon Mobile Endoscopy Unit Mumbai, Maharashtra India

Amit Shah MD MRCOG Consultant Obstetrician and Gynecologist Reproductive Medicine and Surgery and Assisted Conception Homerton Fertility Center Homerton University Hospital NHS Foundation Trust, London UK

Andrea Borini MD Director Tecnobios Procreazione–Center for Reproductive Health Bologna Italy

Angela Falbo MD PhD Obstetrician and Gynecologist Department of Obstetrics and Gynecology Arcispedale Santa Maria Nuova of Reggio Emilia Viale Risorgimento Italy

prelims.indd 7 10-10-2015 09:42:40

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocolsviii

Anil Gudi MD MRCOG Consultant and Director Reproductive Medicine and Surgery and Assisted Conception Homerton Fertility Center Homerton University Hospital NHS Foundation Trust, London UK

Anna Palatnik MD Maternal-Fetal Medicine Fellow Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Feinberg School of Medicine Northwestern University Chicago, Illinois USA

Ayse Seyhan MD Obstetrician and Gynecologist Department of Obstetrics and Gynecology Soranus IVF Center, Bursa Turkey

Baris Ata MD, MCT Associate Professor of Obstetrics and Gynecology Director Assisted Reproduction Unit Uludag University Medical School Bursa Turkey

Bennett Boyd Medical Student Odessa Reproductive Medicine Center Candelaria, Helotes, Texas USA

Bernadette Mannaerts MD Head of Fertility Global Clinic Research Women’s Health and Endocrine MSD, Oss The Netherlands

Bruno Lunenfeld MD (Endocrinology) FRCOG

FACOG (Hon) POGS (hon) Professor Emeritus Faculty of Life Sciences Bar-llan University Ramat Gan Israel

Carola Albano MD MSc Specialist in Reproductive Medicine Platteau-Abano Fertility Center Center for Reproductive Medicine University Hospital, Dutch-speaking Brussels Free University (Vrije Universiteit Brussel) Brussels Belgium

Christophe Blockeel MD PhD Professor of Obstetrics and Gynecology Medical Director Center for Reproductive Medicine Laarbeeklaan, Brussels Belgium

Claudio A Benadiva MD ELD HCLD (ABB) Clinical Professor of Obstetrics and Gynecology Director, Preimplantation Genetics Diagnosis Program Laboratory Director, Center for Advanced Reproductive Services President, In Vitro Sciences Inc. Farmington, Connecticut USA

Daniel E Stein MD Interim Chair Department of Obstetrics and Gynecology Mount Sinai St Luke’s Roosevelt Assistant Clinical Professor Department of Obstetrics and Gynecology Columbia University College of Physicians and Surgeons Medical Director In Vitro Fertilization Program Continuum Reproductive Center New York USA

Daniel S Seidman MD MMSc Professor of Obstetrics and Gynecology Department of Obstetrics and Gynecology The Chaim Sheba Medical Center Tel-Hashomer Sackler School of Medicine Tel Aviv University, Tel Aviv Israel

prelims.indd 8 10-10-2015 09:42:40

Jayp

ee B

rothe

rs

ixContributors

Efstratios M Kolibianakis MD PhD

Consultant The Center for Reproductive Medicine Senior Lecturer in Obstetrics and Gynecology and Human Reproduction Unit for Human Reproduction Aristotle University Thessaloniki Greece

Eitan Lunenfeld MD MHA Professor and Chairman Department of Obstetrics and Gynecology Soroka University Medical Center Faculty of Health Sciences Ben-Gurion University of the Negev Beer-Sheva Israel

Eliahu Levitas MD Director Fertility and IVF Unit Soroka University Medical Center Faculty of Health Sciences Ben-Gurion University of the Negev Beer-Sheva Israel

Eric Scott Sills MD PhD Medical Director Center for Advanced Genetics In Vitro Fertilization Program HRC Fertility California USA

Ester Polak de Fried MD Professor of Obstetrics and Gynecology Director Department of Reproductive Medicine CER Medical Institute School of Medicine Buenos Aires University Buenos Aires Argentina

Gautam N Allahbadia MD DNB FNAMS

FCPS DGO DFP FICMU FICOG Medical Director Department of Assisted Reproduction Rotunda—The Center for Human Reproduction, Bandra Rotunda Blue Fertility Clinic and Keyhole Surgery Center, Parel Mumbai, Maharashtra India

Giovanni Battista La Sala MD Professor of Obstetrics and Gynecology Arcispedale Santa Maria Nuova of Reggio Emilia Viale Risorgimento Italy

Gogsen Onalan MD Associate Professor Department of Obstetrics and Gynecology Medical School, Bas kent University Reproductive Endocrinology and IVF Department Ankara Turkey

Goral Gandhi MSc Laboratory Director Department of Assisted Reproduction Rotunda—The Center for Human Reproduction, Bandra Mumbai, Maharashtra India

Gurkan Bozdag MD Associate Professor Department of Obstetrics and Gynecology School of Medicine Hacettepe University Hacettepe, Ankara Turkey

prelims.indd 9 10-10-2015 09:42:40

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocolsx

Hakan Yarali MD Professor Department of Obstetrics and Gynecology School of Medicine Hacettepe University Hacettepe, Ankara Turkey

Hatem Abu Hashim MD MRCOG PhD (VUB, Brussels) Professor of Obstetrics and Gynecology Faculty of Medicine Mansoura University, Mansoura Egypt

Hesham Al-Inany MD PhD Professor Department of Obstetrics and Gynecology Cairo University, Cairo Egypt

Hisham Mitwally MD Research Assistant Odessa Reproductive Medicine Center Candelaria, Helotes, Texas USA

Hong Ye MD Medical Director Chongqing Genetic and Reproductive Institute Chongqing Obstetrics and Gynecology Hospital Chongqing, People’s Republic of China China

Hulusi Bulent Zeyneloglu MD Professor Bas kent University Faculty of Medicine Department of Obstetrics and Gynecology Division of Reproductive Endocrinology and Infertility, Ankara Turkey

Irina Zorina MD PhD Reproductive Endocrinologist Altravita IVF Clinic Moscow Russia

Jahnavi Ambani MD DGO Consultant Fertility Physician Rotunda—The Center for Human Reproduction, Bandra Mumbai, Maharashtra India

Joseph L Kennedy MD Assistant Professor Department of Obstetrics and Gynecology Harrogate, Tennessee USA

Juliette Koch FRANZCOG CREI MS (Reproductive Medicine)

Fertility Specialist Department of Reproductive Medicine Royal Hospital for Women, Randwick New South Wales Australia

Kalyani Patel DNB MNAMS Fellow in Reproductive Medicine (ICOG) Consultant—Reproductive Medicine and Infertility Rotunda—The Center for Human Reproduction, Bandra Mumbai, Maharashtra India

Karin Bock MD Obstetrician and Gynecologist Clinic of Gynecology University Hospital Philipps University, Marburg Germany

Kemal Ozgur MD Clinical Director Consultant Gynecologist and Obstetrician Antalya IVF, Antalya Turkey

Khaled Mitwally MD Research Assistant Odessa Reproductive Medicine Center Odessa Regional Medical Center Odessa, Texas USA

prelims.indd 10 10-10-2015 09:42:41

Jayp

ee B

rothe

rs

xiContributors

Laura Kanzepolsky MD Obstetrician and Gynecologist Specialist in Reproductive Medicine Department of Reproductive Medicine CER Reproductive Health Center Buenos Aires Argentina

Laurel A Stadtmauer MD PhD Professor Department of Obstetrics and Gynecology Jones Institute for Reproductive Medicine Eastern Virginia Medical School Norfolk, Virginia USA

Luis Arturo Ruvalcaba Castellón MD Director General and CEO Mexican Institute of Infertility Specialist in Obstetrics and Gynecology Endoscopy, Gynecological Robotic Surgery Assisted Reproduction Techniques Puerta de Hierro Medical Center Guadalajara, Jalisco Mexico City Mexico

Manisha Kundnani MD FNB

Department of Reproductive Medicine Medical Director Fertility Square, The IVF Clinic Mumbai, Maharashtra India

Mark Perloe MD Medical Director Obstetrician and Gynecologist Reproductive Endocrinologist Georgia Reproductive Specialists Atlanta USA

Markus Eckart Nitzschke MD Scientific Director Medical Doctor, Specialist in Obstetrics and Gynecology Subspecialist in Reproductive Medicine Canary Institute of Infertility Las Palmas de Gran Canaria Spain

Martha Isolina García Amador MD Teaching Chief Mexican Institute of Infertility (IMI) Guadalajara, Jalisco, Mexico City Mexico

Marzia Barberi Clinical Embryologist IVF Lab Tecnobios Procreazione Bologna Italy

Michael Costello MMed (RH and HG) FRANZCOG CREI Fertility Specialist and Reproductive Endocrinologist Royal Hospital for Women, Randwick University of New South Wales, Sydney New South Wales Australia

Mohamed Aboulghar MD Professor Department of Obstetrics and Gynecology Faculty of Medicine, Cairo University The Egyptian IVF Center Maadi, Cairo Egypt

Mohamed Mitwally MD HCLD FACOG Medical Director and Head Odessa Reproductive Medicine Center Division Head, Division of Reproductive Endocrinology and Infertility Odessa Regional Medical Center Associate Professor Department of Obstetrics and Gynecology, Texas Tech University Odessa, Texas USA

Mohamed Youssef MD Professor Department of Obstetrics and Gynecology Faculty of Medicine, Cairo University Egyptian International Fertility Center–IVF (EIFC–IVF) Cairo Egypt

prelims.indd 11 10-10-2015 09:42:41

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocolsxii

Murat Berkkanoglu MD Consultant Gynecologist and Obstetrician Antalya IVF, Antalya Turkey

Natalia Dmitrieva MD PhD Reproductive Endocrinologist Altravita IVF Clinic Moscow Russia

Paul Devroey MD Professor Director of Medical Education of the International Federation of Fertility Societies (IFFS) Former Clinical and Scientific Co-ordinator Center for Reproductive Medicine Brussels Belgium

Peter Kovacs MD PhD Medical Director Kaali Institute IVF Center Budapest Hungary

Peter Platteau MD FRCOG (London) Specialist in Reproductive Medicine Platteau-Abano Fertility Center Center for Reproductive Medicine University Hospital, Dutch-speaking Brussels Free University (Vrije Universiteit Brussel) Brussels Belgium

Preeti Yogesh Bhandari MS DNB MICOG

DRM (Germany) PGDMLS Specialist Obstetrician and Gynecologist LLH Hospital, Abu Dhabi UAE

Randle S Corfman MD Specialist in Reproductive Endocrinology Department of Obstetrics and Gynecology Essentia Health Saint Mary’s Medical Center Maple Grove Hospital North Memorial Medical Center Minnesota USA

Renato Pasquali MD Professor Division of Endocrinology Department of Clinical Medicine University Alma Mater Studiorum S. Orsola-Malpighi Hospital Bologna Italy

Ricardo H Asch MD Scientific Director INMATER México City México

Ritu Hinduja Singh MD Fellow in Reproductive Medicine (Rotunda) Fertility Consultant and Research Co-ordinator Rotunda—The Center for Human Reproduction, Bandra Mumbai, Maharashtra India

Robert J Norman AO BSc (Hons) MBChB

(Hons) MD FRANZCOG FRCPA FRC Path

FRCOG CREI Professor of Reproductive and Periconceptual Medicine Robinson Institute Discipline of Obstetrics and Gynecology School of Pediatrics and Reproductive Health The University of Adelaide South Australia Subspecialist in Reproductive Endocrinology and Infertility Medical Director Fertility, South Australia Visiting Consultant Gynecologist Royal Adelaide Hospital President of the Asia Pacific Initiative on Reproduction (ASPIRE) Alliance ASPIRE, 2014 Emeritus and Founding Director Robinson Institute Adelaide South Australia

prelims.indd 12 10-10-2015 09:42:41

Jayp

ee B

rothe

rs

xiiiContributors

Roy Homburg FRCOG MD Professor of Reproductive Medicine Head of Research Reproductive Medicine and Assisted Conception Homerton Fertility Center Homerton University Hospital NHS Foundation Trust London UK

Rubina Merchant PhD Embryologist Department of Assisted Reproduction Rotunda—The Center for Human Reproduction, Bandra Mumbai, Maharashtra India

(Late) Samuel S Thatcher MD PhD Center for Applied Reproductive Science (CARS), Johnson City Tennessee USA

Sarit Avraham MD Obstetrician and Gynecologist Department of Obstetrics and Gynecology Tel Aviv Sourasky Medical Center The Chaim Sheba Medical Center The Sackler School of Medicine Tel Aviv University, Tel Aviv Israel

Seang Lin Tan MBBS MBA James Edmunds Dodds Professor of Obstetrics and Gynecology McGill University, Montreal Canada

Sergey Yakovenko PhD Director and Head of the Embryology Laboratory AltraVita IVF Clinic, Moscow Russia

Shahar Kol MD Director, IVF Unit Rambam Health Care Campus Technion, Israel Institute of Technology Haifa Israel

Sheetal Sawankar BND (Ob/Gy) DRM Consultant Fertility Specialist Rotunda—The Center for Human Reproduction, Bandra Mumbai, Maharashtra India

Shilpa Surendra Saple MD Consultant Fertility Specialist and Gynecological Endoscopist Aarush IVF and Endoscopy Center Mumbai, Maharashtra India

Shrutika Kamath Thakker MS DNB

Clinical Associate Rotunda Blue Fertility Clinic and Keyhole Surgery Center, Parel Mumbai, Maharashtra India

Silvio Cuneo Pareto MD Medical Director CONCIBE Reproducción Asistida México City México

Sneha Sathe MS (Obstetrics and Gynecology) Consultant Reproductive Medicine Nova IVI Fertility Mumbai, Maharashtra India

Soumya Ramesh MD Gynecologist and Infertility Specialist Icchapurti Clinic Mumbai, Maharashtra India

Soumya Shetty MS Core Fertility Specialist Morpheus Nucleus International IVF Center Mumbai, Maharashtra India

Stefano Palomba MD Associate Professor of Obstetrics and Gynecology Department of Obstetrics, Gynecology and Pediatrics Arcispedale Santa Maria Nuova of Reggio Emilia, Viale Risorgimento Italy

prelims.indd 13 10-10-2015 09:42:41

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocolsxiv

Sulbha Arora MD DNB Consultant Fertility Specialist Tulip Gynecare Mumbai, Maharashtra India

Susanne Waldmann-Rex Department of Andrology University Hospital Philipps University Marburg Germany

Swati G Allahbadia MD DGO DGE (Germany)

Consultant Gynecologist Rotunda Blue Fertility Clinic and Keyhole Surgery Center, Parel Mumbai, Maharashtra India

Tali Silberstein MD Obstetrician and Gynecologist Department of Gynecology and Obstetrics Soroka University Hospital Beer-Sheva Israel

Tarang Majmudar MD MRCOG Clinical Lead for the Women’s Health Division Gynecological Cancer MDT Lead Lead Colposcopist, Minimal Access Surgeon, Ambulatory Mulberry Private Healthcare Hinchingbrooke Hospital Hinchingbrooke Park, Huntingdon Cambridgeshire UK

Teresa G Bremner MD Specialist in Reproductive Endocrinology and Infertility Center for Fertility and Reproductive Endocrinology New Britain General Hospital New Britain, Connecticut USA

Tristan Hardy MBBS (Hons 1) Masters

Reproductive Medicine (UNSW)

RANZCOG (Trainee) Royal Hospital for Women Barker Street, Randwick New South Wales Australia

Valentina Spadoni Tecnobios Procreazione Center for Reproductive Health Bologna Italy

Walter Krause MD DM Professor Department of Andrology Clinical Training Center of the European Academy of Andrology School of Medicine Philipp University Marburg Germany

William Ledger MA DPhil (Oxon) MB ChB

FRCOG FRANZCOG CREI

Professor Royal Hospital for Women, Randwick University of New South Wales, Sydney New South Wales Australia

William M Buckett MB ChB MD FRCOG Medical Director McGill University Health Center Reproductive Center Royal Victoria Hospital Montreal, Quebec Canada

Yuval Or MD Head—Ultrasound Unit Department of Obstetrics and Gynecology Kaplan Medical Center Rehovot Israel

Zeev Shoham MD Director Reproductive Medicine Infertility and IVF Unit Kaplan Medical Center, Rehovot Professor of Obstetrics and Gynecology Hadassah Medical School Hebrew University Jerusalem Israel

prelims.indd 14 10-10-2015 09:42:41

Jayp

ee B

rothe

rsThe introduction of Clomiphene citrate in Clinical Medicine by Robert Kistner and others in the early 1960s was a milestone in the practice of Reproductive Medicine. This early discovery was followed in the same decade by the introduction of pituitary gonadotropins by Carl Gemzell and others, and subsequently, the introduction of human urinary gonadotropins by Bruno Lunenfeld and others. These milestones ushered the introduction of more ovulation induction therapies including other antiestrogen preparations (Cyclophenyl, Tamoxifen, Epimestrol, etc.), aromatase inhibitors and recombinant FSH, LH and human chorionic gonadotropin (hCG) preparations. The list of discoveries continues, with the introduction of long-term FSH preparations and probably, of an oral FSH preparation in the foreseeable future. And, although the first in vitro fertilization (IVF) baby was born from a non-stimulated cycle, today, ovulation induction and controlled ovarian stimulation are integral parts of every assisted reproduction program. The birth of more than 5 million babies from the various techniques of assisted reproduction since the introduction of IVF could not have been achieved in such a short time without the giant leaps taken in ovarian stimulation. This book is an honest and practical testimony to these achievements. It is an excellent compilation of the work of world’s experts in the field from at least 14 countries spanning the six inhabited continents, thanks to the great efforts of the editors and, in particular, the incessant activity of Dr Gautam N Allahbadia. It covers all aspects of ovulation induction and controlled ovarian stimulation. The section on the Fundamentals of Stimulation is a necessary introduction to the subject and bridges the gap between basic science and clinical application. It helps to clarify the intricate relationships between the different elements of the hypothalamic-pituitary-ovarian axis and the various hormones and molecules involved in the process of natural ovulation, and how this can be manipulated for induction of ovulation in anovulatory women, as well as for controlling superovulation in assisted reproduction. It also discusses the up-to-date techniques for monitoring ovarian stimulation and addresses the important questions of whether the repeated ovarian stimulation has an effect on the ovarian reserve and whether some LH activity is indispensable for proper ovulation induction. The following section is a journey into the world of ovarian stimulation and its chapters span various subjects from mild stimulation protocols to more aggressive protocols for various applications in assisted reproduction. It starts by discussing the place of Clomiphene citrate in the modern world of assisted reproduction and the possibility of combining it with other preparations, namely hMG or FSH, a particularly important subject for low-resource settings in developing countries.

Foreword

prelims.indd 15 10-10-2015 09:42:41

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocolsxvi

It continues with the still hot debate between the GnRH agonist and antagonist protocols in the light of the latest evidence-based analyses. In addition, the different regimens of FSH and hMG administration are discussed, including the step-up and step-down protocols and the use of Clomiphene citrate and oral contraceptives to manipulate the cycle for better clinical outcomes. It also addresses the question of whether any of these regimens has an effect on the luteal phase and the best way of supporting it. It finally discusses the supplementation of the various protocols with LH, hCG and estradiol in order to achieve the ultimate goal of a livebirth. The subsequent section discusses the role of aromatase inhibitors, embracing their advantages and disadvantages and comparing them to other ovulation induction therapies. This is followed by the special section on ovarian stimulation in the still enigmatic polycystic ovary syndrome (PCOS), addressing the subject from all angles. In particular, the role of Metformin in this group of patients is discussed in detail as in the use of corticosteroids. The section ends with the role of surgery in the light of recent evidence and is followed by a section on triggering ovulation. Here, the different methods of achieving the final step in ovarian stimulation are discussed including LH, hCG as well as triggering ovulation by GnRH agonists in patients with PCOS. A special section is dedicated to the complications of controlled ovarian stimulation, including the ovarian hyperstimulation syndrome, multiple pregnancies, as well as the possible relationship between ovarian stimulation and gynecological tumors. This is followed by a section that addresses the subject of poor responders, its causes and the best management protocols in these unfortunate patients in the light of the most recent. The final section is a look into the future of the subspecialty and discusses the new long-term FSH preparations, as well as state-of-the-art methods of monitoring ovarian stimulation. With such a widespread text, the book is an indispensable addition to our library and is an excellent companion to all clinicians working in the field. It is also essential reading material for young doctors aspiring to work in our exciting and expanding world of assisted reproduction. I finally hope that this edition will be followed by more to come as the subject continues to evolve.

Hassan N Sallam MD FRCOG PhD (London)

Professor of Obstetrics and Gynecology Department of Obstetrics and Gynecology

Alexandria University, Alexandria Egypt

prelims.indd 16 10-10-2015 09:42:41

Jayp

ee B

rothe

rsThe ability to exogenously induce the ovaries to achieve multifollicular growth by overpowering natural physiology with ovarian stimulation drugs, credited to the pioneering work of clinicians and researchers and the undaunted advance in science and technology, is a leap that has blessed a million couples with families—a pleasure that so far eluded them. Four decades down the line since the discovery of the first ovulation-inducing agent, Clomiphene citrate (CC), the field of assisted reproduction continues to revel in its glorious success that seems more promising with the synchronous developments in drug regimens, culture media, stimulation protocols, and assisted reproduction techniques. However, the unpleasant complications of ovarian stimulation, such as ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies, that lurk in the background of these lucrative success rates, spiral us back to the thought-provoking questions: Mild, Milder, Mildest or Back to Nature? Which protocol should it be? What drug regimen and dose should be used for which patient? Is the pursuit of success with assisted reproductive technology (ART) financially, psychologically, emotionally and ethically justified for infertility patients, especially for those from developing countries with low-resource settings, poor responders to stimulation and advance-aged women? Is the treatment safe for women at risk for a flare response to stimulation? This monograph, divided into nine significant sections, with 67 carefully designed chapters, contributed by world authorities with clinical and scientific excellence, is a complete guide that aims to answer all these baffling questions and more in a single edition. The introductory section on the fundamentals of stimulation forms the scaffold, giving a thorough insight into the physiology of folliculogenesis and ovulation, regulation of gonadotropin secretion, their roles in follicular development and the menstrual cycle, and the effect of controlled ovarian hyperstimulation (COH) on cycle characteristics, indispensable to the understanding of cycle manipulation with ovulation indication (OI) drugs. The clinical significance of evaluating the ovarian reserve and monitoring folliculogenesis with ovarian reserve markers (AMH AFC, basal FSH, estradiol) to predict the ovarian response to COH is detailed, with particular relevance to high and poor responders to COH—the two most challenging patient groups. The value of LH supplementation, evaluation of the luteal phase and the significance of luteal phase support in COH are addressed to optimize the pregnancy outcomes with COH. The section on ovarian stimulation regimens that follows comprehensively, discusses the gamut of ovarian stimulation drugs (CC, urinary and recombinant gonadotropins, GnRH agonists and antagonists, and the novel recombinant long-acting Corifollitropin-alfa), the various protocols in which they are used (long, short, ultrashort, microdose-flare GnRH protocols, step-up protocols, step-down protocols), their clinical applications, comparative clinical efficacies, routes of administration and clinical outcomes, endowing the clinicians with the

Preface

prelims.indd 17 10-10-2015 09:42:41

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocolsxviii

ability to appropriately individualize the treatment to patients. The mechanism of action of aromatase inhibitors and their indications, clinical outcomes, and their comparative clinical efficacy and safety with CC in women with polycystic ovary syndrome (PCOS) throws light on this particularly interesting alternative OI drug. The versatile strategies for ovulation induction in PCOS patients, with an evidence-based approach to Metformin treatment, clears the cobwebs in the management of this still mysterious syndrome, leaving the reader with conclusive choices. While a critical evaluation of the roles of recombinant LH, recombinant hCG and GnRH agonist to trigger ovulation aims to present the ideal ovulation trigger to keep OHSS at bay, the possible benefit of a dual LH and FSH surge for final oocyte maturation forces a relook at the traditional hCG trigger. Complications of ovulation induction, specifically OHSS and multiple pregnancies, have been highlighted with precautions and strategies, such as in vitro maturation, natural cycle in vitro fertilization (IVF), minimal and modified natural cycle IVF, for their effective management. An entire section is dedicated to the optimal management of poor responders, an extremely challenging group that presents with a poor ovarian response to conventional stimulation, culminating in reduced oocytes and embryos, and thus, reduced pregnancy rates or canceled cycles. A stimulating discussion on the when, why and how of embarking on mild- stimulation protocols, natural cycle IVF and its advantages over conventional protocols, such as reduced medication, a physiological milieu, reduced complications, better clinical outcomes and higher cost-effective ratio, aims to increase its awareness to help make ovarian stimulation, softer, safer and cost-effective for patients. Combined with cryopreservation techniques, such as vitrification, and cryopreserved-thawed embryo transfer, this has important implications in low-resource settings. The concluding section on advances in stimulation science is a window to technology at its ultimate. Remarkable advances in recombinant DNA technology, resulting in the highly potent, long-acting recombinant FSH (FSH-CTP, Corifollitropin-alfa), a single injection of which can sustain follicular growth for a week in a GnRH antagonist cycle, obviating the need for the daily painful injections for seven days, is now a relieving treatment option for patients undergoing COH for IVF/ICSI. The advantages of the applicability, reproducibility, and accuracy of Sonography-based Automated Volume Count (Sono AVC) for monitoring follicular growth, in addition to its value in time and patient management, and perhaps, even self-control by the patient, give it a special place in the clinic. We earnestly hope that we have been able to effectively reach out to clinicians, infertility professionals, both medical and paramedical including postgraduate students through this practical, problem-orientated handbook, successfully platform evidence-based, and satisfying solutions to their clinical dilemmas, and inspire future path-breaking researches. We would like to thank the contributors for their scholarly contributions that have enabled us to further disseminate indispensable knowledge in this intriguing and rapidly advancing field of Reproductive Endocrinology.

Gautam N Allahbadia Rubina Merchant

prelims.indd 18 10-10-2015 09:42:42

Jayp

ee B

rothe

rs

Acknowledgments

Best friends are treasures. Hug them for their caring. Applaud their accomplishments. Laugh with them gratefully.

—Amy Leigh Mercree

This work in its third edition would never have been possible without the strong women in my life at home, at work and abroad who took charge of the mundane and just let me write…

Never turn your back to those who have faced your problems on your behalf. Never shut your mouth on those who have opened their hearts to receive you!

—Israelmore Ayivor, Daily Drive 365

prelims.indd 19 10-10-2015 09:42:42

Jayp

ee B

rothe

rs

Contents

SECTION 1Fundamentals of Stimulation

1. Regulation of the menstrual cycle and the effect of controlled ovarian hyperstimulation on cycle characteristics 3

Peter Kovacs

Clinical discussion 4

2. Regulation of gonadotropin secretion 20 Bruno Lunenfeld

3. The role of gonadotropins in follicular development and their use in ovulation induction protocols for assisted reproduction 26

Anna Palatnik, Daniel S Seidman

Historical introduction 26; Clinical discussion 27

4. Predictors of ovarian response to controlled ovarian stimulation: are they useful? 38

Sarit Avraham, Daniel S Seidman

Rationale 38; Clinical discussion 39

5. Clinical significance of antral follicle count and anti-Müllerian hormone in predicting the stimulation outcome 46

Gautam N Allahbadia, Soumya Ramesh, Kalyani Patel, Akanksha G Allahbadia

Clinical discussion 47; Recent advances 49

6. Human ovulation and transvaginal sonography 52 Gautam N Allahbadia, Swati G Allahbadia, Akanksha G Allahbadia


7. The significance of monitoring folliculogenesis 60 Shrutika Kamath Thakker, Gautam N Allahbadia, Akanksha G Allahbadia


8. Identification of patients at high risk for excessive response to ovarian stimulation 67

Kalyani Patel, Gautam N Allahbadia, Akanksha G Allahbadia


prelims.indd 21 10-10-2015 09:42:42

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocolsxxii

9. The impact of repeated ovarian stimulation on the ovarian reserve 77 Albert Opoku, Anil Gudi, Amit Shah, Roy Homburg

Rationale 77; Clinical discussion 78; Recent advances 81

10. Luteinizing hormone activity in ovarian stimulation for IVF: is it Indispensible? 83

Gautam N Allahbadia, Ritu Hinduja Singh, Jahnavi Ambani, Akanksha G Allahbadia


11. Luteal phase support in controlled ovarian hyperstimulation protocols: why and how? 90

Shilpa Surendra Saple, Gautam N Allahbadia, Akanksha G Allahbadia


SECTION 2Ovarian Stimulation Regimens

12. Ovarian stimulation protocols 103 Gogsen Onalan, Hulusi Bulent Zeyneloglu


13. Clomiphene citrate for ovarian stimulation 111 Susanne Waldmann-Rex, Karin Bock, Walter Krause

14. Combination protocols using Clomiphene plus gonadotropins 119 Tali Silberstein, Eitan Lunenfeld


15. Routes of administration of gonadotropins and ovarian response 125 Ester Polak de Fried, Laura Kanzepolsky


16. Clinical application of recombinant follicle-stimulating hormone 136 Yuval Or, Zeev Shoham


17. Induction protocols of the 2000s using r-hLH and r-hCG 145 Gautam N Allahbadia, Akanksha G Allahbadia, Goral Gandhi

Rationale for the use of r-hLH as an ovulation trigger 146; Rationale for the use of r-hLH for ovulation induction and superovulation 146; Clinical applications 148; Recent advances 151

18. Step-up protocols 155 Teresa G Bremner, Claudio A Benadiva


prelims.indd 22 10-10-2015 09:42:42

Jayp

ee B

rothe

rs

xxiiiContents

19. Step-down protocols for ovulation induction 163 Ritu Hinduja Singh, Gautam N Allahbadia, Akanksha G Allahbadia


20. The role of gonadotropin-releasing hormone agonists in ovulation induction 168

William M Buckett


21. Gonadotropin-releasing hormone antagonist protocols: fixed versus flexible 176

Mohamed Youssef, Mohamed Aboulghar


22. GnRH agonists versus GnRH antagonists for ovarian stimulation: pros and cons 181

Shrutika Kamath Thakker, Gautam N Allahbadia, Akanksha G Allahbadia


23. Fine-tuning the role of GnRH antagonists in ART programs 190 Carola Albano, Efstratios M Kolibianakis, Peter Platteau, Paul Devroey


24. Evaluation of the luteal phase in GnRH agonist/antagonist IVF protocols 197

Eliahu Levitas, Eitan Lunenfeld


25. Recombinant human FSH versus HP-hMG for controlled ovarian stimulation in GnRH agonist down-regulated cycles 205

Sneha Sathe, Gautam N Allahbadia, Akanksha G Allahbadia


26. Can endogenous LH support treatment with recombinant FSH only in a GnRH antagonist protocol in normogonadotropic patients? 213

Bernadette Mannaerts


27. The efficacy of recombinant LH supplementation to recombinant FSH in GnRH agonist protocols 227

Manisha Kundnani, Gautam N Allahbadia, Akanksha G Allahbadia


28. Substitution of recombinant FSH by low-dose hCG in the late follicular phase in a GnRH antagonist protocol: is it clinically effective? 233

Christophe Blockeel


prelims.indd 23 10-10-2015 09:42:42

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocolsxxiv

29. The benefit of luteal estradiol pre-treatment in GnRH antagonist versus long GnRH agonist protocols 240

Hong Ye


30. Impact of long GnRH agonist and GnRH antagonist stimulation protocols on endometrial receptivity 252

Rubina Merchant, Gautam N Allahbadia, Akanksha G Allahbadia


31. The efficacy of Clomiphene citrate in preventing a premature LH surge during controlled ovarian stimulation with human menopausal gonadotropins 260

Hesham Al-Inany, Akmal El-Mazny


32. Pre-treatment with oral contraceptives prior to stimulation: does it help? 264

Jahnavi Ambani, Gautam N Allahbadia, Akanksha G Allahbadia


SECTION 3Aromatase Inhibitors for

Ovarian Stimulation

33. Aromatase inhibitors for ovulation induction: indications and clinical outcomes 275



34. Clomiphene citrate versus aromatase inhibitors: mechanism of action 293

Hisham Mitwally, Khaled Mitwally, Bennett Boyd, Mohamed Mitwally


35. Clinical efficacy and safety of Letrozole versus Clomiphene citrate for ovulation induction in women with polycystic ovary syndrome 302

Preeti Yogesh Bhandari, Gautam N Allahbadia, Akanksha G Allahbadia


prelims.indd 24 10-10-2015 09:42:42

Jayp

ee B

rothe

rs

xxvContents

SECTION 4Ovulation Induction in

Polycystic Ovary Syndrome

36. Management strategies for ovulation induction in Clomiphene citrate-resistant PCOS women 313

Soumya Shetty, Gautam N Allahbadia, Akanksha G Allahbadia


37. Induction of monofolliculogenesis in patients with polycystic ovary syndrome 323

Alan B Copperman, Daniel E Stein, Randle S Corfman

Rationale 323; Clinical discussion 325; Recent advances and conclusion 329

38. Low-dose step-down regimen for ovulation induction in polycystic ovary syndrome 333

Sheetal Sawankar, Gautam N Allahbadia, Akanksha G Allahbadia

Rationale 334; Clinical discussion 336; Results 340; Recent advances and conclusion 342

39. Chronic ultra low-dose step-up protocol for patients with polycystic ovary syndrome 347



40. GnRH agonist versus antagonist protocols for controlled ovarian hyperstimulation in women with PCOS 354

Laurel A Stadtmauer


41. Influence of body mass index on the IVF outcome in PCOS patients undergoing stimulation with GnRH agonists or antagonists 364

Ritu Hinduja Singh, Gautam N Allahbadia, Akanksha G Allahbadia


42. Adjunctive glucocorticoids for ovulation induction in polycystic ovary syndrome 374

Samuel S Thatcher, Joseph L Kennedy

Rationale 375; Clinical discussion 376; Recent advances and conclusion 379

prelims.indd 25 10-10-2015 09:42:42

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocolsxxvi

43. Metformin treatment of Clomiphene-resistant polycystic ovary syndrome 382

Mark Perloe, Eric Scott Sills


44. Mechanism of action of Metformin for ovulation induction in PCOS patients 392

Stefano Palomba, Angela Falbo, Giovanni Battista La Sala


45. Clomiphene citrate, Metformin or both for the treatment of anovulatory women with PCOS: evidence-based recommendations 405

Renato Pasquali, Alessandra Gambineri


46. Metformin and Clomiphene citrate versus highly purified FSH for ovulation induction in CC-resistant PCOS women 415

Soumya Shetty, Gautam N Allahbadia, Akanksha G Allahbadia


47. The current place of Metformin in infertile patients with PCOS: an evidence-based approach 423

Hatem Abu Hashim

Rationale 424; Clinical discussion 424; Conclusion and recommendations 428

48. Laparoscopic ovarian drilling for surgical induction of ovulation in PCOS 432

Ameya B Padmawar, Gautam N Allahbadia, Akanksha G Allahbadia


SECTION 5Ovulation Triggering

49. Role of the GnRH agonist as an ovulation trigger 443 Gautam N Allahbadia, Tarang Majmudar, Akanksha G Allahbadia


50. Recombinant LH, recombinant hCG and GnRH agonist to trigger ovulation: a critical evaluation 454

Michael Costello, Juliette Koch, William Ledger


51. LH and FSH surges for final oocyte maturation: is a dual surge beneficial? 463

Shahar Kol


prelims.indd 26 10-10-2015 09:42:42

Jayp

ee B

rothe

rs

xxviiContents

SECTION 6Complications of Controlled Ovarian

Hyperstimulation

52. Complications of ovulation induction 473 Sulbha Arora, Gautam N Allahbadia, Akanksha G Allahbadia


53. Intravenous administration of calcium in the management of OHSS 491 Sergey Yakovenko, Irina Zorina, Natalia Dmitrieva

Materials and methods 492; Results 494; Clinical discussion 496

54. The role of in vitro maturation in high responders and patients at risk of OHSS undergoing assisted reproductive technology 500



SECTION 7

Poor Responders

55. Canceled cycles in poor response: what next? 517 Ricardo H Asch, Silvio Cuneo Pareto, Alejandra Bermúdez,

Alfonso Gutierrez Nájar


56. Management options for poor responders to controlled ovarian stimulation 524

Gautam N Allahbadia, Soumya Ramesh, Sulbha Arora, Shrutika Kamath Thakker, Akanksha G Allahbadia


57. The efficacy of microdose GnRH agonist flare versus GnRH antagonist/Letrozole protocols in poor responders undergoing in vitro fertilization 538

Hakan Yarali, Gurkan Bozdag


58. Optimum maximal gonadotropin dosage used in microdose flare-up cycles 545

Murat Berkkanoglu, Kemal Ozgur

Rationale 545; Clinical discussion 546; Case studies and recent advances 547

59. Role of androgens in the treatment of patients with a low ovarian response 551



prelims.indd 27 10-10-2015 09:42:42

Jayp

ee B

rothe

rs

Manual of Ovulation Induction and Ovarian Stimulation Protocolsxxviii

60. Addition of growth hormone to stimulation protocols for poor responders: is it beneficial? 561

Luis Arturo Ruvalcaba Castellón, Martha Isolina García Amador


61. Criteria for cycle cancelation in poor responders to ovarian stimulation 578

Manisha Kundnani, Gautam N Allahbadia, Akanksha G Allahbadia


62. Contribution of in vitro maturation to ovarian stimulation cycles in poor responder patients 584

Marzia Barberi, Valentina Spadoni, Andrea Borini

Clinical discussion 585; Future perspectives 594

SECTION 8Mild Stimulation Protocols

and Natural Cycle IVF

63. Embarking on natural cycle IVF: when and how? 601 Markus Eckart Nitzschke


64. The value of modified natural cycle IVF in normal ovarian responders 608

Markus Eckart Nitzschke

Rationale 608; Clinical discussion 611; Case study 613; Recent advances 614

SECTION 9

Advances in Stimulation Science

65. Long-acting recombinant FSH (FSH-CTP, Corifollitropin alfa) 619 Peter Platteau, Paul Devroey


66. Corifollitropin alfa: a treatment option for patients undergoing controlled ovarian stimulation for IVF/ICSI 623

Tristan Hardy, Robert J Norman


67. Applicability and reproducibility of sonography-based automated volume count (Sono AVC) in monitoring follicular growth 632

Baris Ata, Ayse Seyhan, Seang Lin Tan

Clinical discussion 634; Recent advances and conclusion 641

Index 645

prelims.indd 28 10-10-2015 09:42:42

Jayp

ee B

rothe

rs

The Efficacy of Microdose GnRH Agonist Flare versus GnRH Antagonist/Letrozole Protocols in Poor Responders

Undergoing In Vitro FertilizationHakan Yarali, Gurkan Bozdag

C H A P T E R 57

SUMMARY

According to the available literature, it is hard to define the optimal protocol of controlled ovarian hyperstimulation (COH) in poor ovarian responders. That fact is mainly based on the lack of a universally accepted definition of poor ovarian response (POR) in the available trials, which are all single center based and underpowered. In clinical practice, the microdose flare-up (MF) protocol is currently one of the most common COH protocols used in poor ovarian responders. However, it is inconclusive whether modifications in the gonadotropin releasing hormone (GnRH) agonist dose and scheme bring any advantage when compared with the regular dose of agonist if there is a diminished ovarian reserve. Nevertheless, the disappointment in the management of poor ovarian responders has forced physicians to try co-treatment, which might potentially improve ovarian response. In this respect, the expectancy of a positive effect of Letrozole on in vitro fertilization (IVF) performance comes from a variety of preclinical studies. When three trials comparing MF and GnRH antagonist/Letrozole (AL) protocols are considered, it is hard to conclude clearly. In one trial, while the ongoing pregnancy rate was higher in favor of MF, the others failed to present a statistical difference in achieving success. However, we noticed a higher implantation rate in patients assigned the AL protocol instead of the MF protocol. Hence, there is no doubt that further studies with larger sample sizes are required for conclusive results.

INTRODUCTION

Poor Ovarian Response

Management of poor ovarian reserve is one of the leading issue in in vitro fertilization (IVF) and embryo transfer (ET) cycles. Although a history of ovarian surgery, chemotherapy/radiotherapy, severe endometriosis and heavy smoking are significant risk factors, most of the women do not have any risk factor at all.1 Of note, to a certain rate, X-chromosome related aneuploidies or Fragile–X premutations might be encountered in young women suffering from severely diminished ovarian capacity.2

Ch-57.indd 538 15-09-2015 13:39:41

Jayp

ee B

rothe

rs

539Microdose GnRH agonist flare vs GnRH antagonist/Letrozole protocols in poor responders …

Based on the available literature, it is hard to define the optimal COH protocol in poor ovarian responders. That fact is mainly based on the lack of a universally accepted definition of poor ovarian response in available trials. Hence, the prevalence of POR in available trials is 9 to 24% and such a wide range clearly reflects the heterogeneity of the definitions.3 While some studies define the phrase of ‘poor’ on the basis of a low number of oocytes retrieved, others do it with a low number of developing follicles and/or low estradiol (E2) levels in the running or previous cycle. In this respect, the Bologna criteria1 should be used in future trials for the selection of the patients to obtain homogeneity of the data. Secondly, most of the studies are retrospective in nature, which underestimates the finding that 30 percent of women will present a better stimulation performance in the following cycle without any intervention.4 Thirdly, the limited number of prospective trials include patients that are ‘suspected’ but not ‘proven’ to be poor ovarian responders. Given the fact that ovarian reserve tests are not 100 percent specific and they carry a 5 percent false positive rate,5 that means some normoreponders would be assigned as poor ovarian responders in some of the prospective trials when definitions were based on ovarian reserve tests. And lastly, all the available studies assessing different COH protocols on POR, are single center based and underpowered.

CLINICAL DISCUSSION

Microdose Flare-up Protocol

The GnRH microdose flare-up (MF) protocol is currently one of the most common COH protocols used in poor ovarian responders. Commonly, after a 21-day course of an oral contraceptive pill, Leuprolide acetate with a dose of 40 µg (twice daily) is commenced 3 days after the last pill and continued until the day of human chorionic gonadotropin (hCG) administration. In clinical practice, if 4.6 mL of sterile water is added to 0.4 mL of Leuprolide acetate (Lucrin, 5 mg/mL; Abbott, Cedex, Istanbul, Turkey) 10 IU will include 40 µg of Leuprolide acetate in each injection. Two days after initiation of Leuprolide acetate, follicle stimulating hormone (FSH) and/or human menopausal gonadotropin (hMG) can be initiated, according to preference. The rationale of the MF protocol is to induce release of endogenous gonadotropins by low-dose gonadotropin agonist (GnRH-a) administration in the early follicular phase, which might potentially enhance ovarian response to the subsequent administration of exogenous gonadotropins.6-8 Clinically, Scott and Navot 7 first reported the use of the GnRH MF agonist protocol in poor ovarian responders (n=34) by comparing their previous cycle with long GnRH-a protocol. The authors reported a significant improvement in peak estradiol (E2) levels, number of follicles with mature oocytes retrieved.7 With a similar study design, when compared with their initial cycle of long GnRH-a protocol, Schoolcraft et al.6 and Surrey et al.8 reported the beneficial effect of the MF protocol on ovarian response as well as on pregnancy rates in 32 and 34 patients, respectively. However, two randomized controlled trials (RCTs) failed to demonstrate any beneficial effect of MF protocol when compared with the GnRH antagonist protocol with regard to number of oocytes or pregnancy rates.9, 10 Finally,

Ch-57.indd 539 15-09-2015 13:39:41

Jayp

ee B

rothe

rs

Poor responders540

it is inconclusive whether modifications in the GnRH agonist dose and scheme bring any advantage when compared with regular dose of GnRH agonist or antagonist in poor ovarian responders.

GnRH Antagonist/Letrozole Protocol in Poor Ovarian Responders

The disappointment in the management of poor ovarian responders forced physicians try co-treatment, which might potentially improve ovarian response. In this respect, Letrozole is a non-steroidal aromatase inhibitor and an androgen- modulating agents, which has increasingly been used in IVF cycles during the last decade. It inhibits the aromatase enzyme with a high selection to the ‘heme’ of the cytochrome P450 subunit of the enzyme, which blocks conversion of androgens into estrogens and leads to a subsequent increase in intraovarian androgens.3,11 Just 1 to 5 mg of Letrozole is strong enough to block 99% of the activity.12

The expectancy of a positive effect of Letrozole on IVF performance comes from a variety of preclinical studies. To cite an example, androgen administration stimulates the early stages of follicular growth,13, 14 increases the number of both preantral and antral follicles15, 16 and inhibits apoptosis. Besides, by increasing the androgen levels in the ovary, expression and production of FSH receptors16 on the granulosa cells rise.16-18 That finding might be also an important with regard to the pathophysiology of PCOS and the increased risk of ovarian hyper-response in such cases. Of interest, the experience from testosterone-treated female trans-sexuals suggest that exposure to exogenous androgens may lead to an increased number of developing follicles, regardless of gonadotropin stimulation.17, 19

In clinical IVF, GnRH antagonist/letrozole (AL) protocol has been compared with several regimens in PORs. Among PORs, the two RCTs20, 21 comparing AL versus GnRH antagonist-only protocol yielded a similar number of oocytes retrieved and clinical pregnancy rate but with a significant reduction of FSH17 use favoring Letrozole use. Subsequently, Lee et al.27 evaluated the ‘sequential’ use of Letrozole and gonadotropins in poor ovarian responders in an RCT.22 Patients (n = 53) with less than four oocytes retrieved in previous IVF cycles or less than five antral follicles were randomized to either Letrozole 2.5 mg/day for 5 days followed by hMG or hMG alone. In both the arms, GnRH antagonist was administered. In the Letrozole group, a lower dosage of hMG was used, fewer oocytes, but comparable live birth rates were obtained. Similarly, in another RCT23 that compared AL with long GnRH agonist protocol, the authors reported comparable pregnancy rates but a lower dose of FSH requirement in the AL protocol. To sum up, RCTs that use the AL protocol result in lesser consumption of FSH but present inconclusive results regarding the number of oocytes or pregnancy rates. Other than the RCTs, in an observational study by Garcia Velasco et al,3 the authors assigned 147 patients with at least one previous cancelled IVF cycle either AL or GnRH antagonist-only arm. Although the pregnancy rates were similar between the groups, the AL group had revealed a higher number of oocytes (6.1 vs 4.3, respectively) and implantation rates (14.5% vs 9.8%, respectively) despite similar doses of FSH/hMG. A recent study attempted to find the optimal dose of aromatase inhibitor by comparing extended high dose Letrozole (5 mg/day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days) versus short

Ch-57.indd 540 15-09-2015 13:39:41

Jayp

ee B

rothe

rs


low dose Letrozole regimen (2.5 mg/day from cycle day 3–7) in a GnRH antagonist protocol.24 However, there were no significant differences between both the groups with regard to the number of oocytes retrieved and clinical pregnancy rates.

Microdose Flare-up versus GnRH Antagonist/Letrozole Protocols

According to the available literature, there are three trials comparing MF and AL protocol (Table 57.1). In a prospective controlled trial, Schoolcraft et al25 assigned 578 patients with a 2:1 ratio to either the MF or GnRH AL protocols. Although, the gonadotropin dose, duration of stimulation, oocytes retrieved and implantation rates were comparable, the ongoing pregnancy rate was significantly superior in the ML arm than in the AL arm (52% vs 32%, respectively). However, such a high pregnancy rate in both arms and the fact that the ratio of patients with a basal antral follicle count (AFC) of <6 was less than 10 percent brings to mind that they might not be ideal patients for the assessment of POR.25

In a retrospective study from our institution,26 1383 cycles (n=885), predicted to have or with a history of poor ovarian response who were undergoing intracytoplasmic sperm injection (ICSI) were enrolled in either MF (n=1026 cycles) or AL groups (n=357 cycles). The rate of patients having an AFC of <6 was 71 percent. Of note, in the AL group, the number of previous cancelled cycles and basal AFC were lower when compared with MF. The total gonadotropin use (4020 ± 1178 vs 4538 ± 1493 IU), duration of stimulation (9.0 ± 2.5 vs 10.2 ± 4.0 days), number of oocytes retrieved (4.1 ± 3.4 vs 6.7 ± 4.5) and rate of mature oocytes (71% vs 78%) were significantly lower in the AL protocol compared with the MF protocol, respectively. However, the fertilization rate (85.0% vs 80.0%, respectively), the rate of at least one top-quality embryo transferred (55.0% vs 49.6%, respectively) and implantation rates (14.5% vs 9.8%, respectively) were all higher in the AL arm, but clinical pregnancy rates per ET (22.8% vs 17.4%, respectively) were similar.26 These findings suggest a significantly lower rate of mature oocytes (metaphase II oocytes/oocyte retrieved) in the AL protocol despite similar hCG administration criteria, and that, triggering be better planned when the leading follicle diameter is at least 20 mm in diameter, as suggested earlier.27 Of note, in spite of lower AFC and higher rate of failed IVF cycles, higher top quality embryos and implantation rates may suggest a possible beneficial effect of Letrozole on the oocyte and/or endometrium. Recently, in a prospective controlled trial,28 women having at least one previous failed IVF cycle in which <3 follicles were achieved and/or serum E2 level of < 500 pg/mL on the day of hCG administration were evaluated (n=94),28 the authors reported a higher number of mature oocytes retrieved and rate of top quality embryos in the MF arm (Table 57.1). However, the implantation and pregnancy rates failed to present any significance among the groups.28 The main issue, related to Letrozole use, is the lack of approval by Food and Drug Administration (FDA) for use in ovulation induction. The initial report presented possibly increased congenital cardiac malformations among 150 patients treated with Letrozole or Letrozole and gonadotropins.29 However, another study revealed a prevalence of 2.4 percent (14/514) for congenital malformations and chromosomal abnormalities and 1.2 percent for major malformations, which is consistent with the general obstetrics population.30

Ch-57.indd 541 15-09-2015 13:39:42

Jayp

ee B

rothe

rs

Poor responders542

Tabl

e 57

.1: A

vaila

ble

stud

ies

com

parin

g G

nRH

mic

rodo

se fl

are-

up v

ersu

s G

nRH

ant

agon

ist/L

etro

zole

pro

toco

ls

Au

thor

(ye

ar)

Nu

mbe

r of

P

atie

nts

G

onad

otro

pin

dos

e N

um

ber

of o

ocyt

es

retr

ieve

dC

lin

ical

pre

gnan

cy /

embr

yo tr

ansf

er (

%)

Impl

anta

tion

rat

e (%

)

Sch

oolc

raft

WB

(20

08)25

MF

: 355

AL

: 179

52.5

±13.

0 am

pu

les

56.3

±9.9

am

pu

les

13.0

± 5

.312

.0 ±

6.0

52*

3721 15

Yara

li H

(20

09)26

MF

: 673

AL

: 212

4537

.5±1

492.

5 IU

a

4020

.0±1

197.

5 IU

6.7

± 4.

5 a

4.1

± 3.

417

.422

.89.

8b

14.5

Dav

ar R

(20

10)28

MF

: 49

AL

: 45

46.1

±7.1

amp

ule

sc

42.1

±7.5

am

plu

es4.

4 ±

2.7 d

2.8

± 2.

714

.35.

37.

73.

8

All

valu

es a

re e

xpre

ssed

as

mea

n ±

SD

, un

less

sta

ted

oth

erw

ise.

*on

goin

g p

regn

ancy

rat

ea

= p

< 0

.01;

b =

p: 0

.01;

c =

p :

0.00

9; d

= p

: 0.

008

Ch-57.indd 542 15-09-2015 13:39:42

Jayp

ee B

rothe

rs


CONCLUSION

The management of PORs is still an important issue and the AL protocol does not bring superior pregnancy rates when compared with the MF protocol, even though lower dose of FSH requirement seems to be a significant advantage. In this respect, multicenter based randomized controlled trials with higher number of patients are needed for clear results. Other than androgenic modulating agents like aromatase inhibitors, adjuvants that have direct androgenic effect, such as testosterone, should be also investigated. Currently, based on the two RCTs,31,32 transdermal testosterone pretreatment seems to increase clinical pregnancy and live birth rates in poor responders undergoing ovarian stimulation for IVF. Additionally, growth hormone (GH) supplementation might also have a positive effect regarding the clinical pregnancy and live birth rates.33 However, small sample sizes in the available studies and lack of consensus in the dose and scheme of treatment are the main reasons that limit its clinical use.

REFERENCES 1. Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. ESHRE

consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod 2011;26:1616-24.

2. Cordts EB, Christofolini DM, Dos Santos AA, Bianco B, Barbosa CP. Genetic aspects of premature ovarian failure: a literature review. Arch Gynecol Obstet 2011;283:635-43.

3. Garcia-Velasco JA, Moreno L, Pacheco A, Guillen A, Duque L, Requena A, et al. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril 2005;84:82-87.

4. Klinkert ER, Broekmans FJ, Looman CW, Te Velde ER. A poor response in the first in vitro fertilization cycle is not necessarily related to a poor prognosis in subsequent cycles. Fertil Steril 2004;81:1247-53.

5. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006;12:685-718.

6. Schoolcraft W, Schlenker T, Gee M, Stevens J, Wagley L. Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol. Fertil Steril 1997;67:93-97.

7. Scott RTNavot D. Enhancement of ovarian responsiveness with microdoses of gonadotropin-releasing hormone agonist during ovulation induction for in vitro fertilization. Fertil Steril 1994;61:880-85.

8. Surrey ES, Bower J, Hill DM, Ramsey J, Surrey MW. Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil Steril 1998;69:419-24.

9. Akman MA, Erden HF, Tosun SB, Bayazit N, Aksoy E, Bahceci M. Comparison of agonistic flare-up protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial. Hum Reprod 2001;16:868-70.

10. Schmidt DW, Bremner T, Orris JJ, Maier DB, Benadiva CA, Nulsen JC. A randomized prospective study of microdose leuprolide versus ganirelix in in vitro fertilization cycles for poor responders. Fertil Steril 2005;83:1568-71.

11. Akhtar M, Njar VC, Wright JN. Mechanistic studies on aromatase and related C-C bond cleaving P-450 enzymes. J Steroid Biochem Mol Biol 1993;44:375-87.

12. Mitwally MFCasper RF. Aromatase inhibitors in ovulation induction. Semin Reprod Med 2004;22:61-78.

13. Vendola K, Zhou J, Wang J, Famuyiwa OA, Bievre M, Bondy CA. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol Reprod 1999;61:353-57.

Ch-57.indd 543 15-09-2015 13:39:42

Jayp

ee B

rothe

rs

Poor responders544

14. Vendola KA, Zhou J, Adesanya OO, Weil SJ, Bondy CA. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest 1998;101:2622-29.

15. Hillier SG, Tetsuka M, Fraser HM. Location and developmental regulation of androgen receptor in primate ovary. Hum Reprod 1997;12:107-11.

16. Weil SJ, Vendola K, Zhou J, Adesanya OO, Wang J, Okafor J, et al. Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations. J Clin Endocrinol Metab 1998;83:2479-85.

17. Bosdou JK, Venetis CA, Kolibianakis EM, Toulis KA, Goulis DG, Zepiridis L, et al. The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update 2012;18:127-45.

18. Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab 1999; 84:2951-56.

19. Spinder T, Spijkstra JJ, Gooren LJ, Burger CW. Pulsatile luteinizing hormone release and ovarian steroid levels in female-to-male transsexuals compared to heterosexual women. Psychoneuroendocrinology 1989;14:97-102.

20. Kashyap S, Wells G, Davis O, Williams-Pittman MA, Rosenwaks Z. Aromatase inhibitors improve IVF outcomes in poor responders: a randomized controlled pilot study. J Soc Gyn Invest 2005;2:709.

21. Ozmen B, Sonmezer M, Atabekoglu CS, Olmus H. Use of aromatase inhibitors in poor-responder patients receiving GnRH antagonist protocols. Reprod Biomed Online 2009; 19:478-85.

22. Lee VC, Chan CC, Ng EH, Yeung WS, Ho PC. Sequential use of letrozole and gonadotrophin in women with poor ovarian reserve: a randomized controlled trial. Reprod Biomed Online 2011;23:380-88.

23. Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 2004;19:2031-35.

24. Fouda UM, Sayed AM. Extended letrozole regimen versus clomiphene citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: a randomized controlled trial. Reprod Biol Endocrinol 2011;9:84.

25. Schoolcraft WB, Surrey ES, Minjarez DA, Stevens JM, Gardner DK. Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol? Fertil Steril 2008;89:151-56.

26. Yarali H, Esinler I, Polat M, Bozdag G, Tiras B. Antagonist/letrozole protocol in poor ovarian responders for intracytoplasmic sperm injection: a comparative study with the microdose flare-up protocol. Fertil Steril 2009;92:231-35.

27. Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryocryopreservation. J Clin Oncol 2005;23:4347-53.

28. Davar R, Oskouian H, Ahmadi S, Firouzabadi RD. GnRH antagonist/letrozole versus microdose GnRH agonist flare protocol in poor responders undergoing in vitro fertilization. Taiwan J Obstet Gynecol 2010;49:297-301.

29. Biljan MM, Hemmings R, Brassard N. The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins. Fertil Steril 2005;84:S95.

30. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761-65.

31. Massin N, Cedrin-Durnerin I, Coussieu C, Galey-Fontaine J, Wolf JP, Hugues JN. Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique: a prospective, randomized, double-blind study. Hum Reprod 2006;21:1204-11.

32. 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;95:679-83.

33. Kolibianakis EM, Venetis CA, Diedrich K, Tarlatzis BC, Griesinger G. Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update 2009; 15:613-22.

Ch-57.indd 544 15-09-2015 13:39:42

aypee Brothers - Jaypee Apps

Documents

Transcript of aypee Brothers - Jaypee Apps