INTERNATIONAL CONFERENCE FINAL PROGRAMME AND ABSTRACT BOOK
First world conference on luteinizing hormone in ART: A flight of discovery 27-28 May 2016 - Naples, Italy
Dear Colleagues,
It is a great pleasure to welcome you to the First world conference on luteinizing hormone in ART: A flight of discovery. This is the first international conference to focus on LH and it is a unique opportunity for researchers and medical practitioners to become better acquainted with this expanding area and share their results and experience. Our goal is to offer a global and comprehensive update of the most recent results and developments in LH research; to this end, some of the world’s top experts are here to share their knowledge with you. As your hosts, we look forward to making this event scientifically rewarding for you. Welcome to Naples: we hope you enjoy your flight.
Best Regards,
Giuseppe De Placido Carlo Alviggi Sandro C. Esteves Federico II University Federico II University ANDROFERT - Andrology & Naples, Italy Naples, Italy Human Reproduction Clinic São Paulo, Brazil
1 First world conference on luteinizing hormone in ART: A flight of discovery
Overview The role of luteinizing hormone (LH) during folliculogenesis has heightened curiosity for at least three decades. In particular, the scientific community is still divided over recognizing the relevance of LH containing drugs during controlled ovarian stimulation (COS). Availability of recombinant drugs has offered, for the first time, the opportunity to explore the role of the follicle stimulating hormone (FSH) and luteinizing hormone (LH) separately. Despite this opportunity, the role of recombinant LH is still a matter of debate. What recently emerged is that LH is actively able to improve the outcome of IVF in specific subgroup of patients, including advanced age women and the so-called “hypo-responders”. The latter group is represented by subjects that, despite being young, having normal ovarian reserve, and being classified as nomonadotrophic, show “slow” and sub-optimal response to conventional FSH doses. It was estimated that the profile of ovarian response is evident in 10-12% of women undergoing COS. More interestingly, the increase in ongoing pregnancy rates in these two subgroups of women does not seem to be correlated with the number of oocytes, suggesting that improvement in oocyte quality and/or extragonadal effects of LH could be implicated. Although a growing body of evidence is defining the role of LH during COS, clear guidelines and practical recommendations on this aspect are lacking. This conference will show evidence from basic science to clinical practice regarding the use of recombinant LH and will illustrate its possible benefits as well as its physiopathological mechanism. Guided by an expert, participants will grasp the rationale for using recombinant LH in assisted reproductive technology as well as understand the role of LH in human reproduction.
Learning objectives By attending this live educational conference, participants will be able to: • Understand the physiology of LH and its role in ovulation induction • Grasp the state of the art regarding the use of recombinant LH use • Individualise groups of patients that required LH during stimulation protocols • Identify specific ovarian reserve markers and genotype polymorphism useful for tailoring treatments and choosing the best approach
Target audience This programme is intended for clinicians, embryologists, biologists and scientists working in ART.
2 Honorary President Giuseppe De Placido Federico II University Naples, Italy
Chairs Carlo Alviggi Federico II University Naples, Italy
Sandro C. Esteves ANDROFERT - Andrology & Human Reproduction Clinic Campinas, Brazil
Local scientific committee Coordinator Ida Strina Federico II University Naples, Italy
Members Luisa Avino Federico II University Naples, Italy
Alessandro Conforti Federico II University Naples, Italy
Pasquale De Rosa Federico II University Naples, Italy
Silvia Picarelli Federico II University Naples, Italy
Roberta Vallone Federico II University Naples, Italy
3 CME Provider EXCEMED is a non profit foundation dedicated, since the last four decades, to the development of high-quality medical education programme all over the world. EXCEMED adheres to the guidelines and standards of the European Accreditation Council for Continuing Medical Education (EACCME ®) which states that continuing medical education must be balanced, independent, objective, and scientifically rigorous.
Continuing medical education EXCEMED ( www.excemed.org ) is accredited by the European Accreditation Council for Continuing Medical Education (EACCME ®) to provide the following CME activity for medical specialists. The EACCME ® is an institution of the European Union of Medical Specialists (UEMS), www.uems.net The CME workshop “First world conference on luteinizing hormone in ART: A flight of discovery” held on 27-28 May 2016 in Naples, Italy, is designated for a maximum of 6 (six) hours of European CME credits (ECMEC). Each medical specialist should claim only those credits that he/she actually spent in the educational activity. EACCME ® credits are recognized by the American Medical Association (AMA) towards the Physician's Recognition Award (PRA). To convert EACCME ® credit to AMA PRA category 1 credit, please contact the AMA.
The CME conference has been designated for 1,8 Italian CME Credits . N. Event 150342 Ed. 1 - Provider Id n. 3255 from the Italian Ministry of Health .
EXCEMED adheres to the principles of the Good CME Practice group (gCMEp).
4 GENERAL INFORMATION
Language The official language of this conference is English.
CME Provider EXCEMED - Excellence in Medical Education Senior Programme Manager: Chloé Xilinas T +39 06 420413 505 - F +39 06 420413 677 [email protected] Medical Advisor: Alessandro Conforti [email protected]
For any logistic support please contact: Event Planet srl Project Coordinator: Morena Trematerra | Paola Federico T +39 (0)81.5529399 - F +39 (0)81.4206734 [email protected]
Format This live educational event is accompanied by innovative technological tools allowing participants to express their own views and opinions through real-time surveys, discussions, questions cards and mobile application.
Mobile application To stay up to date with all conference activities: Downlaod the LH2016 app on your smartphone or tablet √ Enter the invitation code printed on your badge √
Any questions? You can pose your questions on the: Question card √ Mobile app √
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5 PROGRAMME Friday, 27 May 2016 Saturday, 28 May 2016 X. Xxx (Xxx) From 12.00 Registration Welcome lunch Session III Landing in the real world 13.30 Opening Chairs: S.K. Sunkara (UK) - F. Zullo (Italy) R. Fischer (Germany) Real-time voting app 13.40 Local welcome 08.45 L7: The European point of view G. De Placido (Italy) K. Bühler (Germany) 13.50 Introduction 09.10 L8: The Indian point of view C. Alviggi (Italy) - S.C. Esteves (Brazil) M. Banker (India)
Session I Taking off from basic science 09.35 L9: The Latin America approach S.C. Esteves (Brazil) Chairs: A. Ferraretti (Italy) - M.A. Sirard (Canada) Revisiting real-time voting app Real-time voting app 10.00 Panel discussion 14.00 L1: Physiology of LH and differences with hCG M. Simoni (Italy) 10.45 Coffee break
14.25 L2: Polymorphisms of LH and its receptor Session IV What about next flights I. Huhtaniemi (UK) Chairs: N. Colacurci (Italy) - E. Porcu (Italy) 14.50 L3: Facts and myths on the “Liaisons dangereuses” between LH and Progesterone Real-time voting app C.Y. Andersen (Denmark) 11.15 L10: Matching patient and protocols in low Revisiting real-time voting app prognosis; is it possible? P. Humaidan (Denmark) 15.15 Panel discussion 11.40 L11: ESHRE Bologna criteria: where are we? 16.00 Coffee break N.P. Polyzos (Belgium)
Session II Flying through literature 12.05 L12: The flip side of LH R. Fanchin (France) Chairs: R. Fischer (Germany) - A. La Marca (Italy) Revisiting real-time voting app Real-time voting app 12.30 Panel discussion 16.30 L4: Is there a role for LH in elderly patients? E. Bosch (Spain) 13.15 Concluding remarks 16.55 L5: LH in low prognosis patients 13.30 End of the conference C. Alviggi (Italy) Closing lunch 17.20 L6: LH in antagonist cycles; is the story really written? R. Orvieto (Israel) Revisiting real-time voting app 17.45 Panel discussion 18.30 End of the first day
Legend: L : Lecture
7 DISCLOSURE OF FACULTY RELATIONSHIPS
EXCEMED adheres to guidelines of the European Accreditation Council for Continuing Medical Education (EACCME ®) and all other professional organizations, as applicable, which state that programmes awarding continuing education credits must be balanced, independent, objective, and scientifically rigorous. Investigative and other uses for pharmaceutical agents, medical devices and other products (other than those uses indicated in approved product labeling/package insert for the product) may be presented in the programme (which may reflect clinical experience, the professional literature or other clinical sources known to the presenter). We ask all presenters to provide participants with information about relationships with pharmaceutical or medical equipment companies that may have relevance to their lectures. This policy is not intended to exclude faculty who have relationships with such companies; it is only intended to inform participants of any potential conflicts so that participants may form their own judgements, based on full disclosure of the facts. Further, all opinions and recommendations presented during the programme and all programme-related materials neither imply an endorsement nor a recommendation on the part of EXCEMED. All presentations represent solely the independent views of the presenters/authors.
The following faculty provided information regarding significant commercial relationships and/or discussions of investigational or non-EMEA/FDA approved (off-label) uses of drugs: Carlo Alviggi Declared receipt of honoraria or consultation fees from Merck Claus Yding Andersen Declared no potential conflict of interest Manish Banker Declared receipt of grants; member of a company advisory board, board of director or similar group Ernesto Bosch Declared no potential conflict of interest Klaus Bühler Declared Receipt of honoraria or consultation fees for lectures from Merck and Takeda Giuseppe De Placido Declared no potential conflict of interest Sandro C. Esteves Declared receipt of honoraria or consultation fees from Merck Renato Fanchin Declared receipt of honoraria or consultation fees from Merck and Ferring; to be member of Merck and Ferring advisory board Annapia Ferraretti Declared no potential conflict of interest Robert Fischer Declared no potential conflict of interest Ilpo Huhtaniemi Declared no potential conflict of interest Peter Humaidan Declared receipt of unrestricted research grants from Merck and Ferring; of honoraria or consultation fees for lectures from Merck and MSD Antonio La Marca Declared no potential conflict of interest Raoul Orvieto Declared no potential conflict of interest Nikolaos P. Polyzos Declared receipt of grants from Merck, Ferring, MSD, Besins International, Roche Diagnostics; of honoraria or consultation fees from Merck and MSD; participation in a Ferring, MSD and Besins sponsored speakers’ bureau Manuela Simoni Declared receipt of grants and contracts from Merck and IBSA; of honoraria or consultation fees from Merck Marc-André Sirard Declared receipt of grants and contracts from Merck; of honoraria or consultation fees from Merck Sesh K. Sunkara Declared no potential conflict of interest
The following faculty have provided no information regarding significant relationship with commercial supporters and/or discussion of investigational or non-EMEA/FDA approved (off-label) uses of drugs as of 10 May 2016. Nicola Colacurci Eleonora Porcu Fulvio Zullo
8 SPEAKER BIOGRAPHIES SPEAKER BIOGRAPHIES
Carlo Alviggi Federico II University Naples, Italy
Carlo Alviggi obtained his MD degree (1994) with a specialty in Obstetrics and Gynaecology (1998), and a PhD in 2001 at the Faculty of Medicine, University of Naples “Federico II”, Italy. In 1998 he was a visiting fellow in the IVF Unit of the Imperial College of London– Hammersmith Campus, where he also collaborated with the Department of Immunology (Imperial College of London). Thereafter, he collaborated with the Laboratory of Immunology of the Italian National Research Council (Naples), the laboratory of Autoimmunity and Tolerance of the University of California (Los Angeles). This collaborative network resulted in various publications some of which concern new hypotheses on the pathogenesis of pelvic endometriosis. Over recent years, he has been working as associate professor in reproductive medicine at the Fertility Unit of the University of Naples “Federico II” (Department of Neuroscience, Reproductive Science and Odontostomatology). Dr Alviggi has published extensively and has been invited to lecture at over 100 international meetings dealing with reproductive medicine and gynaecological endocrinology. He has also served as ad- hoc reviewer for international journals in these fields. He has participated in several national and international (phase II-III) multi- centric, prospective randomised trials. Dr Alviggi’s current research interests are the role of LH in folliculogenesis, the use of LH- containing drugs in patients undergoing ovarian controlled stimulation for IVF, the pathogenesis of pelvic endometriosis, oncofertility, reproduction endocrinology and the genetics of human reproduction.
Claus Yding Andersen University Hospital of Copenhagen Copenhagen, Denmark
Claus Yding Andersen is Professor in human reproductive physiology at University of Copenhagen and has since 2009 been heading the Laboratory of Reproductive Biology at the University Hospital of Copenhagen, Denmark. He qualified first as a Master of Science and is then earned a Doctorate of Medical Science from University of Copenhagen. He was a member of the team which introduced IVF to Denmark in the mid 1980s and has worked in reproduction since then. He leads a national program for cryopreservation of human ovarian tissue and his major research interests include ovarian endocrinology and human embryonic stem cells. He has published more than 300 peer-reviewed papers and has given numerous international presentations.
10 Manish Banker Nova IVI Fertility Pulse Women's Hospital Gujarat, India
Manish Banker is an infertility specialist and the Executive Director of Nova IVI Fertility Clinics India’s largest group of IVF clinics with 12 clinics in 10 cities and Pulse Women’s Hospital Ahmedabad. He completed his undergraduate and post-graduate work with honors at VS Medical College and Hospital, Ahmedabad. After completing his studies, he received advanced training in IVF and Endoscopy in Australia and Germany. He is one of the pioneers in IVF in India and started his IVF practice in 1996; he has more than 6000 successful IVF pregnancies to his credit. He has been the President of the Indian Society for Assisted Reproduction (ISAR) and Chairman of the infertility Committee of the Federation of Obstetric and Gynecological Societies of India [ FOGSI ]. He sits on the International Affairs Committee of the American Society for Reproductive Medicine, Board of Directors of Pacific Rim Society of Reproductive Medicine and Surveillance Board of IFFS, is a Member of the Draft Committee for ART Bill of India, I. C. M. R., Ministry of Health and is the Regional representative for the International Committee for Monitoring ART [ ICMART ], a WHO affiliate. He is also a Founding Board Member of the Asia Pacific Initiative for Reproductive Endocrinology [ASPIRE] [2006 – 2008]. Dr. Banker has delivered numerous talks at International and National Conferences and has to his credit numerous publications and has contributed many chapters to text books. He has been publishing the National ART Registry of India since 2000. Nova IVI Fertility Clinics was launched in August 2011 when Pulse Women’s Hospital joined hands with Nova Medical Centres and IVI, Spain to form India’s largest, most trusted and technologically advanced IVF group. Nova IVI Fertility has well established IVF clinics in Ahmedabad, Bangalore, Chennai, Delhi, Hyderabad, Jalandhar, Kolkata, Mumbai, Pune and Surat and plans to open up 25 IVf clinics across India and the Middle East. Nova IVI has made commendable developments in Indian healthcare within two years of starting operations, and therefore hopes to live up to its vision of being the foremost infertility treatment center in South East Asia.
Ernesto Bosch Instituto Valenciano de Infertilidad Valencia, Spain
Ernesto Bosch was born in Philadelphia, USA, in 1968. He completed Medical School at the University of Valencia in 1992 and from 1993 to 1997, worked as a Specialist in Obstetrics and Gynaecology at Hospital La Fe, Valencia. Ernesto trained in Human Reproduction at the Hospital of the University of Pennsylvania in 1997; and in 1999, he completed his doctoral thesis on the influence of LH in oocyte quality, with “cum laude” qualification, at the University of Valencia. In January 2000, Dr. Bosch joined the team at the Human Reproduction Unit of the Instituto Valenciano de Infertilidad in Valencia; and in 2008 he obtained the title of Master in Research on Health Sciences, by the Autonomous University if Barcelona. Dr. Bosch has published 49 papers and written more than 50 book chapters in the field of IVF; has given over 150 lectures at international meetings around the world; he also belongs to the Editorial Board of Fertility & Sterility , and Reproductive Biomedicine Online as well as being a regular reviewer for Human Reproduction , and Reproductive Biology and Endocrinology among others. He belonged to the Special Interest Group on Reproductive Endocrinology of the Spanish Fertility Society and received the Scientific Program Prize Paper Award at the 2008 Annual Meeting of the American Society for Reproductive Medicine. In May 2010, Dr. Bosch was appointed Medical Director of the Human Reproduction Unit of the Instituto Valenciano de Infertilidad in Valencia.
11 SPEAKER BIOGRAPHIES
Klaus Bühler Centre for Gynaecological Endocrinology and Reproductive Medicine Stuttgart, Germany
Klaus Bühler studied medicine at the University of Heidelberg and obtained his Doctorate in 1976, before specializing in Obstetrics & Gynaecology at the University of Tübingen and serving as a Senior Assistant there. Dr Bühler then became the Assistant Medical Director at the University of Essen, serving under the Head of Department Prof. Dr. A.E. Schindler, with a special field of engagement in gynaecological endocrinology and reproductive medicine. Dr Bühler also served at the Centres for Reproductive Medicine, Saarbrücken, Hamburg & Hanovre; and since April 2012, Centre for Reproductive Medicine and Endocrinology Stuttgart & Ulm. Holding an avid interest in advancing the field, Dr Bühler is a member of the German Society for Obstetrics & Gynaecology; ESHRE, ASRM; The European Society for Obstetrics & Gynaecology of the French and German Languages; Directorial Board of the German Endometriosis Research Foundation; Scientific & Organizing Committee of the International Symposium on GnRH Analogues; Directorial Board of the National IVF Registry (D•I•R); and since 2007, Chairman of the National IVF-Registry (Deutsches IVF- Register). He is also a member of the European IVF Monitoring Group (EIM) of ESHRE. An author of more than 100 scientific publications, Dr Bühler has been invited to join the Editorial Board Journal of Reproductive Medicine and Endocrinology. Current President of the German Dachverband (peak organisation) für Reproduktionsbiologie und Reproduktionsmedizin (DVR), Dr Bühler has had the privilege of being awarded Honorary Membership to the Società Italiana di Medicina Perinatale, as well as receiving a Research Award from the German Endometriosis Research Foundation.
Nicola Colacurci Outpatient Fertility Clinic Second University of Naples Naples, Italy
Nicola Colacurci, Director of the Gynecology and Obstetrics department and Coordinator & President of the triennial Bachelor’s degree in Obstetrics at the Second University of Naples (SUN). Graduated in 1977, Dr. Colacurci boasts numerous managements, is author of more than 450 publications on national and international journals, is editor of 20 monographs on specialized topics, and is a member of the editorial staff of the scientific journal, Italian Journal of Gynecology and Obstetrics ; he is also an investigator in various trials and referee of a great number of international journals.
12 Giuseppe De Placido Federico II University Naples, Italy
Giuseppe De Placido graduated in Medicine and Surgery at University of Naples in 1982 and Clinical fellow in the Department of Gynecological and Obstetric Physiopathology of the II Faculty of Medicine and Surgery, University of Naples. Between 1982 and 1988 he was also Research Fellow of the II Faculty of Medicine and Surgery, University of Naples, whereas in May 1988 he became Associate Professor of Obstetrics and Gynecology at the Obstetrics and Gynecology Clinic of II Faculty of Medicine and Surgery, University of Naples. In 1998 he started covering the role of President of the Course of University Diploma per Obstetrics of the University of Naples “Federico II” (Satellite centres of Avellino and Salerno) and in 2001 he became Ordinary Professor in Gynecology and Obstetrics. Consequently in 2004 he was appointed as Director of the EEC School of Gynecology and Obstetric. Since the academic year 2005-2006, he has been Director of the Postgraduate School of Gynecology and Obstetrics of the University of Naples "Federico II" and Functional Area Director of Surgery Obstetrics and Gynecology, Laparotomy and Endoscopic and Center for the Study and Treatment of Infertility and Infertility Couple. He has also been the author of about 500 scientific publications, published extensively in both international and national journals, and invited speaker to more than 600 national and international medical congresses and conventions.
Sandro C. Esteves ANDROFERT - Andrology & Human Reproduction Clinic Campinas, Brazil
Sandro C. Esteves is the Medical and Scientific Director of ANDROFERT - Andrology and Human Reproduction Clinic referral Fertility Center for male reproduction in Brazil. His Center was the first in Brazil to obtain full ISO 9001 certifications. Dr. Esteves obtained his MD in 1990 from the University of Campinas (UNICAMP), Brazil, where he did his residency training in Urology & Andrology. He completed his training in the United States (1995-1996) as a Fellow at the Cleveland Clinic’s Center for Reproductive Medicine. He was awarded his PhD in 2001 from the Federal University of São Paulo (UNIFESP), Brazil. Dr. Esteves is a Board-certified Urologist and Infertility Consultant with over 15 years of experience. He is a Collaborating Professor in the Department of Surgery (Division of Urology) at the University of Campinas (Brazil) and Research Collaborator at both the Cleveland Clinic's Center for Reproductive Medicine (USA) and the Genetic Unit, Department of Biology, Universidad Autónoma de Madrid, (Spain). He is holds an honorary title of Clinical Tutor in Urology at the University of Edinburgh (UK). His research/clinical interests include male infertility, reproductive endocrinology, cleanroom technology and quality management. Dr. Esteves has published over 130 scientific papers and review articles in peer-reviewed scientific journals, authored over 60 book chapters, and presented over 150 papers at both national and international scientific meetings. His current Hirsch index (h-index) is 24 while his citation count is approximately 2,000. He has served as an editor of five textbooks related to reproductive medicine and assisted reproductive technology. He is the guest editor of three special issues in scientific journals on topics related to reproductive medicine. Sandro serves on the Editorial Board of several Journals and is Associate Editor of the International Brazilian Journal of Urology . Dr. Esteves has been invited as a guest speaker of many international meetings in over 30 countries. He is the recipient of the "Alumni of the Year" Award from the Cleveland Clinic Center for Reproductive Medicine, and the Star Award from the American Society for Reproductive Medicine for the last 4 years.
13 SPEAKER BIOGRAPHIES
Renato Fanchin Hospital A. Béclère and University Paris-Sud Clamart, France
Renato Fanchin is the Chief of the Division of Reproductive Medicine, Department of Gynaecology and Obstetrics, Antoine Béclère Hospital, Clamart, France. He accomplished his specialization in Obstetrics and Gynaecology and Reproductive Medicine in France and obtained his PhD degree from University of Paris-Sud 11 in 2005. Professor Fanchin has been invited to speak in over 150 international meetings, is a full member of the Society for Gynecologic Investigation, and was awarded the Society for Assisted Reproductive Technology Prize Paper by the American Society for Reproductive Medicine in 1999. He is an active member of the INSERM unit 782 and his current research interests include the assessment of ovarian follicular status, ovarian ageing, and controlled ovarian hyperstimulation strategies. Prof. Fanchin, along with his colleagues, has published over 170 peer-reviewed articles in international journals. Under his clinical direction, the Center for Reproductive Medicine at Antoine Béclère Hospital, Clamart, France, is currently ranked number #1 in France in terms of delivery/oocyte retrieval.
Annapia Ferraretti Società Italiana Studi di Medicina della Riproduzione Bologna, Italy
Anna Pia Ferraretti holds a University Degree in Obstetrics and Gynecology and a PhD in Endocrinology. She has been a specialist in Reproductive Medicine since the late 1970s. At present, she is Coordinator of Gynecological Endocrinology at S.I.S.Me.R. Reproductive Medicine Unit, Bologna, Italy. She is a member of several national and international scientific societies in the field of Reproductive Medicine and Biology. From 2011 to 2013 she was chairman of the EIM (European IVF Monitoring) Consortium of the European Society of Human Reproduction and Embryology (ESHRE). Moreover, she is a current member of the ESHRE Special Interest Group on Socio-cultural aspects of (in)fertility. She is author (or co-author) of more than 250 publications and collaborates with several scientific journals as a reviewer.
14 Robert Fischer Fertility Centre Hamburg Hamburg, Germany
Robert Fischer is founder and Medical Director of the IVF unit at the Fertility Center Hamburg - one of Germany’s largest and leading IVF centres. In July 1998 the Fertility Center Hamburg was one of the first centres in Germany, and worldwide, to introduce certified quality management according to the ISO 9001. In 2002, the IVF laboratory became ISO 17025 certified. Prior to these developments, in 1983 he pioneered and was medical director of the first outpatient IVF unit in Hamburg. Author of numerous publications in national and international scientific journals and books, as wellas lecturer at conferences worldwide, he is also an active member of the American Society of Reproductive Medicine, founding member of the European Society of Human Reproduction and past member of its advisory committee as well as founding member of the German reproductive organisations, “AG Gynäkologische Endokrinologie und Fortpflanzungsmedizin” and “Berufsverband Reproduktionsmedizinischer Zentren”.
Ilpo Huhtaniemi Institute of Reproductive and Developmental Biology Hammersmith Campus, Imperial College London London, UK
Ilpo Huhtaniemi received his MD and PhD from the University of Helsinki, Finland, did postdoctoral training in the USA (UC San Francisco and NIH, Bethesda), and has been on sabbatical leave in Germany, USA and Scotland. He held 1986-2002 the post of Professor and Chairman of Physiology at the University of Turku, Finland. He moved in 2002 to the UK to become Chair of Reproductive Endocrinology at Imperial College London. He has received several national and international honours, among them a fellowship of The Academy of Medical Sciences (UK) and a Doctor Honoris Causa at the Medical University Lodz, Poland, and University of Szeged, Hungary. He has been the Chief Managing Editor of Molecular and Cellular Endocrinology since 1999, has served on the Editorial Board of Endocrinology and Endocrine Reviews and is/has been the Editor or Editorial Board Member of several other scientific journals (e.g. Eur J Endocrinol, Clin Endocrinol, Hum Reprod Update, J Endocrinol, Mol Hum Reprod, Reproduction, Asian J Androl ). He has extensive experience as Official of international scientific organizations (e.g. Past President of International Society of Andrology). His research interests include clinical and basic reproductive endocrinology, in particular the function of gonadotrophins and male reproductive endocrinology. He also has long-term interests in development of male contraception, hormone-dependent cancer, and the endocrinology of ageing. His H factor is 71, and he has authored >650 peer- reviewed research articles and reviews.
15 SPEAKER BIOGRAPHIES
Peter Humaidan Fertility Clinic Skive Regional Hospital and Faculty of Health Aarhus University Aarhus, Denmark
Peter Humaidan is a specialist in reproductive endocrinology, Professor at The Fertility Clinic at Skive Regional Hospital, Aarhus University, Denmark, and Honorary Professor at Odense University, Denmark. He trained at the Sahlgrenska University Hospital, Gothenburg, Sweden. During his scientific work he has primarily focused on developing individualized treatment protocols for the infertile patient. His doctoral thesis (DMSc) explored the role of LH during the follicular and luteal phases in controlled ovarian stimulation. His main fields of interest are triggering ovulation with GnRH agonist, the use of GnRH antagonists, and OHSS prevention. He is the founder of the international society “The Copenhagen GnRHa Triggering Workshop Group” and board member of the ESHRE SIG Endocrinology Group. He has authored 100 + articles (H-index 26) in international peer reviewed journals as well as the Danish guidelines for OHSS prevention and chapters in textbooks. Peter Humaidan has a wide international scientific network and is frequently invited as a speaker at international conferences.
Antonio La Marca University of Modena and Reggio Emilia and Clinica Eugin Modena, Italy
Antonio La Marca is Professor of Obstetrics and Gynecology at the Mother-Infant Department of the University of Modena and Reggio Emilia, Italy and he is the Medical Director of Clinica Eugin, Modena, Italy. He graduated in Medicine and Surgery at the University of Siena in 1996, specializing in Obstetrics and Gynaecology at the same institution in 2001. In 2006 he obtained a PhD, again at the University of Siena. He has been working at the Institute of Gynaecology and Obstetrics of the University Hospital of Modena since 2003. His clinical activity covers all the field of Reproductive Medicine and Surgery and has taken part in thousands of IVF cycles, laparoscopic and hysteroscopic surgical procedures. Present scientific interests include: ovarian reserve and pharmacological manipulation of ovarian activity. His most impactful articles concerned the physiological significance of AMH and AFC, their measurement and clinical utility. Moreover, he has published a long list of original articles dealing with the prediction of ovarian reserve and response in IVF and the personalization of ovarian stimulation protocols. He is author or co-author of 128 articles published in peer-reviewed journals and authored many chapters in national and international textbooks. He has been an Invited speaker in more than 100 international congresses. He is involved in several phase three and four trials as Principal Investigator and is the recipient of many competitively assigned research funds. He is an active member of many national and international professional and scientific societies and a consultant for the Italian Ministry of Health for female fertility-related issues.
16 Raoul Orvieto The Chaim Sheba Medical Center Tel Hashomer, Israel
Raoul Orvieto is a full Professor at the Sackler Faculty of Medicine, Tel Aviv University and the Director of the Infertility and IVF unit, at the Sheba (Tel-Hashomer) Medical Center, Israel. He has been author and co-author of more than 200 publications in national and international journals. His scientific interests include various aspects of controlled ovarian hyperstimulation (COH). The role of GnRH-analogues, and specifically GnRH agonist versus antagonist in COH for IVF and several aspects of ovarian hyperstimulation syndrome (OHSS): pathophysiology, prediction, prevention and its relation to the inflammatory response.
Nikolaos P. Polyzos Vrije Universiteit Brussel Center for Reproductive Medicine Universitair Ziekenhuis Brussel Brussels, Belgium
Nikolaos P. Polyzos is a Professor in the Vrije Universiteit Brussel and Medical co-director in the Center for Reproductive Medicine in the Universitair Ziekenhuis Brussel in Belgium. Since 2015 he is also an Honorary Professor in Reproductive Endocrinology at the University of Aarhus in Denmark. Professor Polyzos is a key opinion leader regarding the treatment of poor ovarian responders in IVF programs, prediction of ovarian response and premature ovarian ageing. He is an invited speaker in approximately 20 conferences and congress per year in Europe, Asia and South America and has published more than 100 publications in peer reviewed journals indexed in Pubmed. He serves as a reviewer in 23 journals including BMJ, JCEM, Hum Reprod, Hum reprod Update, Fertil Steril, RBMonline, BJOG . His research interests include reproductive endocrinology, ovarian reserve markers, poor ovarian response to stimulation and genetics of premature ovarian ageing
17 SPEAKER BIOGRAPHIES
Eleonora Porcu University of Bologna Bologna, Italy
Eleonora Porcu has been Medical Doctor and Assistant Professor in Reproductive Medicine at the University of Bologna since 1977. She is an Obstetrician and Gynecologist and the Director of the Infertility and Assisted Reproduction Center at the S. Orsola-Malpighi University Hospital in Bologna. Her fields of research include adolescent hyperandrogenism and PCOS, endocrinology of infertility, reproductive cryostorage with special involvement in human oocyte cryopreservation. She published a number of peer-reviewed papers, gave several invited main lectures including the ASRM and the ESHRE meetings and received the International Federation of Fertility Societies 30th Anniversary Recognition Award for significant contributions in Infertility and Reproductive Medicine.
Manuela Simoni University of Modena and Reggio Emilia Modena, Italy
Manuela Simoni obtained her MD in 1982, a Specialisation in Endocrinology and Metabolism in 1985 and a PhD in Endocrinology and Metabolism in 1991. Between 1990 and 2007 she worked at the Institute of Reproductive Medicine of the University of Münster, Germany, where she was Professor for Endocrinology and Molecular Biology of Reproduction from 1998. Since 2008 she is full Professor for Endocrinology at the University of Modena and Reggio Emilia, Italy, where she currently holds the following positions: Chair of Endocrinology; Director of the Clinical Unit of Endocrinology at the NOCSAE Hospital, Director of the School of Specialization in Endocrinology, and Deputy Director of the Department of Biomedical, Metabolic and Neural Sciences. Her research interests are gonadotropin and androgen action, testicular function, genetics of male infertility, as well as endocrinology and pathophysiology of reproduction. She is a member of several societies, including the European Academy of Andrology (EAA) and the European Society of Endocrinology (ESE, serving as the Secretary) and is active on the editorial boards of several journals in the fields of endocrinology and reproduction.
18 Marc-André Sirard Centre de Recherche en Biologie de la Reproduction Laval University Québec, Canada
Marc-André Sirard after completing graduate studies at the University of Laval (Canada) during which in vitro fertilization generated the first clinical method producing test-tubes calves in 1985. Dr. Sirard attended post-doctoral training at the laboratory of Neal First in Wisconsin (USA) to study in vitro maturation of oocytes. Dr. Sirard returned to Québec in 1987 and became a industrial chair professor in 1990. He founded the Centre de Recherche en Biologie de la Reproduction in 1995 which has grown to employ more than 100 people today. He obtained a senior Canadian Research Chair in 2000 in genomics applied to reproduction and is leading an international effort to define the normal genomic program in early mammalian embryos which became an NSERC strategic network in 2008. He has published over 252 scientific papers and has been invited to give over 70 invited lectures in international meetings. His current research activities focus on the influence of the ovarian environment on oocyte quality in humans and large animals.
Sesh K. Sunkara Aberdeen Fertility Centre Aberdeen Maternity Hospital Aberdeen, UK
Sesh K. Sunkara is a Consultant Gynaecologist and Subspecialist in Reproductive Medicine and Surgery. She specialised in the field of Obstetrics and Gynaecology and is a Member of the Royal College of Obstetricians and Gynaecologists (MRCOG), UK. She undertook translational research in Reproductive Medicine at the Assisted Conception Unit, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London which formed the basis for her Research degree in Reproductive Medicine; Doctor of Medicine (MD) awarded by King’s College London. She has dual accreditation with the UK General Medical Council as a specialist in Obstetrics and Gynaecology as well as Reproductive Medicine. She worked as a Consultant gynaecologist and Subspecialist in Reproductive Medicine at the Aberdeen Fertility Centre, University of Aberdeen before moving to Barking Havering and Redbridge University Hospitals to set up a new IVF service. In addition to her clinical work, she has published in the field of Reproductive Medicine and authored several book chapters. She has organised and participated in several national and international symposia and workshops in the field of Reproductive Medicine. She is the Associate Editor for Human Reproduction Journal by the European Society of Human Reproduction and Embryology (ESHRE). She is on the executive board for the RCOG – Reproductive Medicine Clinical Studies Group which is actively involved in supporting multi-centre research studies in the UK.
19 SPEAKER BIOGRAPHIES
Fulvio Zullo Reggio Calabria University Catanzaro, Italy
Fulvio Zullo graduated in Medicine and Surgery in 1984 from the University of Naples and was admitted to the PhD course in “Perinatal Medicine” at the University of Perugia which he completed in 1990. In 1988 he specialized in Obstetrics & Gynecology at University of Naples and, between June 1998 and December 1990, he was a Post-doctoral Fellow at the Reproductive Immunology Laboratory of Eastern Virginia Medical School and at Jones Institute for Reproductive Medicine. In 1994 he also specialized in General Surgery at the University of Naples. Since 1998 he has been Director of a Bachelor’s degree course in Obstetrics at University “Magna Graecia” of Catanzaro and since November 2000, he has also filled the role of Associate Professor. Since 2006 Professor Zullo has also served as Director of the Operating Unit of Oncological Gynecology of the “Tommaso Campanella” University Campus Excellency Cancer Centre. Professor Zullo has also filled the role of Coordinator for the PhD course in Advanced Research Methodologies in applied surgery at the Oncology XXIV department of University Magna Graecia of Catanzaro, since 2008.
20 ABSTRACTS L1. Physiology of LH and differences with hCG
Manuela Simoni 1,2 and Livio Casarini 1 1. Department of Biomedical, Metabolic and Neural Sciences, University of Modena & Reggio Emilia and 2. Unit of Endocrinology, Azienda USL of Modena, Modena, Italy
Luteinizing hormone (LH) and choriogonadotropin (hCG) are glycoprotein hormones regulating ovarian function and pregnancy, respectively. Since these molecules act on the same receptor (LHCGR), they were traditionally assumed as equivalent in assisted reproduction techniques (ART), although differences between LH and hCG were demonstrated at molecular and physiological level. We recently demonstrated that co-treatment with a follicle-stimulating hormone (FSH) dose in the ART therapeutic range potentiates different LH- and hCG-dependent responses in vitro , measured in terms of cAMP, phospho-CREB, -ERK1/2 and -AKT activation, gene expression, progesterone and estradiol production in human granulosa-lutein cells (hGLC). In addition we showed that, in the presence of FSH, hCG biopotency is about 5-fold increased, in the presence of FSH, in terms of cAMP activation. Accordingly, CREB phosphorylation and steroid production is increased under hCG and FSH co-treatment. LH effects, evaluated as steroidogenic cAMP/PKA pathway activation, do not change in the presence of FSH, which, however, increases LH-dependent ERK1/2 and AKT, but not CREB phosphorylation, resulting in antiapoptotic effects. The different modulatory activity of FSH on LH and hCG action in vitro corresponds to their different physiological functions.
22 L2. Polymorphisms of LH and its receptor
Ilpo Huhtaniemi Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College London London, UK
The genes of luteinizing hormone -subunit (LHB) and luteinizing hormone/choriongonadotrophin receptor (LHCGR) contain several β common polymorphisms, and their occurrence has been studied in relation to various phenotypic signs of male and female gonadal dysfunction, including hypogonadism and infertility. The best known LHB polymorphism is W8R/I15N, also called LH variant, which has a vastly varying frequency around the world. The two amino acid alterations in LH structure clearly affect the behaviour of LH in vivo and in vitro. The majority of findings indicate that variant LH has increased in vitro bioactivity but shortened half-life in circulation, thus apparently influencing the kinetics of physiological LH action. The connection of variant LH with human fertility remains largely elusive, but studies especially from Asia have found its association with polycystic ovary syndrome (PCOS) and marginal female subfertility. In boys it has ben found at higher frequency in cryptorchidism and upon slow pace of pubertal maturation, and in men in connection with sporadic prostate cancer. As concerns LHCGR , less obvious functional associations have been detected with polymorphisms. There are some reports on their association with male undermasculinization. In women some LHCGR polymorphisms have been shown to associate with PCOS. Ii is possible that with increasing knowldge about the genotype/phenotype correlates of LHB and LHCGR polymorphisms they might offer novel pharmacogenomics toosl for individualized hormone treatment of subfertility.
23 L3. Facts and myths on the “Liasons dangerous” between LH and Progesterone
Claus Yding Andersen University Hospital of Copenhagen, Copenhagen, Denmark
Human ovarian steroidogenesis has two end products; oestradiol is the most well-known with many well described endocrine functions, whereas progesterone being the other one end product is less well established and has recently mistakenly been described as an intermediate in the biosynthesis of oestradiol. Progesterone is synthesized primarily by the granulosa cells and intrafollicular concentrations of progesterone increase in parallel with growth and development of the follicle during the follicular phase of the menstrual cycle. Close to ovulation, concentrations of progesterone in follicular fluid is more than a thousand times higher than in circulation and considerably higher than concentrations of oestradiol. Progesterone also exerts physiological functions in the follicular phase among which is a pituitary function in eliciting the mid-cycle surge of gonadotropins. Regulation of human ovarian steroidogenesis is complicated and involves gonadotropins, growth factors and hormones acting both locally and systemically. Granulosa cells progesterone synthesis is stimulated by both FSH and LH, but it appears that LH is more potent than FSH in stimulating progesterone synthesis. Interest in how progesterone synthesis is regulated has received a lot of attention recently because several studies and meta-analyses have demonstrated that women who show a small progesterone rise, usually just above 1.5 ng/ml (≈ 5 nmol/L), have a reduced chance of conceiving in connection with infertility treatment. Many studies have addressed the issue without demonstrating an underlying mechanism for the observed reduction in pregnancy rate. An apparent paradox exists: 1. Embryos from cycles with elevated progesterone implanted equally well and other embryos in FER cycles suggesting that embryo quality is not compromised. 2. Others concluded that the premature elevation of the progesterone caused an advancement of the endometrium resulting in a less receptive state. However, high responder women with elevated progesterone show similar or even better pregnancy rates than those with low progesterone suggesting that the endometrium is not the cause. Metaphorically it could be argued that these data demonstrate that it is neither the soil nor the seed which is causing an attenuated reproductive outcome. The lecture will present a totally new theory on the underlying cause of the reduced reproductive potential in patients with an elevated follicular phase progesterone level including a closer analysis of how gonadotropins regulate progesterone synthesis and prime granulosa cells.
24 L4. Is there a role for LH in elderly patients?
Ernesto Bosch Instituto Valenciano de Infertilidad, Valencia, Spain
Older patients have different endocrine features than younger patients, which make controlled ovarian stimulation (COS) more challenging for this population. On one hand, older patients have an increased early follicular phase FSH, without an accompanied elevation of LH levels. This increase starts in the luteal-follicular transition and as a consequence, older patients have a shorter follicular phase with an accelerated follicular growth, and presents follicular rupture at a smaller diameter. However, despite being the best known age-related endocrine change, is not the only one. There is also a steady decrease of androgens that ranges from menarche to menopause. This diminishment is as much as 49% of testosterone levels, or 77% of DHEA levels. And moreover, this decrease in androgen concentrations occurs without a diminishment of SHBG levels. Apart from this reduction in the basal concentrations of androgens, there is also an impairment of their synthesis in response to stimulation with recombinant FSH: It has been shown that while the capability of the follicles of older women to produce estradiol in response to rFSH stimulation is well preserved, this is not the case for the synthesis of androstenodione, which is significantly lower in older women when compared to young patients. These findings suggest a deficiency of the theca layer function in older women. It has been shown that the administration of LH for COS from the beginning of stimulation induces a significant and dose dependent increase of follicular androgens, which are later aromatized to estrogens. Therefore, LH administration would restore the follicular environment in these patients, leading to a proper maturation of the oocyte. We have shown that women with lower basal testosterone levels, perform better when LH is supplemented. Conflicting results are shown in clinical trials comparing COS cycles with LH supplementation versus FSH cycles alone. However, a meta-analysis of these trials concludes that there is an increase in clinical pregnancy rates when LH is added. An detailed analysis of these trials suggests that the positive impact of LH supplementation is observed only when it is given from the beginning of stimulation, while LH adding from stimulation day 6 may not be efficient. In anyhow, there is not available a clear biomarker of the need of LH for COS. Age over 35 seems to be he most reliable parameter at this point, but a less arbitrary factor should be defined.
25 L5. LH in low prognosis patients
Carlo Alviggi and Alessandro Conforti Federico II University, Naples, Italy
Despite the advent of new drugs and the consequent development of patient-oriented ovarian stimulation protocols, many patients worldwide receive identical treatment. However, a tailored approach is crucial to maximize results, manage risk and optimize the cost effectiveness profile. In this scenario, a clear definition of patients with impaired response to controlled ovarian stimulation (COS) remains a controversial issue. In 2011, a consensus for a definition of poor ovarian response (POR), known as the “Bologna criteria”, was published. In brief, the system is based on three major criteria: (i) advanced age ( ≥ 40 years) or any other POR risk factor; (ii) a previous episode of POR; and (iii) an abnormal ovarian reserve test (AMH and AFC). Two of these three major criteria are required for a POR diagnosis. These criteria have the indubitable value of attempting, for the first time, to standardize the definition of an intrinsically heterogeneous event. Many studies demonstrated that these criteria are useful in the clinical setting to predict the outcome of IVF and are effective for counselling purposes. However, the use of these criteria in clinical trials has been questioned because they entail the risk of grouping together women that differ meaningfully in terms of biological characteristics. Recently, a group of experts (the Poseidon Group) proposed a more detailed stratification of low responders to ovarian stimulation that moves from the classical POR to a “low prognosis” concept. The definition of “low prognosis” patients introduces two new categories of impaired response to exogenous gonadotropin: (i) a “suboptimal response”, defined as the retrieval of four to nine oocytes, which is associated, at any given age, with a significantly lower live birth rate compared with normal responders; and (ii) a “hyporesponse” in which a higher dose of gonadotropins and more prolonged stimulation are required to obtain an adequate number of oocytes. In detail, several lines of research reinforce the hypothesis that a “hyporesponse” could be related to specific gene polymorphisms. The Poseidon group proposed the following four groups of low prognosis patients:
Group 1: Young patients ( <35 years) with sufficient pre-stimulation ovarian reserve parameters (AFC ≥ 5 and AMH ≥ 1.2 ng/mL) and with an unexpectedly poor or suboptimal ovarian response. This group can be subdivided into: subgroup 1a, constituted by patients with fewer than four oocytes; and subgroup 1b, constituted by patients with four to nine oocytes retrieved after standard ovarian stimulation, who, at any given age, have a lower live birth rate than age-matched normal responders.
Group 2: Older patients ( ≥ 35 years) with sufficient pre-stimulation ovarian reserve parameters (AFC ≥ 5 and AMH1.2 ng/mL) and with an unexpectedly poor or suboptimal ovarian response. This group can be subdivided into: subgroup 2a, constituted by patients with fewer than four oocytes; and subgroup 2b,constituted by patients with four to nine oocytes retrieved after standard ovarian stimulation, who, at any given age, have a lower live birth rate than age-matched normal responders.
Group 3: Young patients ( <35 years) with poor pre-stimulation ovarian reserve parameters (AFC <5 and AMH <1.2 ng/mL). Group 4: Older patients ( ≥ 35 years) with poor pre-stimulation ovarian reserve parameters (AFC <5 and AMH <1.2 ng/mL). Based on this classification, we will propose how to determine the need for LH supplementation in the specific subgroups of low prognosis women. For instance, at least three randomized controlled trials (RCTs) and one meta-analysis have demonstrated that LH supplementation is effective in women with a hyporesponse profile who present features as patients belonging to our Group 1. In addition, LH administration has been associated with improvement in the outcome of IVF in women between 35 and 39 years of age, who would be classified in our Groups 2 and 4. Conversely, a recent RCT did not identify any benefit from LH administration in POR patients selected according to the Bologna criteria. In conclusion, the stratification proposed by the Poseidon group may serve as a guide to personalize treatment protocols by, for example, using different GnRH analogue regimens, detecting polymorphisms of gonadotropins and their receptors, tailoring the FSH starting dose and LH supplementation.
26 L6. LH in antagonist cycles; is the story really written?
Raoul Orvieto The Chaim Sheba Medical Center, Tel Hashomer, Israel
The aim of the presentation is to illustrate the available evidence that examine the role of LH supplementation and methods to trigger final follicular maturation in patients undergoing controlled ovarian hyperstimulation (COH), using the GnRH-antagonist protocol. With this purpose in mind, a literature review was conducted for all relevant articles assessing methods for identifying patients most likely to benefit from the addition of “LH activity” supplementation to their COH protocol and the mode and timing of ovulation triggering, aiming to improve IVF outcome while eliminating of severe OHSS. According to our findings, the available studies on the role of LH supplementation in patients undergoing ART use different preparations, different daily doses and mode of administration. Moreover, variability exists between the commercial kits and the cut- off used when assessing the different biomarkers. Patients undergoing COH with the GnRH-antagonist protocol that may benefit from LH supplementation, and could be identified prior to COH, are high and poor responder patients, those with advanced age and those with high basal FSH/LH ratio. Moreover, patients demonstrating raised progesterone levels at day of hCG administration may benefit from the addition of LH to their subsequent COH for IVF. In patients at risk of developing severe OHSS, GnRH agonist (GnRHa) trigger is offered for final follicular maturation. While in those achieving >20 oocytes, the freeze all policy with the subsequent frozen-thawed embryo transfers (ET) is recommended, while in those where less than 20 oocytes are retrieved, an additional bolus of 1500 IU of HCG may be supplemented. In patients not at risk of developing severe OHSS- three different modes of concomitant administration of both GnRHa and a standard bolus of hCG (5000–10,000 units) prior to oocyte retrieval are suggested. Standard hCG dose concomitant with GnRHa (dual trigger), 35-37h before oocyte retrieval is offered to normal responders patients, resulting in improved oocyte/embryo quality and IVF outcome. GnRHa 40h and standard hCG added 34h prior to oocyte retrieval (double trigger), respectively, are offered to patients demonstrating abnormal final follicular maturation despite normal response to COH. The double trigger results in significantly higher numbers of retrieved oocytes, higher proportions of the number of oocytes retrieved to the number of follicles >10mm and >14mm in diameter on the day of hCG administration, a higher number of MII oocytes and proportion of MII oocytes per number of oocytes retrieved, with the consequent significantly increased number of top-quality embryos, as compared to the hCG-only trigger cycles. Standard hCG dose concomitant with GnRHa (dual trigger), 34h before oocyte retrieval should be offered to poor responder patients, aiming to overcome premature luteinization, while achieving a high yield of mature oocytes. In conclusion, the use of LH supplementation is associated with a tendency toward an improved IVF outcome in different subgroups of patients undergoing COH for IVF. While few of the selected indications for LH supplementation are based on evidence-based medicine, others are supported by observational studies. Therefore, further large studies are needed to investigate the true impact of LH supplementation on IVF outcome and to identify the selected groups of patients who are most likely to benefit from the addition of “LH activity” supplementation to their COH protocol. While a personalized, tailored mode and timing of triggering final follicular maturation seem to improve IVF outcome, further studies are required to support this new concept prior to its universal implementation to IVF practice.
27 L7. The European point of view
Klaus Bühler Centre for Gynaecological Endocrinology and Reproductive Medicine, Stuttgart, Germany
The number of papers published with randomised controlled trial (RCT) or meta analysis (MA) has increased sharply within the last ten years in the field of reproductive medicine. A single study is at great risk of not detecting with certitude differences of diverse treatment options. Single trials often are very low in number of included patients and therefore the statistical power is seldom very strong even if the trial was conducted as RCT. MA and systematic reviews are viewed as providing the highest level of evidence and are established in order to overcome the pitfalls of very often underpowered studies in reproductive medicine. However, even statistical evidence does not mean clinical evidence. And nevertheless, such studies are not completely free of drawbacks and can also show several biases such as selection, performance, detection, publication or e.g. time lag bias. The examined patient groups are mostly well selected and a lot of inclusion and exclusion criteria are limiting the results to be applied to a great number of patients in the daily treatment of subfertility. So, real world data become more and more important. They reflect our daily general practice. If data collection is done in an appropriate way, e.g. prospectively, with the high number of cases, selected powerful statistics can be performed. So, the use of gonadotropins during the last decades is evaluated on the basis of the data of one of the greatest and oldest IVF registries. We focused our attention on the use of recombinant LH in daily routine controlled ovarian stimulation.
28 L8. The Indian point of view
Manish Banker Nova IVI Fertility, Pulse Women's Hospital, Gujarat, India
India has a population of 1.3 billion people with Infertility affecting 10-15% of married couples, which amounts to about 27.5 million couples of reproductive age. However, only 1% of infertile couples in India seek treatment. India’s population has a high youth percentage, with approximately 50% of the population in the fertility age bracket. For a 27.5 million infertile population, only 0.1 million IVF cycles are performed every year; i.e. around 75 – 80 cycles / million population. India has the potential to conduct approximately 1500 cycles /million population. The market is expected to grow at a CAGR (Cumulative Average Growth Rate) of ~20% from the current 100,000 cycles to 260,000 cycles in 2020. The estimated IVF market is projected to be 12.6 million USD by 2030. Then why is this potential not realized? This is due to a variety of factors including: affordability of treatment and awareness. Only 21% of households in India can afford treatment for infertility. In addition, the IVF market in India is fragmented, with 55% of all IVF cycles being performed in the 8 main metro cities. Out of 118 centers that contributed to NARI in 2014, only 1 center performed more than 500 cycles / year, 89 out of 118 centers performed less than 50 cycles a year. This affects access to quality treatment. In this scenario, when it comes to LH use in India, apart from the science, financial aspects also play a major role. This is mainly due to 3 reasons: first, the relatively higher contribution of IVF medications in the IVF package, especially recombinant drugs. The average cost of an IVF cycle in India is Rs. 100,000- Rs. 200,000 [ 1500 to 3000 USD ], out of which drugs contribute to 30- 50% of the total cost, depending on whether indigenous urinary or recombinant drugs are used. Many centers use hMG as a surrogate LH supplement to reduce costs and thus reduce the patient’s financial burden. The second reason is the fragmented market. The third is the lack of convincing data that rec FSH + rec LH is at least as cost effective as rec FSH + hMG OR hMG alone, in the Indian patient population where LH use is recommended (patients with advanced maternal age and poor ovarian reserve). In places where the market is structured and organized, SOP driven, and where affordability is not a problem, LH use is a lot more prevalent. The data I present is mainly sourced from: 1. NARI (National ART Registry of India): this is a voluntary registry by the Indian Society for Assisted Reproduction [ ISAR ]. It covers approximately 15 % of all clinics and 25 - 30 % of all cycles. 2. E&Y market survey report. 3. Nova IVI Fertility database. According to the NARI registry data, which covers cycles from 2002- 2006, the use of recombinant LH along with recombinant FSH was 0.03% in 2005 and 0.7% in 2006. The use of hMG in combination with recombinant FSH between 2002- 2006 was as follows:
Drug used (%) 2002 2003 2004 2005 2006 hMG + FSH 24.2 26 27.4 25 22.9 hMG + recFSH 18.7 29.3 34.6 26.4 24.1
Our NIF database shows that recombinant LH was used in 2.33% (192 / 8252) of IVF cycles between January 2014 and March 2016. The lineal pregnancy rate in these cycles was 34.4%. The primary indications for LH use were advanced maternal age, poor ovarian reserve and endometriosis. In NIF Ahmedabad, the results [Jan 2014 to June 2015] according to the medications used was as follows:
Total No: 1024 Clinical pregnancy rate Live birth rate
FSH alone (277) 49.8 % (138/277) 41.1 % (114/277) HMG alone (197) 38.6 % (76/197) 27.4 % (54/197) recFSH + HMG (550) 42.7 % (235/550) 31.6 % (174/550)
29 L9. The Latin America approach
Sandro C. Esteves ANDROFERT - Andrology & Human Reproduction Clinic, Campinas, Brazil
At the completion of this presentation, participants should be able to: 1. Appraise the Latin America Registry data concerning LH supplementation in ART; 2. Understand the general experience of Latam doctors with LH supplementation, and how this compares with our own experience at Androfert Center. 3. Discuss our confidence in the use of LH supplementation in clinical practice. Although exogenous FSH is the main regulator of follicular growth in stimulated cycles, LH plays a key role in promoting steroidogenesis and follicle development. Despite being mandatory in patients with hypogonadotropic hypogonadism, stimulation protocols with LH supplementation in normogonadotropic women undergoing controlled ovarian stimulation (COS) for ART are equivocal. In Latin America there are three groups of commercially available gonadotropin preparations containing LH activity, namely, (i) hMG/HP-hMG, in which LH activity is provided by hCG, (ii) recombinant LH (lutropin alfa), and (iii) a combination of recombinant FSH (follitropin alfa) and recombinant LH (lutropin alfa) in a fixed ratio of 2:1. While purified urinary preparations and recombinant LH have been available since 2001, the new 2:1 ratio combination of rec-hFSH and rec-hLH in was launched in 2010. REDLARA (Registro Latinoamericano de Reprodución Asistida) 2012-2013 data indicates that ovarian stimulation protocols which include exogenous LH are adopted in over 60% of ART cycles. Of these, urinary LH activity has been the preferred approach and comprised ~80% of all cycles involving exogenous LH. Notably, there is a marked variation among clinicians with regard to LH supplementation regimens and start time of supplementation. Most often, hMG is added to rec-hFSH during stimulation. Notwithstanding, GnRH antagonist cycles represented the vast majority of those carried out with LH supplementation in 2013 (82.7%). Also, a clear tendency toward the use of ovarian stimulation with exogenous LH in older women is noted (82.6% and 70.2% of all cycles among women aged 35-39 and ≥40, respectively, and 56% of all cycles among those aged 34 or less). Recombinant LH is given more often to women aged 35-39 years (32.2% of cycles) than to other age groups (14.6% and 8.7% of all cycles in women aged ≥40 and ≤34 years, respectively). According to REDLARA data with regard to delivery rates, differences were not noted between those receiving or not exogenous LH irrespective of the type of LH activity provided across age groups. On the contrary, our practices have been remarkably different than those reported by REDLARA within the same period. Despite having used LH supplementation in a similar proportion of cycles (58.3%), rec-hLH was our preferred approach and comprised 93% of all cycles involving exogenous LH. LH supplementation was prescribed to only 33% of patients aged ≤34 and to 88% and 95.6% of those with 35-39 and ≥40 years, respectively. Among all treated patients, we have used GnRH antagonists in over 90% of all treated patients. In our practice, exogenous rec-hLH is prescribed in combination with rec-hFSH in a ratio of 1:2 to: i. Expected or proved poor responders at any age; ii. Hypo-responders at any age; and iii. Women of 35 years of age or older not fitting in the aforesaid categories. As far as live birth rates per fresh transfers are concerned, we have compared our results to those of REDLARA. Likewise in the gonadotropin regimes, the differences in LBR were also significant across all age groups. The magnitude of effect size was more pronounced among women receiving exogenous LH within the age 35-39 age group (19.2% vs. 37%; p <0.0001). In conclusion, our data analysis indicates that ovarian protocols which include exogenous LH are widely used in Latin America. LH activity from hMG preparations is the prevailing practice among doctors. Exogenous LH is prescribed widely to women aged 35 years and older; this practice is applied to 3 out of 4 treatment cycles, but delivery rates as per REDLARA data do not seem to differ as a function of exogenous LH across all age groups. As far as our experience is concerned, not only our practices differ but also do the outcomes. Our center’s data are reassuring and add confidence to the way we use LH supplementation. Although ART success is dependent on a multitude of controlled and non-controlled factors, this data analysis suggest that exogenous LH mode of use has an important impact on pregnancy outcomes. This indicates that ample educational opportunities exist in Latin America with regard to the use of LH supplementation to maximize cycle outcome.
30 L10. Matching patient and protocols in low prognosis; is it possible?
Peter Humaidan Fertility Clinic, Skive Regional Hospital, and Faculty of Health, Aarhus University, Aarhus, Denmark
The incidence of poor response during ART has been previously reported to vary from 9 – 24 %. However, until the ESHRE Bologna criteria for POR (2011) was established, no strict criteria to define POR existed, which hampered the conclusions made from previous clinical trials and meta-analyses. However, even the Bologna criteria have subsequently been criticized for being too strict and in reality defining patients with low success rates and who in reality are better off with oocyte donation. In this lecture a further attempt to define the poor responder patient will be made, taking into account ovarian reserve and age which are the two most important key factors to predict success after IVF treatment. Four different sub-groups of poor responder patients will be defined as well as suggestions for matching protocols and regimens which per definition might increase the success rate of the patient. Moreover, a review of strategies and adjuvants as well as future therapeutical options for the poor responder patient will be presented. The impact of different stimulation protocols on the ovarian response to stimulation in the poor responding group of patients will be discussed. However, handling poor responder patients still presents a therapeutic challenge.
31 L11. ESHRE Bologna criteria: where are we?
Nikolaos P. Polyzos Vrije Universiteit Brussel, Center for Reproductive Medicine, Universitair Ziekenhuis Brussel, Brussels, Belgium
Poor ovarian responders are one of the most difficult groups of patients attending an IVF clinic. Over the last 20 years a significant amount of evidence has been published assessing different options for the treatment of poor ovarian responders. Nonetheless, despite the various treatment modalities tested, at the moment none of the available ovarian stimulation protocols has been established as the “gold standard of care”. A considerable limitation of all the randomized trials to date is the striking variability in the definitions used to describe poor ovarian responders, which makes efforts futile in identifying the optimal treatment for these women. Recently, the European Society of Human Reproduction and Embryology (ESHRE) developed a new definition in order to select patients suitable for inclusion in future clinical trials as poor ovarian responders, the so-called “Bologna criteria”. Several studies have been conducted in “Bologna poor responders”; however, it is rather unclear whether any substantial benefit can be anticipated for these women, taking into account that most of the studies demonstrated very poor reproductive outcome. The scope of the current presentation is to analyze the new definition of poor ovarian response developed by ESHRE and highlight the actual prognosis for these women. Finally, it aims to investigate whether intermediate prognosis patients such as the “suboptimal responders” might be the ovarian response group on which we need to focus in the future.
32 L12. The flip side of LH
Renato Fanchin Hospital A. Béclère and University Paris-Sud, Clamart, France
Available cost-effectiveness analysis indicate that the cost of IVF-ET per live birth exceeds 15,000 Euro in France, mainly because per-cycle effectiveness of such treatments remains relatively low. In an effort to improve the efficacy of IVF-ET, thereby reducing time to pregnancy, we became interested in the possibility of alleviating some potential detrimental effects of controlled ovarian hyperstimulation (COH) on embryo quality and uterine receptivity. Indeed, COH seeks to improve IVF-ET results by increasing per- cycle oocyte and embryo availability. This procedure allows adequate embryo selection for ET and may avoid repeating oocyte retrieval in case of failure or desire of subsequent pregnancy, through the cryopreservation of spare embryos. Yet, the coexistence of multiple preovulatory follicles resulting from COH engenders compulsory alterations in the endocrine milieu of the follicular phase. The most striking of them is the extremely high (over 10-fold) estradiol (E2) levels. Such supraphysiologic E2 levels may trigger unwanted consequences both in early embryo development and the endometrial and myometrial readying for embryo implantation. A. Possible detrimental effects of COH on embryo quality A wealth of evidence indicates that E2 may exert deleterious consequences in several stages of the assisted reproduction process. From the embryo competence standpoint, Valbuena et al. have demonstrated that blastulation and embryo adhesion rates were negatively affected by the exposure of mouse embryos to increasing E2 concentrations. These authors have shown that, when 2-day mouse embryos were treated with increasing E2 concentrations up to day 5, the rate of blastocyst formation and embryonic adhesion significantly decreased. They concluded that high E2 levels are deleterious to embryo adhesion in vitro, mainly because they have a direct toxic effect on the embryo that may occur at the cleavage stage. B. Possible detrimental effects of COH on endometrial receptivity From the endometrial standpoint, Simón et al. have shown that imbalanced E2 levels alter endometrial receptivity. These investigators observed that embryo implantation and pregnancy rates per cycle were significantly lower in high responder patients with serum E2 concentrations >1700 pg/mL compared with those having E2 concentrations ≤1700 pg/mL, as well as in normal responder patients with serum E2 concentrations >2200 pg/ml compared with those having E2 concentrations ≤2200 pg/mL. Considering all patients altogether, significant decreases in pregnancy and implantation rates were observed when E2 concentrations were >2500 pg/mL compared with patients having lower E2 concentrations. Their results suggest that high serum E2 concentrations on the day of HCG injection in high and normal responder patients, regardless of the number of oocytes retrieved and the serum progesterone (P4) concentration, are detrimental to uterine receptivity without affecting embryo quality. C. Possible detrimental effects of COH on uterine contractility The third potential detrimental effect of high E2 levels may be targeted in the contractile activity of the myometrium. In previous studies, we demonstrated that hypercontractility of the uterus at the time of ET may adversely affect IVF-ET and that uterine contractions are, to a large extent, regulated by ovarian steroids, in particular E2 and P4. During the follicular phase of the menstrual cycle, E2 stimulates uterine contraction frequency, probably to assist sperm transport and, after ovulation, P4 exerts a remarkable utero-relaxing effect to facilitate the proper positioning of embryos in the uterine cavity and foster embryo implantation. We have previously observed that, in the presence of supraphysiological E2 levels comparable to those obtained after COH, the myorelaxing action of P4 is significantly hampered, a phenomenon that may have a negative effect embryo implantation. D. Explaining an apparent controversy It is noteworthy, however, that some publications have reported that high E2 levels are associated with adequate IVF-ET outcome. Yet, these results may be explained by the fact that “hyper-responders” and “good-prognosis” patients are often the same. According to this, their favorable IVF-ET outcome would be the consequence of the inherent competent oocytes in these “good-prognosis” patients that overcome the detrimental effects of high E2 levels described above. In line with this, studies focusing exclusively in a “hyper-responder” population have shown that, in this selected sub-group of patients, it is those who had relatively lower E2 levels rather than higher E2 levels who reached higher pregnancy rates, which suggests that high E2 levels may be deleterious for IVF-ET outcome.
33 The flip side of LH Therefore, to overcome these unsuitable effects of COH while maintaining large oocyte availability, we elaborated an innovative protocol (NATural Ovarian Stimulation) that dissociates the magnitude of E2 production from the intensity of multiple follicle development. For obtaining this effect, we elected to virtually curtail endogenous LH levels by using strong and frequent GnRH antagonist doses. For this, we considered the “two cell-two gonadotropin” theory that indicates that E2 is produced in the granulosa cells through FSH-stimulated aromatization of androgens that are produced in the theca cells as a result of LH stimulation. Therefore, profound suppression of LH secretion could be effective to significantly reduce E2 production during COH. A. NATOS strategy to profoundly suppress LH levels The paramount challenge of NATOS was to elaborate an effective way of profoundly suppressing circulating LH levels during COH. To obtain this effect, we used GnRH antagonists, which are commercially available peptides that act dose-dependently and directly on the pituitary production of gonadotropins. Because the minimal effective dose of GnRH antagonist to curtail LH was unknown, for practical reasons we chose to use daily 3-mg GnRH antagonist doses. With this strong and repeated GnRH antagonist doses, a remarkable attenuation on serum E2 production during COH was obtained, which was associated with encouraging IVF-ET outcome. Subsequently, the pharmaceutical company decided to withdraw the 3-mg dose from the French market for other reasons. Hence, given that daily 0.25 mg doses were not enough to profoundly suppress LH and control per COH E2 rise (--), we had to multiply 0.25 mg doses to obtain the expected biological effect. Then, after having tried 1 mg (4 doses of 0.25 mg each, daily) and noted that the LH suppression obtained was inconstant from one patient to another, we decided to administer daily 6 doses of 0.25 mg (1.5 mg/day). This dose allowed suppression of LH to levels that prevented an E2 rise during COH over the physiological range. B. Results of a pilot study with NATOS Below the results of our 2 pilot studies (3 mg and 1.5 mg) are summarized. Altogether, they included 15 good prognosis IVF-ET candidates, aged 25-35 years, who volunteered to undergo NATOS. All patients started daily recombinant-FSH paralleled with daily GnRH-antagonist administration on cycle-day 2. This combined treatment continued until the day of hCG administration (dhCG). Daily GnRH-antagonist doses were 3 mg/day (n=5) or 1.5 mg/day (n=10). On dhCG, serum E2 levels remained at 343 (134-579) pg/mL and 236 (103-689) pg/mL for the 3 mg and 1.5 mg groups, respectively, and serum LH levels were, as expected, undetectable in both groups. Contrasting with the natural estradiol environment, we obtained 11 (11-26) and 10 (4-22) mature oocytes in the two groups, respectively. Eleven out of 15 patients achieved a pregnancy (nine of them delivered already healthy babies and two are currently developing normally). C. “LH-null” models Another point to be considered is that NATOS is by no means an “LH-null” model. Indeed, previous experience by other investigators both in hypophysectomized rodents and in patients suffering from hypothalamic amenorrhea in whom circulating LH levels were barely null and who were stimulated with FSH alone was disappointing. Indeed, FSH stimulation in complete absence of LH activity, as in those preceding experimental models, results in adequate follicle development but not in pregnancy. This model differs from NATOS, in which LH levels are rendered indetectable by high GnRH antagonist doses, but probably not null. In NATOS, contrary to hypo-hypo or hypophysectmized patients, there still is remaining LH activity, as illustrated by the marginal E2 production, which is probably sufficient and allows encouragement of IVF-ET outcome observed in our pilot study. In keeping with NATOS results, a minimal LH amount is sufficient for an adequate biological effect. D. NATOS for good prognosis patients Furthermore, given that high E2 levels are commonly reached in patients having a normal follicle endowment, is it plausible that NATOS could target this group of good prognosis IVF-ET candidates. In this case, the physiological estrogenic milieu obtained with NATOS could considerably reduce time to pregnancy in these patients by increasing IVF-ET effectiveness. The results of our pilot studies spurred us to conduct a prospective, randomized trial to demonstrate that, in a good prognosis IVF-ET population, the physiological E2 environment resulting from NATOS significantly improves IVF-ET outcome when compared to the conventional GnRH antagonist protocol.
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