FINAL PROGRAM AND ABSTRACTS

Transcription

1 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 1 FINAL PROGRAM AND ABSTRACTS 2010 Montreal, Canada - November 26, Treating the Ovary to Obtain Better Eggs Your Continuing Medical Education Partner

2 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 2 GENERAL INFORMATION VENUE The Symposium will take place at the: Loews Hôtel Vogue 1425 de La Montagne (Street) Montreal, Quebec H3G 1Z3 Phone: Fax: Toll Free Reservations: LANGUAGE The official language of this Symposium will be English. TRAVEL INFORMATION Montreal is the second largest city and the cultural capital of Canada. A cultural heart of classical art is the Place des Arts that harbours the headquarters of one of the world's foremost orchestras, the Montreal Symphony Orchestra. Also performing at Place des Arts is the Opéra de Montréal and Les Grands Ballets Canadiens company. The city is also a centre of film and television production. Montreal is an important centre of commerce, finance, industry and technology. Industries include aerospace, electronic goods, software engineering, telecommunications, and transportation. Montreal is renowned for its churches: Mary, Queen of the World Cathedral, the Notre-Dame Basilica, St. Patrick's Basilica, and Saint Joseph's Oratory. Montreal s renowned duality of Old World charm infused with North American energy lies at its very heart; the plurality of cultures really makes this metropolis tick. Montreal is as romantically traditional as it is cutting-edge innovative, as cosmopolitan dynamic as it is small-town friendly. Yet despite this diversity, an underlying homogeneity exists in this vibrant population who collectively and confidently live and let live.

3 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 3 Treating the ovary to obtain better eggs Serono Symposia International Foundation Symposium on: TREATING THE OVARY TO OBTAIN BETTER EGGS Montreal, Canada - November 26, 2010 AIM OF THE SYMPOSIUM One of the key factors to improve ART outcomes is the improvement of quality of oocytes used for the fertilization procedures. Assisted reproduction specialists have now a wide range of approaches aimed to collect the best oocyte possible. The availability of such different options improves dramatically the possibility of tailoring the approach on the infertility profile of the couple, but only if reliable criteria are used to define the couple s infertility profile and evaluate the outcomes, starting from the oocytes quality assessment. The aim of this Symposium is to review the different options now available to optimize ART outcomes improving oocytes quality, emphasizing the use of objective and reliable markers to select the right approach. LEARNING OBJECTIVES Participants in this Symposium will: Be updated on the range of approaches available to obtain good quality oocytes Be informed about the most reliable markers of infertility profile Discuss the best criteria to evaluate oocytes quality TARGET AUDIENCE Clinicians and scientists working in assisted reproduction. ACCREDITATION This event is an Accredited Group Learning Activity (Section 1) as defined by the Maintenance of Certification Program of The Royal College of Physicians and Surgeons of Canada and approved by the Canadian Fertility and Andrology Society. Section 1: 1 CME credit per hour for each core content module, therefore for the entire duration of this symposium: 8 CME credits will be awarded to the participants. Cet événement est une activité d'apprentissage de groupe (section 1), telle que défini par le Programme du Maintien du Certificat du Collège Royal des Médecins et Chirurgiens du Canada et approuvé par la Société Canadienne de Fertilité et d'andrologie. Section 1 : 1 crédit EMC par heure de participation, alors pour la durée entière de ce Symposium : 8 crédits EMC seront accordés aux participants. All Serono Symposia International Foundation programs are organized solely to promote the exchange and dissemination of scientific and medical information. No forms of promotional activities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of the named speakers, and do not represent an endorsement or recommendation on the part of Serono Symposia International Foundation. This program is made possible thanks to the unrestricted Educational grant received from: Centre d Esclerosi Multiple de Catalunya, Vall d'hebron University Hospital, ComtecMed, Congrex Sweden, Congrex Switzerland, Cryo-Save, Datanalysis, Esaote, Fundación IVI, ISFP International Society for Fertility Preservation, ISMH International Society of Men s Health, K.I.T.E., Merck Serono, Ministry of Health of the State of Israel, University of Catania.

4 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 4 SCIENTIFIC ORGANIZER Marc-André Sirard Centre de Recherche en Biologie de la Reproduction Université Laval Québec, Canada LIST OF SPEAKERS AND CHAIRMEN David F. Albertini Department of Molecular & Integrative Physiology University of Kansas Medical Center Kansas City, USA Jean-Daniel Baki Board of Directors Serono Symposia International Foundation Geneva, Switzerland Marco Filicori Reproductive Medicine Unit GynePro Medical Group Bologna, Italy SCIENTIFIC SECRETARIAT Serono Symposia International Foundation (Switzerland) 1707 Avenue Carpentier Boisbriand, Quebec, Canada J7G 3G1 Senior Project Manager: Christian G. Thuot Phone: Fax: Mobile: info@seronosymposia.org Serono Symposia International Foundation is a Swiss Foundation with headquarters in 14, rue du Rhône, 1204 Genève, Switzerland ORGANIZING SECRETARIAT MedPlan Communications Inc. 5524, rue Saint-Patrick, bureau 200 Montreal, Quebec, Canada H4E 1A8 Coordinator, Meetings & Events: Mélanie Usereau Phone: Toll Free Phone: Fax: Toll Free Fax: musereau@medplan.ca Robert Fischer IVF Unit Fertility Centre Hamburg Hamburg, Germany Stephen G. Hillier Department of Reproductive Endocrinology Centre for Reproductive Biology University of Edinburgh Edinburgh, UK Arthur Leader Department of Obstetrics, Gynaecology and Medicine (Endocrinology) University of Ottawa Ottawa Fertility Centre Ottawa, Canada Donna R. Session Reproductive Endocrinology and Infertility IVF Emory Reproductive Centre Atlanta, USA Marc-André Sirard Centre de Recherche en Biologie de la Reproduction Université Laval Québec, Canada

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6 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 6 FRIDAY - NOVEMBER 26, Registration Welcome on behalf of Serono Symposia International Foundation Jean-Daniel Baki, SSIF Board of Directors, Switzerland Robert Fischer, SSIF Scientific Committee, Germany Introduction and Opening Marc-André Sirard, Canada SESSION I FUNDAMENTALS OF THE OVARIAN PHYSIOLOGY Chairmen: Marc-André Sirard, Canada - Donna R. Session, USA L1: Lessons from Animal Studies Marc-André Sirard, Canada L2: The Physiological Limit of Ovarian Stimulation Arthur Leader, Canada Coffee Break L3: The Respect of Ovarian Physiology Stephen G. Hillier, UK Discussion Working Lunch

7 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 7 SESSION II CLINICAL APPLICATIONS OF THE OVARIAN PHYSIOLOGY Chairmen: Arthur Leader, Canada - Stephen G. Hillier, UK L4: Mild Stimulation: When and Why Donna R. Session, USA L5: The Use of LH Activity to Drive Folliculogenesis Marco Filicori, Italy Coffee Break L6: What are Objective Oocyte Quality Markers David F. Albertini, USA L7: Genomic Analysis of the Response to Stimulation Marc-André Sirard, Canada Discussion SESSION III PANEL DISCUSSION Chairman: Robert Fischer, Germany Optimizing Ovarian Stimulation to Improve Oocyte Quality Marco Filicori, Italy Stephen G. Hillier, UK Marc-André Sirard, Canada Discussion Closing Remarks by Scientific Organizer Marc-André Sirard, Canada End of the Symposium

8 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 8 DISCLOSURE OF FACULTY RELATIONSHIPS Serono Symposia International Foundation adheres to guidelines of the European Accreditation Council for Continuing Medical Education (EACCME) and all other professional organizations, as applicable, which state that programs 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 program (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 participants may form their own judgments, based on full disclosure of the facts. Further, all opinions and recommendations presented during the program and all program-related materials neither imply an endorsement, nor a recommendation, on the part of Serono Symposia International Foundation. All presentations solely represent 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: David F. Albertini Declared no potential conflict of interest. Jean-Daniel Baki Marco Filicori Robert Fischer Stephen G. Hillier Arthur Leader Donna R. Session Marc-André Sirard Declared no potential conflict of interest. Declared receipt of honoraria or consultation fees from Merck Serono, IBSA, Schering Plough and Ferring. Declared receipt of honoraria or consultation fees from SSIF. Declared receipt of grants and contracts from the Medical Research Council (UK). Declared receipt of honoraria or consultation fees: Editor-in-Chief MHR Basic Science of Reproductive Medicine (Oxford Journals). Declared being a member of a company advisory board, board of directors or other similar group: Destination Edinburgh Marketing Alliance (Board of Directors). Declared receipt of grants and contracts: EMD, Merck. Declared receipt of honoraria or consultation fees from Merck. Declared being a member of a company advisory board, board of directors or other similar group: EMD, Merck. Declared no potential conflict of interest. Declared receipt of honoraria or consultation fees from Serono. All Serono Symposia International Foundation programs are organized solely to promote the exchange and dissemination of scientific and medical information. No forms of promotional activities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of the named speakers, and do not represent an endorsement or recommendation on the part of Serono Symposia International Foundation. This program is made possible thanks to the unrestricted Educational grant received from: Centre d Esclerosi Multiple de Catalunya, Vall d'hebron University Hospital, ComtecMed, Congrex Sweden, Congrex Switzerland, Cryo-Save, Datanalysis, Esaote, Fundación IVI, ISFP International Society for Fertility Preservation, ISMH International Society of Men s Health, K.I.T.E., Merck Serono, Ministry of Health of the State of Israel, University of Catania.

9 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 9 ABSTRACTS (L1 L7)

10 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 10 L1 LESSONS FROM ANIMAL STUDIES Marc-André Sirard Centre de Recherche en Biologie de la Reproduction, Université Laval, Québec, Canada Oocyte quality is not a problem that is specific or limited to humans. In large animals, especially those who produce limited numbers of oocytes per cycle, the oocyte quality varies, even without the use of hormonal stimulation. Therefore, it is of interest to review the interactions between the hormonal milieu, ovarian follicles and the ability of oocytes to further develop. In addition, in several species such as the cow, the use of synchronized recipients provides an opportunity to minimize uterine effects on the outcome. The use of ovarian stimulation results in an increase in the number of oocytes produced in a given cycle. This approach has been used, especially in cows, to increase the number of offspring. Some differences are observed in ovarian stimulation regimens used in animals compared with those used in humans, such as the absence of ovulation inhibitors (GnRH agonists or antagonists), which is mainly due to the high costs associated with the procedure. The same is true for recombinant gonadotropins. Nevertheless, the general observation extrapolated from mice and cows is that stimulation can sometimes change oocyte quality. Possible explanations for this include ovarian resistance, perturbation of LH patterns, overall increase in oestradiol and DNA methylation changes in resulting embryos. Some of these changes can also affect the uterine response and only a careful experimental design can allow ovarian or pre-fertilization events to be firmly linked to embryos of lower quality. In humans, the use of agonists/antagonists gives us a different perspective. The possibility of controlling ovulation often creates heterogeneity in the oocyte population. Direct evidence of such a phenomenon is provided by the variability in the quality of oocytes or ensuing embryos from the same patient within the same stimulation cycle. It is rare that all the oocytes of a cycle are of good quality; sometimes they are all of poor quality, which can be confounded by a male factor. The same pattern is observed in mono-ovulating animal species. Experiments that can shorten or prolong the interval from stimulation to ovulation have shown deleterious effects in several species. In cows, where ovarian physiology is similar to humans, postponing ovulation by 1 day (by maintaining high progesterone levels) decreases the quality of the oocyte, as measured by its ability to form a viable blastocyst after fertilization or by pregnancy rates. In our laboratory, we found a way to manipulate oocyte quality by using different intervals of oocyte recovery post-fsh treatment. This type of coasting can induce rates of blastocyst development to increase from 20% to 85% and then decrease to 20% in the same animal treated with different stimulation periods. This model suggests that there is an optimal differentiation level in the follicle that translates into better oocyte quality. Similar studies in humans have suggested similar effects. It is appropriate, therefore, to optimize stimulation protocols to ensure ideal maturity of the majority of follicles prior to ovulation. The applicability of observations from fertile/infertile animals in experimental models and cattle herds to infertility in humans will be discussed.

11 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 11 ABSTRACTS L2 THE PHYSIOLOGICAL LIMIT OF OVARIAN STIMULATION Arthur Leader Department of Obstetrics, Gynaecology and Medicine (Endocrinology), University of Ottawa, Ottawa Fertility Centre, Ottawa, Canada The IVF poor responder undergoing controlled ovarian stimulation represents a particular challenge. Predictive outcome models suggest that the best livebirth rates are achieved when a day-5 embryo is transferred and this is most likely when six or more metaphase II oocytes are retrieved. In women of advanced reproductive age who are poor responders, several strategies have been proposed, including the modified natural cycle protocol, microdose agonist flare protocol, oestradiol patch antagonist protocol and flare protocol. Often these protocols involve high-dose gonadotrophins for prolonged periods of time. The use of growth hormone and day-2 embryo transfer has been considered also. While these approaches have helped women to achieve embryo transfer where embryo transfer was previously cancelled, the success rates are low. In young women with poor ovarian reserve, the success rates are not much better, despite these strategies. The impact of high-dose gonadotrophin therapy on the follicle and the endometrium will be discussed.

12 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 12 L3 THE RESPECT OF OVARIAN PHYSIOLOGY Stephen G. Hillier Department of Reproductive Endocrinology, Centre for Reproductive Biology, University of Edinburgh, Edinburgh, UK Advances in our understanding of the developmental and cell biology of folliculogenesis are delineating the follicular physiome through which somatic cellular functions influence oocyte development and vice versa. It is becoming increasingly clear from pre-clinical studies and in-vitro modelling that oocyte quality in terms of maternal contribution to embryogenesis and early development is programmed before ovulation and therefore potentially amenable to endocrine and paracrine manipulation. It is therefore surprising that so little attention has been paid to translating this basic science into clinical practice. This is all the more so given the many patient scenarios that are now potentially amenable to ART. Here the natural follicular lifespan is tracked to locate paracrine checkpoints tractable to endocrine manipulation that are likely to influence oocyte quality. Emphasis is placed on signalling by members of the transforming growth factor-β (TGF-β) superfamily of growth and differentiation factors, which contains the quintessential gonadal paracrines activin and inhibin. Armed with this knowledge, it is suggested that intelligent administration of FSH and LH activity (either LH or hcg) can allow fine-tuning of ovarian stimulation on a patient-by-patient basis to improve individual responses and benefit treatment outcome. (Reproduced from Hillier SG. Paracrine support of ovarian stimulation. Mol Hum Reprod. 2009;15:843-50)

13 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 13 ABSTRACTS L4 MILD STIMULATION: WHEN AND WHY Donna R. Session Reproductive Endocrinology and Infertility, IVF Emory Reproductive Centre Emory University School of Medicine, Atlanta, USA Mild stimulation strategies have been previously referred to as soft, minimal and friendly. Mild stimulation protocols may include lowdose FSH/hMG, oral agents, GnRH antagonists and delayed initiation of FSH administration. Possible indications for use of mild stimulation strategies in ovulation induction and assisted reproductive technologies include improvement in embryo quality, avoidance of ovarian hyperstimulation and reductions in cost. In ovulation induction, the use of mild stimulation with a combination of oral agents and hmg has resulted in similar pregnancy rates as hmg alone, with a reduced cost. However, early studies using mild stimulation in IVF with a combination of oral agents and hmg, before GnRH antagonists were available, demonstrated a higher cancellation rate, lower number of oocytes retrieved and lower pregnancy rates than with conventional IVF. Dual suppression with oral contraceptive agents and a GnRH agonist followed by low-dose FSH has been shown to improve IVF outcome in high responder patients. The recent introduction of GnRH antagonists to a combination of oral agents and FSH or delayed initiation of FSH administration provides alternative protocols for both high and low responders. Both protocols still demonstrate higher cancellation rates for mild stimulation in high responders. However, they also suggest that mild stimulation may be associated with better embryo quality, reflected by a higher pregnancy rate or greater number of high quality embryos. In addition, a low-dose FSH and GnRH antagonist protocol was associated with a lower percentage of aneuploidy embryos compared with conventional IVF. Future studies need to focus on the confirmation of these findings and possible association of embryo quality with type of medication and hormonal milieu.

14 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 14 L5 THE USE OF LH ACTIVITY TO DRIVE FOLLICULOGENESIS Marco Filicori Reproductive Medicine Unit, GynePro Medical Group, Bologna, Italy LH activity can be provided through LH or hcg, which act on the same follicular receptors. LH plays a key role in ovarian stimulation through the stimulation of theca cells to produce androgens that are converted to oestrogens by the aromatase system in granulosa cells. In addition, LH/CG receptors are highly expressed by granulosa cells of more mature follicles, thus making these ovarian cells receptive to LH/CG stimulation; this feature is critical for dominant follicle selection and for triggering final follicle/oocyte maturation and ovulation in both spontaneous and induced menstrual cycles. In addition, it has been repeatedly demonstrated by us and other groups that LH activity supports and stimulates large follicle development when exogenous FSH is reduced or discontinued in the late stages of COS; both lowdose hcg and r-hlh are effective in this model. Finally, LH activity appears to be capable of finely modulating folliculogenesis by reducing the number of small follicles in the preovulatory stage. Due to these physiological and clinical features, the use of LH in OI and COS has increased. LH activity must supplement FSH when treating patients with hypogonadotrophic hypogonadism to optimize oestrogen secretion and follicle/oocyte maturity. The combined administration of FSH and LH activity in COS can improve follicular phase hormone dynamics and treatment duration, but effects on therapeutic efficacy are still controversial. When r-hlh is added to FSH, most studies have not shown any significant improvement versus FSH alone. However, low amounts of r-hlh ( IU/day) were used in most of these studies and this may have negatively affected treatment outcomes; we have shown that low-dose hcg supplementation at a dose of 50 IU/day (corresponding to IU/day of LH) significantly reduced treatment duration and FSH consumption. Finally, partial or complete replacement of exogenous FSH with low-dose hcg or high-dose r- hlh leads to mature follicle development and excellent clinical outcomes in IVF. Both GnRH agonists and antagonists can be employed in this setting. Occurrence of ovarian hyperstimulation may be curtailed by these regimens, as few small ovarian follicles are found in late COS. In summary, use of supplemental LH activity to drive folliculogenesis represents a physiological, effective and, potentially, safe way to achieve ovarian stimulation and good clinical outcomes in OI and COS.

15 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 15 ABSTRACTS L6 WHAT ARE OBJECTIVE OOCYTE QUALITY MARKERS David F. Albertini Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, USA XXXX xxxxxxxxxxxxxxxx Abstract not in hand at the time of going to press.

16 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 16 L7 GENOMIC ANALYSIS OF THE RESPONSE TO STIMULATION Marc-André Sirard Centre de Recherche en Biologie de la Reproduction, Université Laval, Québec, Canada Recently developed genomic tools are providing us with new insights into ovarian physiology. The analysis of several blood parameters, such as oestrogens, FSH, AMH, LH or inhibin levels to measure response to treatment, has dictated most of the current ovarian stimulation protocols in animals and humans. Although more methodologically complex, the use of transcriptome and proteome analyses to investigate intra-ovarian conditions provides us with thousands of indicators of treatment response. In fact, the field is now overwhelmed with the amount of data generated by microarray experiments and similar technologies. In addition, the availability of knock-out mice is improving our understanding of the effects of individual genes during late folliculogenesis. One of the first observations obtained from such experiments is that ovarian stimulation has an impact on the follicular as well as the oocyte transcriptome. While these changes are numerous, they do not necessarily affect the pregnancy rate. The first challenge is the integration of the immense data sets for each individual species and the comparative analysis. This should lead to a better understanding of the consequences of perturbations at the gene/protein expression levels. In humans, the most readily available tissues for study are the follicular/cumulus cells obtained during oocyte collection in COS. Studies can be divided into two groups: those in pools of cumulus cells post-recovery and those in oocyte-associated cells in individually aspirated follicles. Although more practical, cumulus cell analysis does not provide much information on the condition of the follicle before oocyte removal. To correlate the individual follicular context with the ensuing developmental competence of the oocyte, an individual collection scheme must be used. Few studies have explored these tissues in individual follicles as this requires individual follow-up of oocytes during IVF and embryo transfer. Our laboratory has obtained such individualized samples through several years of collaboration with the Ottawa fertility clinic. The analysis of such tissues has enabled us to identify 1) markers of a successful cycle (one that results in pregnancy), 2) markers of a successful oocyte (one that gives rise to a pregnancy; same patient, same cycle) and 3) markers of the embryo s ability to result in a pregnancy (across patients). All of these studies have provided markers that can be monitored to improve stimulation protocols. Moreover, the careful analysis of patients who fail to conceive may reveal the unfavourable follicular conditions that may vary from one individual to another. In a bovine model, we have investigated markers of under- and over-follicular maturity. In these experiments, each animal can be its own control through successive cycles of follicle recovery. We have learnt that a growing follicle is not differentiated enough to produce a good quality oocyte and that a differentiated follicle is short-lived. The same approach could be used in humans to study the follicular milieu in patients having a successful cycle following an unsuccessful one. The concept of ideal timing will be developed with regard to the ability of genomic tools to provide a useful diagnostic in returning patients.

17 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 17 ABSTRACTS PANEL DISCUSSION OPTIMIZING OVARIAN STIMULATION TO IMPROVE OOCYTE QUALITY Panellists: Marco Filicori 1, Steve G. Hillier 2, Marc-André Sirard 3 ; 1. Reproductive Medicine Unit, GynePro Medical Group, Bologna, Italy; 2. Department of Reproductive Endocrinology, Centre for Reproductive Biology, University of Edinburgh, Edinburgh, UK; 3. Centre de Recherche en Biologie de la Reproduction, Université Laval, Québec, Canada. XXXX xxxxxxxxxxxxxxxx Abstract not in hand at the time of going to press.

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19 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 19 NOTES

20 FP-Montreal_RH_Layout 1 18/11/10 20:22 Pagina 20 Your Continuing Medical Education Partner Copyright Serono Symposia International Foundation, All rights reserved.