first world conference on luteinizing hormone in art: a ... · it is a great pleasure to welcome...

First world conference on luteinizing hormone in ART: A flight of discovery27-28 May 2016 - Naples, Italy

INTERNATIONAL CONFERENCEFINAL PROGRAMME AND ABSTRACT BOOK

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 forresearchers and medical practitioners to become better acquainted with this expanding area andshare their results and experience.

Our goal is to offer a global and comprehensive update of the most recent results anddevelopments in LH research; to this end, some of the world’s top experts are here to share theirknowledge 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,

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Giuseppe De Placido Federico II UniversityNaples, Italy

Carlo Alviggi Federico II UniversityNaples, Italy

Sandro C. Esteves ANDROFERT - Andrology & Human Reproduction Clinic São Paulo, Brazil

First world conference on luteinizing hormone in ART: A flight of discovery

OverviewThe role of luteinizing hormone (LH) during folliculogenesis has heightened curiosity for at least three decades. In particular, thescientific 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. Whatrecently emerged is that LH is actively able to improve the outcome of IVF in specific subgroup of patients, including advanced agewomen and the so-called “hypo-responders”. The latter group is represented by subjects that, despite being young, having normalovarian reserve, and being classified as nomonadotrophic, show “slow” and sub-optimal response to conventional FSH doses. It wasestimated that the profile of ovarian response is evident in 10-12% of women undergoing COS. More interestingly, the increase inongoing pregnancy rates in these two subgroups of women does not seem to be correlated with the number of oocytes, suggesting thatimprovement in oocyte quality and/or extragonadal effects of LH could be implicated. Although a growing body of evidence is definingthe 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 itspossible benefits as well as its physiopathological mechanism. Guided by an expert, participants will grasp the rationale for usingrecombinant LH in assisted reproductive technology as well as understand the role of LH in human reproduction.

Learning objectivesBy 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 audienceThis programme is intended for clinicians, embryologists, biologists and scientists working in ART.

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Honorary PresidentGiuseppe De PlacidoFederico II UniversityNaples, Italy

ChairsCarlo AlviggiFederico II UniversityNaples, Italy

Sandro C. EstevesANDROFERT - Andrology & Human Reproduction Clinic Campinas, Brazil

Local scientific committeeCoordinatorIda StrinaFederico II UniversityNaples, Italy

MembersLuisa AvinoFederico II UniversityNaples, Italy

Alessandro ConfortiFederico II UniversityNaples, Italy

Pasquale De RosaFederico II UniversityNaples, Italy

Silvia PicarelliFederico II UniversityNaples, Italy

Roberta ValloneFederico II UniversityNaples, Italy

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CME ProviderEXCEMED is a non profit foundation dedicated, since the last four decades, to the development of high-quality medical educationprogramme 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 educationEXCEMED (www.excemed.org) is accredited by the European Accreditation Council for Continuing Medical Education (EACCME®) toprovide the following CME activity for medical specialists. The EACCME® is an institution of the European Union of MedicalSpecialists (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 onlythose credits that he/she actually spent in the educational activity. EACCME® credits are recognized by the American MedicalAssociation (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 ItalianMinistry of Health.

EXCEMED adheres to the principles of the Good CME Practice group (gCMEp).

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GENERAL INFORMATION

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LanguageThe official language of this conference is English.

CME ProviderEXCEMED - Excellence in Medical Education

Senior Programme Manager: Chloé XilinasT +39 06 420413 505 - F +39 06 420413 [email protected]

Medical Advisor: Alessandro [email protected]

For any logistic support please contact: Event Planet srlProject Coordinator: Morena Trematerra | Paola FedericoT +39 (0)81.5529399 - F +39 (0)[email protected]

FormatThis live educational event is accompanied by innovative technological tools allowing participants to express their own views andopinions 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

#LH2016

Follow us on:

PROGRAMME

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Saturday, 28 May 2016X. Xxx (Xxx)

Chairs: S.K. Sunkara (UK) - F. Zullo (Italy)

Real-time voting app

08.45 L7: The European point of view K. Bühler (Germany)

09.10 L8: The Indian point of view M. Banker (India)

09.35 L9: The Latin America approachS.C. Esteves (Brazil)

Revisiting real-time voting app

10.00 Panel discussion

10.45 Coffee break

Chairs: N. Colacurci (Italy) - E. Porcu (Italy)


11.15 L10: Matching patient and protocols in lowprognosis; is it possible?P. Humaidan (Denmark)

11.40 L11: ESHRE Bologna criteria: where are we? N.P. Polyzos (Belgium)

12.05 L12: The flip side of LH R. Fanchin (France)



13.15 Concluding remarks

13.30 End of the conference

Closing lunch

Landing in the real worldSession III

What about next flightsSession IV

Friday, 27 May 2016

From 12.00 RegistrationWelcome lunch

13.30 Opening R. Fischer (Germany)

13.40 Local welcomeG. De Placido (Italy)

13.50 IntroductionC. Alviggi (Italy) - S.C. Esteves (Brazil)

Chairs: A. Ferraretti (Italy) - M.A. Sirard (Canada)


14.00 L1: Physiology of LH and differences with hCGM. Simoni (Italy)

14.25 L2: Polymorphisms of LH and its receptorI. Huhtaniemi (UK)

14.50 L3: Facts and myths on the “Liaisonsdangereuses” between LH and Progesterone C.Y. Andersen (Denmark)



16.00 Coffee break

Chairs: R. Fischer (Germany) - A. La Marca (Italy)


16.30 L4: Is there a role for LH in elderly patients?E. Bosch (Spain)

16.55 L5: LH in low prognosis patientsC. Alviggi (Italy)

17.20 L6: LH in antagonist cycles; is the story reallywritten?R. Orvieto (Israel)



18.30 End of the first day

Taking off from basic scienceSession I

Flying through literatureSession II

Legend: L : Lecture

DISCLOSURE OF FACULTY RELATIONSHIPS

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EXCEMED adheres to guidelines of the European Accreditation Council for Continuing Medical Education (EACCME®) and all otherprofessional 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 otherproducts (other than those uses indicated in approved product labeling/package insert for the product) may be presented in theprogramme (which may reflect clinical experience, the professional literature or other clinical sources known to the presenter). We askall presenters to provide participants with information about relationships with pharmaceutical or medical equipment companies thatmay have relevance to their lectures. This policy is not intended to exclude faculty who have relationships with such companies; it isonly intended to inform participants of any potential conflicts so that participants may form their own judgements, based on fulldisclosure of the facts. Further, all opinions and recommendations presented during the programme and all programme-relatedmaterials neither imply an endorsement nor a recommendation on the part of EXCEMED. All presentations represent solely theindependent views of the presenters/authors.

The following faculty provided information regarding significant commercial relationships and/or discussions of investigational ornon-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 andFerring 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 consultationfees 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; ofhonoraria or consultation fees from Merck and MSD; participation in a Ferring, MSD and Besinssponsored speakers’ bureau

Manuela Simoni Declared receipt of grants and contracts from Merck and IBSA; of honoraria or consultation fees fromMerck

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 discussionof investigational or non-EMEA/FDA approved (off-label) uses of drugs as of 10 May 2016.

Nicola Colacurci

Eleonora Porcu

Fulvio Zullo

SPEAKER BIOGRAPHIES

SPEAKER BIOGRAPHIES

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Carlo Alviggi obtained his MD degree (1994) with a specialty in Obstetrics and Gynaecology (1998), and a PhD in 2001 at the Facultyof 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 ofAutoimmunity and Tolerance of the University of California (Los Angeles). This collaborative network resulted in various publicationssome of which concern new hypotheses on the pathogenesis of pelvic endometriosis. Over recent years, he has been working asassociate professor in reproductive medicine at the Fertility Unit of the University of Naples “Federico II” (Department ofNeuroscience, Reproductive Science and Odontostomatology). Dr Alviggi has published extensively and has been invited to lectureat 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.

Carlo AlviggiFederico II UniversityNaples, Italy

Claus Yding Andersen is Professor in human reproductive physiology at University of Copenhagen and has since 2009 been headingthe Laboratory of Reproductive Biology at the University Hospital of Copenhagen, Denmark. He qualified first as a Master of Scienceand is then earned a Doctorate of Medical Science from University of Copenhagen. He was a member of the team which introducedIVF to Denmark in the mid 1980s and has worked in reproduction since then. He leads a national program for cryopreservation ofhuman ovarian tissue and his major research interests include ovarian endocrinology and human embryonic stem cells. He haspublished more than 300 peer-reviewed papers and has given numerous international presentations.

Claus Yding AndersenUniversity Hospital of CopenhagenCopenhagen, Denmark

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Manish Banker is an infertility specialist and the Executive Director of Nova IVI Fertility Clinics India’s largest group of IVF clinics with12 clinics in 10 cities and Pulse Women’s Hospital Ahmedabad. He completed his undergraduate and post-graduate work withhonors at VS Medical College and Hospital, Ahmedabad. After completing his studies, he received advanced training in IVF andEndoscopy in Australia and Germany. He is one of the pioneers in IVF in India and started his IVF practice in 1996; he has more than6000 successful IVF pregnancies to his credit. He has been the President of the Indian Society for Assisted Reproduction (ISAR) andChairman of the infertility Committee of the Federation of Obstetric and Gynecological Societies of India [ FOGSI ]. He sits on theInternational Affairs Committee of the American Society for Reproductive Medicine, Board of Directors of Pacific Rim Society ofReproductive Medicine and Surveillance Board of IFFS, is a Member of the Draft Committee for ART Bill of India, I. C. M. R., Ministryof Health and is the Regional representative for the International Committee for Monitoring ART [ ICMART ], a WHO affiliate. He isalso a Founding Board Member of the Asia Pacific Initiative for Reproductive Endocrinology [ASPIRE] [2006 – 2008]. Dr. Banker hasdelivered numerous talks at International and National Conferences and has to his credit numerous publications and hascontributed many chapters to text books. He has been publishing the National ART Registry of India since 2000. Nova IVI FertilityClinics was launched in August 2011 when Pulse Women’s Hospital joined hands with Nova Medical Centres and IVI, Spain to formIndia’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 Indiaand 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.

Manish BankerNova IVI FertilityPulse Women's HospitalGujarat, India

Ernesto Bosch was born in Philadelphia, USA, in 1968. He completed Medical School at the University of Valencia in 1992 and from1993 to 1997, worked as a Specialist in Obstetrics and Gynaecology at Hospital La Fe, Valencia. Ernesto trained in HumanReproduction at the Hospital of the University of Pennsylvania in 1997; and in 1999, he completed his doctoral thesis on the influenceof LH in oocyte quality, with “cum laude” qualification, at the University of Valencia. In January 2000, Dr. Bosch joined the team atthe Human Reproduction Unit of the Instituto Valenciano de Infertilidad in Valencia; and in 2008 he obtained the title of Master inResearch on Health Sciences, by the Autonomous University if Barcelona. Dr. Bosch has published 49 papers and written more than50 book chapters in the field of IVF; has given over 150 lectures at international meetings around the world; he also belongs to theEditorial Board of Fertility & Sterility, and Reproductive Biomedicine Online as well as being a regular reviewer for HumanReproduction, and Reproductive Biology and Endocrinology among others. He belonged to the Special Interest Group onReproductive Endocrinology of the Spanish Fertility Society and received the Scientific Program Prize Paper Award at the 2008Annual Meeting of the American Society for Reproductive Medicine. In May 2010, Dr. Bosch was appointed Medical Director of theHuman Reproduction Unit of the Instituto Valenciano de Infertilidad in Valencia.

Ernesto BoschInstituto Valenciano de Infertilidad Valencia, Spain

Nicola Colacurci, Director of the Gynecology and Obstetrics department and Coordinator & President of the triennial Bachelor’sdegree in Obstetrics at the Second University of Naples (SUN). Graduated in 1977, Dr. Colacurci boasts numerous managements, isauthor of more than 450 publications on national and international journals, is editor of 20 monographs on specialized topics, andis a member of the editorial staff of the scientific journal, Italian Journal of Gynecology and Obstetrics; he is also an investigator invarious trials and referee of a great number of international journals.

Nicola ColacurciOutpatient Fertility ClinicSecond University of NaplesNaples, Italy

SPEAKER BIOGRAPHIES

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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 MedicalDirector at the University of Essen, serving under the Head of Department Prof. Dr. A.E. Schindler, with a special field of engagementin 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 GermanEndometriosis 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 scientificpublications, Dr Bühler has been invited to join the Editorial Board Journal of Reproductive Medicine and Endocrinology. CurrentPresident of the German Dachverband (peak organisation) für Reproduktionsbiologie und Reproduktionsmedizin (DVR), Dr Bühlerhas had the privilege of being awarded Honorary Membership to the Società Italiana di Medicina Perinatale, as well as receiving aResearch Award from the German Endometriosis Research Foundation.

Klaus BühlerCentre for Gynaecological Endocrinology and Reproductive MedicineStuttgart, Germany

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Sandro C. Esteves is the Medical and Scientific Director of ANDROFERT - Andrology and Human Reproduction Clinic referral FertilityCenter for male reproduction in Brazil. His Center was the first in Brazil to obtain full ISO 9001 certifications. Dr. Esteves obtainedhis MD in 1990 from the University of Campinas (UNICAMP), Brazil, where he did his residency training in Urology & Andrology. Hecompleted his training in the United States (1995-1996) as a Fellow at the Cleveland Clinic’s Center for Reproductive Medicine. Hewas awarded his PhD in 2001 from the Federal University of São Paulo (UNIFESP), Brazil. Dr. Esteves is a Board-certified Urologistand Infertility Consultant with over 15 years of experience. He is a Collaborating Professor in the Department of Surgery (Division ofUrology) at the University of Campinas (Brazil) and Research Collaborator at both the Cleveland Clinic's Center for ReproductiveMedicine (USA) and the Genetic Unit, Department of Biology, Universidad Autónoma de Madrid, (Spain). He is holds an honorary titleof Clinical Tutor in Urology at the University of Edinburgh (UK). His research/clinical interests include male infertility, reproductiveendocrinology, cleanroom technology and quality management. Dr. Esteves has published over 130 scientific papers and reviewarticles in peer-reviewed scientific journals, authored over 60 book chapters, and presented over 150 papers at both national andinternational scientific meetings. His current Hirsch index (h-index) is 24 while his citation count is approximately 2,000. He hasserved as an editor of five textbooks related to reproductive medicine and assisted reproductive technology. He is the guest editor ofthree special issues in scientific journals on topics related to reproductive medicine. Sandro serves on the Editorial Board of severalJournals and is Associate Editor of the International Brazilian Journal of Urology. Dr. Esteves has been invited as a guest speaker ofmany international meetings in over 30 countries. He is the recipient of the "Alumni of the Year" Award from the Cleveland ClinicCenter for Reproductive Medicine, and the Star Award from the American Society for Reproductive Medicine for the last 4 years.

Sandro C. EstevesANDROFERT - Andrology & Human Reproduction Clinic Campinas, Brazil

Giuseppe De Placido graduated in Medicine and Surgery at University of Naples in 1982 and Clinical fellow in the Department ofGynecological and Obstetric Physiopathology of the II Faculty of Medicine and Surgery, University of Naples. Between 1982 and 1988he was also Research Fellow of the II Faculty of Medicine and Surgery, University of Naples, whereas in May 1988 he becameAssociate 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 theUniversity of Naples “Federico II” (Satellite centres of Avellino and Salerno) and in 2001 he became Ordinary Professor in Gynecologyand Obstetrics. Consequently in 2004 he was appointed as Director of the EEC School of Gynecology and Obstetric. Since theacademic 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 theStudy and Treatment of Infertility and Infertility Couple. He has also been the author of about 500 scientific publications, publishedextensively in both international and national journals, and invited speaker to more than 600 national and international medicalcongresses and conventions.

Giuseppe De PlacidoFederico II UniversityNaples, Italy

Anna Pia Ferraretti holds a University Degree in Obstetrics and Gynecology and a PhD in Endocrinology. She has been a specialistin 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 ofReproductive Medicine and Biology. From 2011 to 2013 she was chairman of the EIM (European IVF Monitoring) Consortium of theEuropean Society of Human Reproduction and Embryology (ESHRE). Moreover, she is a current member of the ESHRE SpecialInterest Group on Socio-cultural aspects of (in)fertility. She is author (or co-author) of more than 250 publications and collaborateswith several scientific journals as a reviewer.

Annapia FerrarettiSocietà Italiana Studi di Medicina della Riproduzione Bologna, Italy

SPEAKER BIOGRAPHIES

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Renato Fanchin is the Chief of the Division of Reproductive Medicine, Department of Gynaecology and Obstetrics, Antoine BéclèreHospital, Clamart, France. He accomplished his specialization in Obstetrics and Gynaecology and Reproductive Medicine in Franceand obtained his PhD degree from University of Paris-Sud 11 in 2005. Professor Fanchin has been invited to speak in over 150international meetings, is a full member of the Society for Gynecologic Investigation, and was awarded the Society for AssistedReproductive Technology Prize Paper by the American Society for Reproductive Medicine in 1999. He is an active member of theINSERM unit 782 and his current research interests include the assessment of ovarian follicular status, ovarian ageing, andcontrolled ovarian hyperstimulation strategies. Prof. Fanchin, along with his colleagues, has published over 170 peer-reviewedarticles 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.

Renato FanchinHospital A. Béclère and University Paris-SudClamart, France

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Robert Fischer is founder and Medical Director of the IVF unit at the Fertility Center Hamburg - one of Germany’s largest and leadingIVF centres. In July 1998 the Fertility Center Hamburg was one of the first centres in Germany, and worldwide, to introduce certifiedquality 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 innational and international scientific journals and books, as wellas lecturer at conferences worldwide, he is also an active memberof the American Society of Reproductive Medicine, founding member of the European Society of Human Reproduction and pastmember of its advisory committee as well as founding member of the German reproductive organisations, “AG GynäkologischeEndokrinologie und Fortpflanzungsmedizin” and “Berufsverband Reproduktionsmedizinischer Zentren”.

Robert FischerFertility Centre HamburgHamburg, Germany

Ilpo Huhtaniemi received his MD and PhD from the University of Helsinki, Finland, did postdoctoral training in the USA (UC SanFrancisco and NIH, Bethesda), and has been on sabbatical leave in Germany, USA and Scotland. He held 1986-2002 the post ofProfessor and Chairman of Physiology at the University of Turku, Finland. He moved in 2002 to the UK to become Chair ofReproductive Endocrinology at Imperial College London. He has received several national and international honours, among thema fellowship of The Academy of Medical Sciences (UK) and a Doctor Honoris Causa at the Medical University Lodz, Poland, andUniversity of Szeged, Hungary. He has been the Chief Managing Editor of Molecular and Cellular Endocrinology since 1999, hasserved on the Editorial Board of Endocrinology and Endocrine Reviews and is/has been the Editor or Editorial Board Member ofseveral 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 Presidentof International Society of Andrology). His research interests include clinical and basic reproductive endocrinology, in particular thefunction of gonadotrophins and male reproductive endocrinology. He also has long-term interests in development of malecontraception, hormone-dependent cancer, and the endocrinology of ageing. His H factor is 71, and he has authored >650 peer-reviewed research articles and reviews.

Ilpo Huhtaniemi Institute of Reproductive and Developmental BiologyHammersmith Campus, Imperial College LondonLondon, UK

Antonio La Marca is Professor of Obstetrics and Gynecology at the Mother-Infant Department of the University of Modena and ReggioEmilia, Italy and he is the Medical Director of Clinica Eugin, Modena, Italy. He graduated in Medicine and Surgery at the Universityof Siena in 1996, specializing in Obstetrics and Gynaecology at the same institution in 2001. In 2006 he obtained a PhD, again at theUniversity of Siena. He has been working at the Institute of Gynaecology and Obstetrics of the University Hospital of Modena since2003. 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 pharmacologicalmanipulation of ovarian activity. His most impactful articles concerned the physiological significance of AMH and AFC, theirmeasurement and clinical utility. Moreover, he has published a long list of original articles dealing with the prediction of ovarianreserve and response in IVF and the personalization of ovarian stimulation protocols. He is author or co-author of 128 articlespublished in peer-reviewed journals and authored many chapters in national and international textbooks. He has been an Invitedspeaker in more than 100 international congresses. He is involved in several phase three and four trials as Principal Investigator andis the recipient of many competitively assigned research funds. He is an active member of many national and internationalprofessional and scientific societies and a consultant for the Italian Ministry of Health for female fertility-related issues.

Antonio La MarcaUniversity of Modena and Reggio Emilia and Clinica EuginModena, Italy

SPEAKER BIOGRAPHIES

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Peter Humaidan is a specialist in reproductive endocrinology, Professor at The Fertility Clinic at Skive Regional Hospital, AarhusUniversity, 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 theinfertile patient. His doctoral thesis (DMSc) explored the role of LH during the follicular and luteal phases in controlled ovarianstimulation. His main fields of interest are triggering ovulation with GnRH agonist, the use of GnRH antagonists, and OHSSprevention. He is the founder of the international society “The Copenhagen GnRHa Triggering Workshop Group” and board memberof the ESHRE SIG Endocrinology Group. He has authored 100 + articles (H-index 26) in international peer reviewed journals as wellas the Danish guidelines for OHSS prevention and chapters in textbooks. Peter Humaidan has a wide international scientific networkand is frequently invited as a speaker at international conferences.

Peter HumaidanFertility ClinicSkive Regional Hospital and Faculty of HealthAarhus UniversityAarhus, Denmark

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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 nationaland international journals. His scientific interests include various aspects of controlled ovarian hyperstimulation (COH). The role ofGnRH-analogues, and specifically GnRH agonist versus antagonist in COH for IVF and several aspects of ovarian hyperstimulationsyndrome (OHSS): pathophysiology, prediction, prevention and its relation to the inflammatory response.

Raoul OrvietoThe Chaim Sheba Medical CenterTel Hashomer, Israel

Nikolaos P. Polyzos is a Professor in the Vrije Universiteit Brussel and Medical co-director in the Center for Reproductive Medicinein the Universitair Ziekenhuis Brussel in Belgium. Since 2015 he is also an Honorary Professor in Reproductive Endocrinology at theUniversity of Aarhus in Denmark. Professor Polyzos is a key opinion leader regarding the treatment of poor ovarian responders inIVF programs, prediction of ovarian response and premature ovarian ageing. He is an invited speaker in approximately 20conferences and congress per year in Europe, Asia and South America and has published more than 100 publications in peerreviewed journals indexed in Pubmed. He serves as a reviewer in 23 journals including BMJ, JCEM, Hum Reprod, Hum reprodUpdate, Fertil Steril, RBMonline, BJOG. His research interests include reproductive endocrinology, ovarian reserve markers, poorovarian response to stimulation and genetics of premature ovarian ageing

Nikolaos P. PolyzosVrije Universiteit BrusselCenter for Reproductive MedicineUniversitair Ziekenhuis BrusselBrussels, Belgium

SPEAKER BIOGRAPHIES

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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-MalpighiUniversity 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-reviewedpapers, gave several invited main lectures including the ASRM and the ESHRE meetings and received the International Federationof Fertility Societies 30th Anniversary Recognition Award for significant contributions in Infertility and Reproductive Medicine.

Eleonora PorcuUniversity of BolognaBologna, Italy

Manuela Simoni obtained her MD in 1982, a Specialisation in Endocrinology and Metabolism in 1985 and a PhD in Endocrinologyand 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 fullProfessor 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 Specializationin Endocrinology, and Deputy Director of the Department of Biomedical, Metabolic and Neural Sciences. Her research interests aregonadotropin and androgen action, testicular function, genetics of male infertility, as well as endocrinology and pathophysiology ofreproduction. She is a member of several societies, including the European Academy of Andrology (EAA) and the European Societyof Endocrinology (ESE, serving as the Secretary) and is active on the editorial boards of several journals in the fields of endocrinologyand reproduction.

Manuela SimoniUniversity of Modena and Reggio EmiliaModena, Italy

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Marc-André Sirard after completing graduate studies at the University of Laval (Canada) during which in vitro fertilization generatedthe first clinical method producing test-tubes calves in 1985. Dr. Sirard attended post-doctoral training at the laboratory of Neal Firstin Wisconsin (USA) to study in vitro maturation of oocytes. Dr. Sirard returned to Québec in 1987 and became a industrial chairprofessor in 1990. He founded the Centre de Recherche en Biologie de la Reproduction in 1995 which has grown to employ morethan 100 people today. He obtained a senior Canadian Research Chair in 2000 in genomics applied to reproduction and is leading aninternational effort to define the normal genomic program in early mammalian embryos which became an NSERC strategic networkin 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.

Marc-André SirardCentre de Recherche en Biologie de la ReproductionLaval UniversityQuébec, Canada

Sesh K. Sunkara is a Consultant Gynaecologist and Subspecialist in Reproductive Medicine and Surgery. She specialised in the fieldof Obstetrics and Gynaecology and is a Member of the Royal College of Obstetricians and Gynaecologists (MRCOG), UK. Sheundertook translational research in Reproductive Medicine at the Assisted Conception Unit, Guy’s and St Thomas’ NHS FoundationTrust 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 andGynaecology as well as Reproductive Medicine. She worked as a Consultant gynaecologist and Subspecialist in ReproductiveMedicine at the Aberdeen Fertility Centre, University of Aberdeen before moving to Barking Havering and Redbridge UniversityHospitals to set up a new IVF service. In addition to her clinical work, she has published in the field of Reproductive Medicine andauthored several book chapters. She has organised and participated in several national and international symposia and workshopsin the field of Reproductive Medicine. She is the Associate Editor for Human Reproduction Journal by the European Society of HumanReproduction and Embryology (ESHRE). She is on the executive board for the RCOG – Reproductive Medicine Clinical Studies Groupwhich is actively involved in supporting multi-centre research studies in the UK.

Sesh K. SunkaraAberdeen Fertility CentreAberdeen Maternity HospitalAberdeen, UK

SPEAKER BIOGRAPHIES

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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 atUniversity of Naples and, between June 1998 and December 1990, he was a Post-doctoral Fellow at the Reproductive ImmunologyLaboratory of Eastern Virginia Medical School and at Jones Institute for Reproductive Medicine. In 1994 he also specialized inGeneral Surgery at the University of Naples. Since 1998 he has been Director of a Bachelor’s degree course in Obstetrics atUniversity “Magna Graecia” of Catanzaro and since November 2000, he has also filled the role of Associate Professor. Since 2006Professor 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 AdvancedResearch Methodologies in applied surgery at the Oncology XXIV department of University Magna Graecia of Catanzaro, since 2008.

Fulvio ZulloReggio Calabria UniversityCatanzaro, Italy

ABSTRACTS

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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 assistedreproduction 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 rangepotentiates different LH- and hCG-dependent responses in vitro, measured in terms of cAMP, phospho-CREB, -ERK1/2 and -AKTactivation, gene expression, progesterone and estradiol production in human granulosa-lutein cells (hGLC). In addition we showedthat, 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 assteroidogenic cAMP/PKA pathway activation, do not change in the presence of FSH, which, however, increases LH-dependentERK1/2 and AKT, but not CREB phosphorylation, resulting in antiapoptotic effects. The different modulatory activity of FSH on LHand hCG action in vitro corresponds to their different physiological functions.

L1. Physiology of LH and differences with hCG

Manuela Simoni1,2 and Livio Casarini1

1. Department of Biomedical, Metabolic and Neural Sciences, University of Modena & Reggio Emilia and 2. Unit of Endocrinology, Azienda USL of Modena, Modena, Italy

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The genes of luteinizing hormone β-subunit (LHB) and luteinizing hormone/choriongonadotrophin receptor (LHCGR) contain severalcommon polymorphisms, and their occurrence has been studied in relation to various phenotypic signs of male and female gonadaldysfunction, including hypogonadism and infertility. The best known LHB polymorphism is W8R/I15N, also called LH variant, whichhas a vastly varying frequency around the world. The two amino acid alterations in LH structure clearly affect the behaviour of LH invivo 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 largelyelusive, but studies especially from Asia have found its association with polycystic ovary syndrome (PCOS) and marginal femalesubfertility. In boys it has ben found at higher frequency in cryptorchidism and upon slow pace of pubertal maturation, and in menin connection with sporadic prostate cancer. As concerns LHCGR, less obvious functional associations have been detected withpolymorphisms. There are some reports on their association with male undermasculinization. In women some LHCGRpolymorphisms have been shown to associate with PCOS. Ii is possible that with increasing knowldge about the genotype/phenotypecorrelates of LHB and LHCGR polymorphisms they might offer novel pharmacogenomics toosl for individualized hormone treatmentof subfertility.

L2. Polymorphisms of LH and its receptor

Ilpo Huhtaniemi Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College LondonLondon, UK

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Human ovarian steroidogenesis has two end products; oestradiol is the most well-known with many well described endocrinefunctions, whereas progesterone being the other one end product is less well established and has recently mistakenly beendescribed as an intermediate in the biosynthesis of oestradiol. Progesterone is synthesized primarily by the granulosa cells andintrafollicular concentrations of progesterone increase in parallel with growth and development of the follicle during the follicularphase of the menstrual cycle. Close to ovulation, concentrations of progesterone in follicular fluid is more than a thousand timeshigher than in circulation and considerably higher than concentrations of oestradiol. Progesterone also exerts physiologicalfunctions 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 bothlocally and systemically. Granulosa cells progesterone synthesis is stimulated by both FSH and LH, but it appears that LH is morepotent than FSH in stimulating progesterone synthesis. Interest in how progesterone synthesis is regulated has received a lot ofattention 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 studieshave addressed the issue without demonstrating an underlying mechanism for the observed reduction in pregnancy rate. Anapparent paradox exists:

1. Embryos from cycles with elevated progesterone implanted equally well and other embryos in FER cycles suggesting thatembryo quality is not compromised.

2. Others concluded that the premature elevation of the progesterone caused an advancement of the endometrium resulting in aless receptive state. However, high responder women with elevated progesterone show similar or even better pregnancy ratesthan 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 attenuatedreproductive outcome.

The lecture will present a totally new theory on the underlying cause of the reduced reproductive potential in patients with an elevatedfollicular phase progesterone level including a closer analysis of how gonadotropins regulate progesterone synthesis and primegranulosa cells.

L3. Facts and myths on the “Liasonsdangerous” between LH and Progesterone

Claus Yding AndersenUniversity Hospital of Copenhagen, Copenhagen, Denmark

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Older patients have different endocrine features than younger patients, which make controlled ovarian stimulation (COS) morechallenging for this population.

On one hand, older patients have an increased early follicular phase FSH, without an accompanied elevation of LH levels. Thisincrease starts in the luteal-follicular transition and as a consequence, older patients have a shorter follicular phase with anaccelerated 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 ofandrogens that ranges from menarche to menopause. This diminishment is as much as 49% of testosterone levels, or 77% of DHEAlevels. And moreover, this decrease in androgen concentrations occurs without a diminishment of SHBG levels. Apart from thisreduction in the basal concentrations of androgens, there is also an impairment of their synthesis in response to stimulation withrecombinant FSH: It has been shown that while the capability of the follicles of older women to produce estradiol in response torFSH stimulation is well preserved, this is not the case for the synthesis of androstenodione, which is significantly lower in olderwomen 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 dependentincrease of follicular androgens, which are later aromatized to estrogens. Therefore, LH administration would restore the follicularenvironment in these patients, leading to a proper maturation of the oocyte. We have shown that women with lower basaltestosterone 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, ameta-analysis of these trials concludes that there is an increase in clinical pregnancy rates when LH is added. An detailed analysisof these trials suggests that the positive impact of LH supplementation is observed only when it is given from the beginning ofstimulation, 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 parameterat this point, but a less arbitrary factor should be defined.

L4. Is there a role for LH in elderly patients?

Ernesto BoschInstituto Valenciano de Infertilidad, Valencia, Spain

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Despite the advent of new drugs and the consequent development of patient-oriented ovarian stimulation protocols, many patientsworldwide receive identical treatment. However, a tailored approach is crucial to maximize results, manage risk and optimize thecost 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 “Bolognacriteria”, was published. In brief, the system is based on three major criteria: (i) advanced age (≥ 40 years) or any other POR riskfactor; (ii) a previous episode of POR; and (iii) an abnormal ovarian reserve test (AMH and AFC). Two of these three major criteria arerequired for a POR diagnosis. These criteria have the indubitable value of attempting, for the first time, to standardize the definitionof an intrinsically heterogeneous event. Many studies demonstrated that these criteria are useful in the clinical setting to predict theoutcome of IVF and are effective for counselling purposes. However, the use of these criteria in clinical trials has been questionedbecause 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 stimulationthat moves from the classical POR to a “low prognosis” concept. The definition of “low prognosis” patients introduces two newcategories of impaired response to exogenous gonadotropin: (i) a “suboptimal response”, defined as the retrieval of four to nineoocytes, 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 numberof oocytes. In detail, several lines of research reinforce the hypothesis that a “hyporesponse” could be related to specific genepolymorphisms. 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) andwith an unexpectedly poor or suboptimal ovarian response. This group can be subdivided into: subgroup 1a, constituted by patientswith fewer than four oocytes; and subgroup 1b, constituted by patients with four to nine oocytes retrieved after standard ovarianstimulation, 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) andwith an unexpectedly poor or suboptimal ovarian response. This group can be subdivided into: subgroup 2a, constituted by patientswith fewer than four oocytes; and subgroup 2b,constituted by patients with four to nine oocytes retrieved after standard ovarianstimulation, 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 lowprognosis women. For instance, at least three randomized controlled trials (RCTs) and one meta-analysis have demonstrated thatLH 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 ofage, who would be classified in our Groups 2 and 4. Conversely, a recent RCT did not identify any benefit from LH administration inPOR 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, forexample, using different GnRH analogue regimens, detecting polymorphisms of gonadotropins and their receptors, tailoring the FSHstarting dose and LH supplementation.

L5. LH in low prognosis patients

Carlo Alviggi and Alessandro Conforti Federico II University, Naples, Italy

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The aim of the presentation is to illustrate the available evidence that examine the role of LH supplementation and methods to triggerfinal 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 mostlikely to benefit from the addition of “LH activity” supplementation to their COH protocol and the mode and timing of ovulationtriggering, 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 differentpreparations, 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 benefitfrom LH supplementation, and could be identified prior to COH, are high and poor responder patients, those with advanced age andthose with high basal FSH/LH ratio. Moreover, patients demonstrating raised progesterone levels at day of hCG administration maybenefit 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 thoseachieving >20 oocytes, the freeze all policy with the subsequent frozen-thawed embryo transfers (ET) is recommended, while inthose 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 standardbolus 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 IVFoutcome. GnRHa 40h and standard hCG added 34h prior to oocyte retrieval (double trigger), respectively, are offered to patientsdemonstrating abnormal final follicular maturation despite normal response to COH. The double trigger results in significantlyhigher 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 ofoocytes retrieved, with the consequent significantly increased number of top-quality embryos, as compared to the hCG-only triggercycles. Standard hCG dose concomitant with GnRHa (dual trigger), 34h before oocyte retrieval should be offered to poor responderpatients, 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 subgroupsof patients undergoing COH for IVF. While few of the selected indications for LH supplementation are based on evidence-basedmedicine, others are supported by observational studies. Therefore, further large studies are needed to investigate the true impactof LH supplementation on IVF outcome and to identify the selected groups of patients who are most likely to benefit from the additionof “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 studiesare required to support this new concept prior to its universal implementation to IVF practice.

L6. LH in antagonist cycles; is the story reallywritten?

Raoul OrvietoThe Chaim Sheba Medical Center, Tel Hashomer, Israel

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The number of papers published with randomised controlled trial (RCT) or meta analysis (MA) has increased sharply within the lastten years in the field of reproductive medicine. A single study is at great risk of not detecting with certitude differences of diversetreatment options. Single trials often are very low in number of included patients and therefore the statistical power is seldom verystrong even if the trial was conducted as RCT. MA and systematic reviews are viewed as providing the highest level of evidence andare established in order to overcome the pitfalls of very often underpowered studies in reproductive medicine. However, evenstatistical evidence does not mean clinical evidence. And nevertheless, such studies are not completely free of drawbacks and canalso show several biases such as selection, performance, detection, publication or e.g. time lag bias. The examined patient groupsare mostly well selected and a lot of inclusion and exclusion criteria are limiting the results to be applied to a great number ofpatients in the daily treatment of subfertility. So, real world data become more and more important. They reflect our daily generalpractice. If data collection is done in an appropriate way, e.g. prospectively, with the high number of cases, selected powerfulstatistics can be performed. So, the use of gonadotropins during the last decades is evaluated on the basis of the data of one of thegreatest and oldest IVF registries. We focused our attention on the use of recombinant LH in daily routine controlled ovarianstimulation.

L7. The European point of view

Klaus Bühler Centre for Gynaecological Endocrinology and Reproductive Medicine, Stuttgart, Germany

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India has a population of 1.3 billion people with Infertility affecting 10-15% of married couples, which amounts to about 27.5 millioncouples 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 27.5million infertile population, only 0.1 million IVF cycles are performed every year; i.e. around 75 – 80 cycles / million population. Indiahas the potential to conduct approximately 1500 cycles /million population. The market is expected to grow at a CAGR (CumulativeAverage Growth Rate) of ~20% from the current 100,000 cycles to 260,000 cycles in 2020. The estimated IVF market is projected tobe 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 118centers that contributed to NARI in 2014, only 1 center performed more than 500 cycles / year, 89 out of 118 centers performed lessthan 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 mainlydue to 3 reasons: first, the relatively higher contribution of IVF medications in the IVF package, especially recombinant drugs. Theaverage 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 thetotal cost, depending on whether indigenous urinary or recombinant drugs are used. Many centers use hMG as a surrogate LHsupplement to reduce costs and thus reduce the patient’s financial burden. The second reason is the fragmented market. The thirdis 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 patientpopulation 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 moreprevalent.

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 coversapproximately 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 FSHwas 0.03% in 2005 and 0.7% in 2006.

The use of hMG in combination with recombinant FSH between 2002- 2006 was as follows:

L8. The Indian point of view

Manish BankerNova IVI Fertility, Pulse Women's Hospital, Gujarat, India

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 ovarianreserve 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)

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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 promotingsteroidogenesis and follicle development. Despite being mandatory in patients with hypogonadotropic hypogonadism, stimulationprotocols with LH supplementation in normogonadotropic women undergoing controlled ovarian stimulation (COS) for ART areequivocal.

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 LHhave 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 whichinclude exogenous LH are adopted in over 60% of ART cycles. Of these, urinary LH activity has been the preferred approach andcomprised ~80% of all cycles involving exogenous LH. Notably, there is a marked variation among clinicians with regard to LHsupplementation 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 LHis 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 womenaged ≥40 and ≤34 years, respectively). According to REDLARA data with regard to delivery rates, differences were not noted betweenthose 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. Despitehaving 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% ofthose with 35-39 and ≥40 years, respectively. Among all treated patients, we have used GnRH antagonists in over 90% of all treatedpatients. In our practice, exogenous rec-hLH is prescribed in combination with rec-hFSH in a ratio of 1:2 to: i. Expected or provedpoor responders at any age; ii. Hypo-responders at any age; and iii. Women of 35 years of age or older not fitting in the aforesaidcategories.

As far as live birth rates per fresh transfers are concerned, we have compared our results to those of REDLARA. Likewise in thegonadotropin regimes, the differences in LBR were also significant across all age groups. The magnitude of effect size was morepronounced 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. LHactivity from hMG preparations is the prevailing practice among doctors. Exogenous LH is prescribed widely to women aged 35 yearsand 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 afunction of exogenous LH across all age groups. As far as our experience is concerned, not only our practices differ but also do theoutcomes. Our center’s data are reassuring and add confidence to the way we use LH supplementation. Although ART success isdependent on a multitude of controlled and non-controlled factors, this data analysis suggest that exogenous LH mode of use hasan important impact on pregnancy outcomes. This indicates that ample educational opportunities exist in Latin America with regardto the use of LH supplementation to maximize cycle outcome.

L9. The Latin America approach

Sandro C. EstevesANDROFERT - Andrology & Human Reproduction Clinic, Campinas, Brazil

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L10. Matching patient and protocols in lowprognosis; is it possible?

Peter HumaidanFertility 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 Bolognacriteria for POR (2011) was established, no strict criteria to define POR existed, which hampered the conclusions made from previousclinical trials and meta-analyses. However, even the Bologna criteria have subsequently been criticized for being too strict and inreality defining patients with low success rates and who in reality are better off with oocyte donation. In this lecture a further attemptto define the poor responder patient will be made, taking into account ovarian reserve and age which are the two most importantkey factors to predict success after IVF treatment. Four different sub-groups of poor responder patients will be defined as well assuggestions for matching protocols and regimens which per definition might increase the success rate of the patient. Moreover, areview of strategies and adjuvants as well as future therapeutical options for the poor responder patient will be presented. Theimpact of different stimulation protocols on the ovarian response to stimulation in the poor responding group of patients will bediscussed. However, handling poor responder patients still presents a therapeutic challenge.

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Poor ovarian responders are one of the most difficult groups of patients attending an IVF clinic. Over the last 20 years a significantamount 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 beenestablished as the “gold standard of care”. A considerable limitation of all the randomized trials to date is the striking variability inthe definitions used to describe poor ovarian responders, which makes efforts futile in identifying the optimal treatment for thesewomen.

Recently, the European Society of Human Reproduction and Embryology (ESHRE) developed a new definition in order to selectpatients suitable for inclusion in future clinical trials as poor ovarian responders, the so-called “Bologna criteria”. Several studieshave been conducted in “Bologna poor responders”; however, it is rather unclear whether any substantial benefit can be anticipatedfor 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 highlightthe 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.

L11. ESHRE Bologna criteria: where are we?

Nikolaos P. PolyzosVrije Universiteit Brussel, Center for Reproductive Medicine, Universitair Ziekenhuis Brussel, Brussels, Belgium

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L12. The flip side of LH

Renato FanchinHospital 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 becauseper-cycle effectiveness of such treatments remains relatively low. In an effort to improve the efficacy of IVF-ET, thereby reducing timeto pregnancy, we became interested in the possibility of alleviating some potential detrimental effects of controlled ovarianhyperstimulation (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 oocyteretrieval in case of failure or desire of subsequent pregnancy, through the cryopreservation of spare embryos. Yet, the coexistenceof multiple preovulatory follicles resulting from COH engenders compulsory alterations in the endocrine milieu of the follicularphase. The most striking of them is the extremely high (over 10-fold) estradiol (E2) levels. Such supraphysiologic E2 levels maytrigger unwanted consequences both in early embryo development and the endometrial and myometrial readying for embryoimplantation.

A. Possible detrimental effects of COH on embryo qualityA 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 werenegatively affected by the exposure of mouse embryos to increasing E2 concentrations. These authors have shown that, when 2-daymouse embryos were treated with increasing E2 concentrations up to day 5, the rate of blastocyst formation and embryonic adhesionsignificantly decreased. They concluded that high E2 levels are deleterious to embryo adhesion in vitro, mainly because they have adirect toxic effect on the embryo that may occur at the cleavage stage.

B. Possible detrimental effects of COH on endometrial receptivityFrom the endometrial standpoint, Simón et al. have shown that imbalanced E2 levels alter endometrial receptivity. Theseinvestigators observed that embryo implantation and pregnancy rates per cycle were significantly lower in high responder patientswith serum E2 concentrations >1700 pg/mL compared with those having E2 concentrations ≤1700 pg/mL, as well as in normalresponder 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 E2concentrations were >2500 pg/mL compared with patients having lower E2 concentrations. Their results suggest that high serumE2 concentrations on the day of HCG injection in high and normal responder patients, regardless of the number of oocytes retrievedand the serum progesterone (P4) concentration, are detrimental to uterine receptivity without affecting embryo quality.

C. Possible detrimental effects of COH on uterine contractilityThe third potential detrimental effect of high E2 levels may be targeted in the contractile activity of the myometrium. In previousstudies, we demonstrated that hypercontractility of the uterus at the time of ET may adversely affect IVF-ET and that uterinecontractions are, to a large extent, regulated by ovarian steroids, in particular E2 and P4. During the follicular phase of the menstrualcycle, E2 stimulates uterine contraction frequency, probably to assist sperm transport and, after ovulation, P4 exerts a remarkableutero-relaxing effect to facilitate the proper positioning of embryos in the uterine cavity and foster embryo implantation. We havepreviously observed that, in the presence of supraphysiological E2 levels comparable to those obtained after COH, the myorelaxingaction of P4 is significantly hampered, a phenomenon that may have a negative effect embryo implantation.

D. Explaining an apparent controversyIt 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. Accordingto 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 levelsrather than higher E2 levels who reached higher pregnancy rates, which suggests that high E2 levels may be deleterious for IVF-EToutcome.

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The flip side of LHTherefore, to overcome these unsuitable effects of COH while maintaining large oocyte availability, we elaborated an innovativeprotocol (NATural Ovarian Stimulation) that dissociates the magnitude of E2 production from the intensity of multiple follicledevelopment. For obtaining this effect, we elected to virtually curtail endogenous LH levels by using strong and frequent GnRHantagonist doses. For this, we considered the “two cell-two gonadotropin” theory that indicates that E2 is produced in the granulosacells 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 levelsThe 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 directlyon 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, aremarkable 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 0.25mg doses to obtain the expected biological effect. Then, after having tried 1 mg (4 doses of 0.25 mg each, daily) and noted that theLH 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 NATOSBelow the results of our 2 pilot studies (3 mg and 1.5 mg) are summarized. Altogether, they included 15 good prognosis IVF-ETcandidates, aged 25-35 years, who volunteered to undergo NATOS. All patients started daily recombinant-FSH paralleled with dailyGnRH-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/mLand 236 (103-689) pg/mL for the 3 mg and 1.5 mg groups, respectively, and serum LH levels were, as expected, undetectable in bothgroups. 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 currentlydeveloping normally).

C. “LH-null” modelsAnother point to be considered is that NATOS is by no means an “LH-null” model. Indeed, previous experience by other investigatorsboth in hypophysectomized rodents and in patients suffering from hypothalamic amenorrhea in whom circulating LH levels werebarely 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 fromNATOS, in which LH levels are rendered indetectable by high GnRH antagonist doses, but probably not null. In NATOS, contrary tohypo-hypo or hypophysectmized patients, there still is remaining LH activity, as illustrated by the marginal E2 production, which isprobably sufficient and allows encouragement of IVF-ET outcome observed in our pilot study. In keeping with NATOS results, aminimal LH amount is sufficient for an adequate biological effect.

D. NATOS for good prognosis patientsFurthermore, given that high E2 levels are commonly reached in patients having a normal follicle endowment, is it plausible thatNATOS could target this group of good prognosis IVF-ET candidates. In this case, the physiological estrogenic milieu obtained withNATOS could considerably reduce time to pregnancy in these patients by increasing IVF-ET effectiveness. The results of our pilotstudies spurred us to conduct a prospective, randomized trial to demonstrate that, in a good prognosis IVF-ET population, thephysiological E2 environment resulting from NATOS significantly improves IVF-ET outcome when compared to the conventionalGnRH antagonist protocol.

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