Human Gametes and Preimplantation Embryos
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1 Human Gametes and Preimplantation Embryos
2
3 David K. Gardner Denny Sakkas Emre Seli Dagan Wells Editors Human Gametes and Preimplantation Embryos Assessment and Diagnosis
4 Editors David K. Gardner, DPhil Department of Zoology University of Melbourne Melbourne, VIC, Australia Emre Seli, MD Department of Obstetrics, Gynecology and Reproductive Sciences Yale School of Medicine New Haven, CT, USA Denny Sakkas, PhD Boston IVF Waltham, MA, USA Dagan Wells, PhD, FRCPath Nuffield Department of Obstetrics and Gynaecology University of Oxford Oxford, UK ISBN ISBN (ebook) DOI / Springer New York Heidelberg Dordrecht London Library of Congress Control Number: Springer Science+Business Media New York 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, speci fi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on micro fi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied speci fi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a speci fi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (
5 Foreword Human reproduction is very inef fi cient. Considering the overpopulation of many regions of our world, how can this be true? The simplistic answer is that the reproductive cycle operates about 13 times each year. In normal reproduction, although greatly in fl uenced by age, on average only about one in fi ve unions of sperm and egg result in a normal neonate. There is abundant evidence that about two-thirds of these failures are due to chromosomal aneuploidy. One can speculate that the remainder are due to mismatches at the molecular level. Clinical IVF superimposes its own inef fi ciency on the inef fi ciency of normal reproduction. On an egg retrieval basis, IVF requires about ten mature eggs for each neonate. To be sure there is some correction by cryopreservation. These considerations point to the great importance for clinical IVF of an ability to identify one or more biomarkers during oogenesis, spermatogenesis, or embryogenesis, which can predict a normal neonate. David Gardner, Denny Sakkas, Emre Seli, and Dagan Wells, all distinguished workers in this pursuit, from Australia, the United States and the United Kingdom, have gathered an inclusive and brilliant group of investigators whose work has contributed and surely will continue to contribute to this search. This encyclopedia of amazing and complicated molecular reactions, which must be just right for each of us to exist, is required reading for anyone who wishes to join the pursuit for the magic biomarker. In addition, every reproductive physician and embryologist will surely be better informed by becoming familiar with the contents of this book as it will give insight and understanding of what is being in fl uenced by their efforts. It needs to be noted that this book concerns the gametes and the embryo and gives no consideration to the role played by the endometrium. This is in keeping with the biblical story of the seed and soil, which has been aptly paraphrased by many, stating that reproductive inef fi ciency is due to the seed and not the soil. However, there may well be a minority of cases where there is a problem with the soil. When a unique biomarker or biomarkers can predict a normal neonate and is widely applied in clinical IVF, a change in mindset of the patient and the physician may well be required. The magic biomarkers will accomplish, in the laboratory, what nature has been doing forever by overcoming what we call the inef fi ciency of human reproduction. Both patient and staff must under- v
6 vi Foreword stand and be prepared that there may be retrieval cycles that will be characterized by no transfers, especially among patients in the latter 30s and beyond. However, there is a real compensating possibility that we will understand how to harvest enough eggs to minimize or eliminate the inef fi ciency of reproduction enhanced by retrieval from a single menstrual cycle. This book should be in the library and minds of every IVF program around the world. Howard W. Jones, Jr., MD Professor Emeritus Eastern Virginia Medical School Norfolk, VA, USA Johns Hopkins University School of Medicine Baltimore, MD, USA
7 Preface The plight of infertile couples has been greatly alleviated over the past three decades. Assisted Reproductive Technologies have facilitated the birth of over fi ve million children and counting. Such a wonderful outcome has only been made possible through the tireless work of numerous physicians, nurses, and scientists all around the world. Advances in ovarian stimulation, and laboratory conditions and procedures, have facilitated greater success rates and safer outcomes. Concomitantly, high-order multiple gestations, once a common complication, are now being retired to the archives of human IVF. Nonetheless, the incidence of twins remains high in several communities, culminating in IVF being responsible for a disproportionate percentage of multiple births. The once elusive goal of routine single embryo transfer is fi nally becoming a reality in some countries. However, in order for single embryo transfer to become the standard of care for all, it is imperative that accurate, rapid, and economical methods of quantifying embryo viability are developed to ensure that the most viable euploid embryo is selected for transfer. Ideally, such tests would be noninvasive, lessening the risks to the embryo and reducing costs and workload in the embryology laboratory. It was with the goal of single embryo transfer for all patients that we set out to review the established and developing methods for embryo selection, outline promising new technologies, and speculate about the future of embryo selection. The scope of this project covers the analysis of embryo morphological characteristics, both as static observations (conventional scoring) or with time as a continuous variable (morphokinetics), the capability of novel genetic screening approaches for the analysis of embryo ploidy and gene defects, and fi nally the analysis of both proteome and metabolome of gametes and embryos. The rapid advancement in several technologies described in this book will not only ensure that we are able to obtain highly valuable and novel insights into events during the fi rst week of human life, but will facilitate the creation of assays to identify the most suitable embryo for transfer (and cryopreservation). vii
8 viii Preface It has been our privilege to have worked with the many distinguished contributors for this volume. We dedicate this book to the millions of infertile couples worldwide. It is our collective goal in the IVF community to make their journey to parenthood short in duration and successful. Melbourne, VIC, Australia Waltham, MA, USA New Haven, CT, USA Oxford, UK David K. Gardner, DPhil Denny Sakkas, PhD Emre Seli, MD Dagan Wells, PhD, FRCPath
9 Contents 1 Current Practices and Regulations for Embryo Transfer Worldwide: Implications on IVF Outcome... 1 Baris Ata and Emre Seli 2 Analysis of the Zona Pellucida as an Indicator of Oocyte Developmental Potential... 9 Markus Montag, Thomas Schimming, and Maria Köster 3 Morphological Assessment of Oocytes, Pronuclear and Cleavage Stage Embryos Laura Rienzi, Benedetta Iussig, and Filippo Ubaldi 4 Morphological Assessment of Blastocyst Stage Embryos: Types of Grading Systems and Their Reported Outcomes Basak Balaban and David K. Gardner 5 Real-Time Imaging Strategies to Improve Morphological Assessment María Cruz, Manuel Muñoz, and Marcos Meseguer 6 Limitations and Benefits of Morphologic Embryo Assessment Strategies: How Far Can Morphological Assessment Go in the Identification of Viable Embryos? Denny Sakkas and David K. Gardner 7 Sperm Morphologic Characteristics and Their Impact on Embryo Quality and Pregnancy Outcome Bhushan K. Gangrade and Ashok Agarwal 8 Objective Biomarkers of Sperm Development and Fertility: Assessment of Sperm-Zona Pellucida Binding Ability and Hyaluronic Acid-Mediated Selection of Sperm for ICSI Fertilization Gabor Huszar 9 Selecting the Best Sperm and Its Implications in Clinical Practice Juan G. Alvarez ix
10 x Contents 10 The Origins of Aneuploidy in Human Embryos Elpida Fragouli and Joy Delhanty 11 Preimplantation Genetic Screening and Diagnosis Using Fluorescent In Situ Hybridization (FISH) Tsilya Gerasimova and Maria D. Lalioti 12 Single Nucleotide Polymorphisms and Next Generation Sequencing Alan H. Handyside and Dagan Wells 13 Use of Comparative Genomic Hybridisation (CGH) and Microarray-CGH for Preimplantation Genetic Screening Leeanda Wilton and Dagan Wells 14 Quantitative SNP Array and Real-Time PCR-Based Human Preimplantation Embryo Aneuploidy Screening Nathan R. Treff 15 Regulation of Gene Expression in the Oocyte and Early Embryo: Implications for Transcriptomic and Proteomic Embryo Assessment Helena Kristiansson and Emre Seli 16 Transcriptomics Technology: Promise and Potential Pitfalls Can Bruce and Asli Uyar 17 Transcriptomic Analysis of Cumulus and Granulosa Cells as a Marker of Embryo Viability Elpida Fragouli and Dagan Wells 18 Mass Spectrometry, Proteomics, and the Study of Sperm Cell Biology Mark A. Baker and R. John Aitken 19 Proteomic Analysis of Embryo Viability Mandy G. Katz-Jaffe and Susanna McReynolds 20 Metabolism of the Viable Human Embryo David K. Gardner 21 Analysis of Respiration as an Indicator of Oocyte and Embryo Developmental Potential David L. Keefe 22 Mitochondrial Activity as a Biomarker of Gamete and Embryo Health Jonathan Van Blerkom 23 Carbohydrate Analysis and Embryo Viability Michelle Lane and David K. Gardner
11 Contents xi 24 Identification of Viable Embryos by Noninvasive Measurement of Amino Acids in Culture Media Franchesca D. Houghton 25 Metabolomic Profiling of Embryos Using Spectroscopy Denny Sakkas and Emre Seli 26 Microfluidic Devices for the Analysis of Gamete and Embryo Physiology George A. Thouas, David L. Potter, and David K. Gardner Index
12
13 Contributors Ashok Agarwal, PhD Clinical Andrology Laboratory and Reproductive Tissue Bank, Glickman Urological and Kidney Institute, Cleveland, OH, USA Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA R. John Aitken, PhD, ScD Discipline of Biological Sciences, Faculty of Science and IT, University of Newcastle, NSW, Australia Juan G. Alvarez, MD, PhD Department of Male Infertility, Centro ANDROGEN, La Coruña, Spain Baris Ata, MD, MCT Department of Obstetrics and Gynecology, Uludag University Hospital, Bursa, Republic of Turkey Mark A. Baker, PhD Discipline of Biological Sciences, Faculty of Science and IT, University of Newcastle, Callaghan, NSW, Australia Basak Balaban, BSc Assisted Reproduction Unit, American Hospital of Istanbul, Istanbul, Turkey Can Bruce, PhD Department of Molecular Biochemistry and Biophysics, W. M. Keck Foundation Biotechnology Resource Laboratory, Yale School of Medicine, New Haven, CT, USA María Cruz, PhD IVI Alicante, Alicante, Spain Joy Delhanty, PhD Fetal and Maternal Medicine, Institute for Women s Health, University College, London, UK Elpida Fragouli, PhD Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK Reprogenetics UK, Oxford, UK Bhushan K. Gangrade, PhD IVF Laboratory, Center for Reproductive Medicine, Orlando, FL, USA David K. Gardner, DPhil Department of Zoology, University of Melbourne, Melbourne, VIC, Australia Tsilya Gerasimova, PhD Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA xiii
14 xiv Contributors Alan H. Handyside, MA, PhD The Bridge Centre, London Bridge, London, UK Franchesca D. Houghton, BSc(Hons), DPhil Centre for Human Development, Stem Cells & Regeneration, Faculty of Medicine, University of Southampton, Southampton, UK Gabor Huszar, MD Sperm Physiology Laboratory, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA Benedetta Iussig, MSc Clinica Valle Giulia, GENERA Rome, Marostica, Italy Ubertide Centre for Reproductive Medicine, Rome, Italy Mandy G. Katz-Jaffe, PhD National Foundation for Fertility Research, Lone Tree, CO, USA David L. Keefe, MD Department of Obstetrics and Gynecology, New York University School of Medicine, NYU Langone Medical Center, New York, NY, USA Maria Köster, DVM Department Gynecological Endocrinology and Reproductive Medicine, University of Bonn, Bonn, Germany Helena Kristiansson, PhD Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA Maria D. Lalioti, PhD Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA Michelle Lane, PhD Repromed, Dulwich, SA, Australia Susanna McReynolds, PhD National Foundation for Fertility Research, Lone Tree, CO, USA Marcos Meseguer, PhD IVF Unit, Clinical Embryology Laboratory, Instituto Valenciano de Infertilidad, Valencia, Spain Markus Montag, MD IVF Laboratory, Department of Gynecological Endocrinology & Fertility Medicine, University of Heidelberg, Heidelberg, Germany Manuel Muñoz, MD Instituto Valenciano de Infertilidad, Alicante, Spain David L. Potter, BSc Department of Zoology, The University of Melbourne, Melbourne, VIC, Australia Laura Rienzi, MS GENERA Centre for Reproductive Medicine, Rome, Italy Denny Sakkas, PhD Boston IVF, Waltham, MA, USA Thomas Schimming, PhD Independent Image Processing IT Professional, Munich, Germany Emre Seli, MD Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
15 Contributors xv George A. Thouas, BSc, MRepSc, PhD Department of Zoology, The University of Melbourne, Melbourne, VIC, Australia Nathan R. Treff, PhD Reproductive Medicine Associates of New Jersey, Basking Ridge, NJ, USA Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ Robert Wood Johnson Medical School, New Brunswick, NJ, USA Filippo Ubaldi, MD Clinica Valle Giulia, GENERA Roma, Marostica, Italy Umbertide Centre for Reproductive Medicine, Rome, Italy Asli Uyar, PhD Department of Obstetrics and Gynecology, Yale School of Medicine, New Haven, CT, USA Jonathan Van Blerkom, PhD Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA Leeanda Wilton, PhD Preimplantation Genetics, Melbourne IVF, East Melbourne, VIC, Australia Dagan Wells, PhD, FRCPath Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK Institute of Reproductive Sciences, Oxford, UK
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