On the path to less intrusive IVF

Transcription

1 23rd Annual Meeting of the European Society of Human Reproduction and Embryology Lyon, France July 1 4, 2007 Organon Sponsored Symposium Monday, July 2, 2007, AM 1.00 PM L Amphithéâtre, Palais des Congrès, Lyon, France On the path to less intrusive IVF Chaired by Bernard Hedon and Nick Macklon Program and abstracts

2 Organon Sponsored Symposium Monday, July 2, 2007, AM 1.00 PM L Amphithéâtre, Palais des Congrès, Lyon, France On the path to less intrusive IVF Chaired by Bernard Hedon & Nick Macklon Hôpital Arnaud de Villeneuve University Medical Center Montpellier, France Utrecht, The difficult transition from inside-out to outside-in thinking Bart CJM Fauser University Medical Center, Utrecht, New therapeutic strategies to address the realities of an aging reproductive population Alan B Copperman Reproductive Medicine Associates, New York, NY, USA A patient-centered approach towards innovative infertility research and drug development Bernadette Mannaerts NV Organon, Oss, 3

3 Name Bernard Hedon French Service de Gynecologie-Obstetrique Hôpital Arnaud de Villeneuve Montpellier France Name Nick Macklon British University Medical Center Utrecht Montpellier University School of Medicine, Montpellier, France Resident Obstetrician and Gynecologist, Montpellier University Hospital, Montpellier, France Clinical Research Fellowship in reproductive microsurgery, Hammersmith Hospital, London, UK President of the 15th World Congress on Fertility and Sterility (1995) President of the French Fertility Society ( ) President of the International Federation of Fertility Societies ( ) Chairman of the Bouisson Bertrand Foundation and Laboratories ( ) Vice-Dean of Montpellier University School of Medicine, Montpellier, France, in charge of international affairs ( ) and student affairs ( ) President of the Montpellier University Hospital Medical Council, Montpellier, France ( ) MD Publications Author or co-author of more than 200 referenced publications and more than 20 book chapters Editor of five books (three in French, two in English) Present Positions Professor of Obstetrics and Gynecology, Montpellier University School of Medicine, Montpellier, France Chairman of the Obstetric and Gynecology Department, Reproductive Medicine Division, Montpellier University Hospital, Montpellier, France Chairman of the Fondation Fertilité Stérilité Doctoral thesis and residency in obstetrics and gynecology in Edinburgh and Glasgow, UK Fellowship in feto-maternal medicine in Rotterdam, Consultant Gynecologist and Head of the Assisted Reproduction Unit, Erasmus University Medical Center, Rotterdam, MB, CHB, MD, FRCOG Publications Has published widely in peer-reviewed journals and international-standard textbooks Editor of a prize-winning textbook entitled IVF in the Medically Complicated Patient: A Guide to Management Present Positions Professor and Head of Infertility and Periconceptional Medicine, University Medical Center, Utrecht, Chairman of the ESHRE Special Interest Group on Reproductive Endocrinology Member of the ESHRE Advisory Board and International Scientific Committee Associate Editor of Human Reproduction 4 5

4 Name Bart CJM Fauser Dutch Department of Reproductive Medicine and Gynecology University Medical Center Utrecht MD, Catholic University of Nijmegen,, 1979 Residency, Obstetrics and Gynecology, PhD, Catholic University of Nijmegen,, 1985 Postdoctoral Fulbright Scholar, Department of Reproductive Medicine, University of California, San Diego, CA, USA, Visiting Professor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA, Professor of Reproductive Medicine, Erasmus Medical Center, Rotterdam,, Editor-in-Chief, Human Reproduction Update, MD, PhD Publications PhD thesis, LH RH and reproductive function in the human male Co-author of approximately 400 international papers, book chapters and books Present Positions Professor of Reproductive Medicine, University Medical Center, Utrecht, Chair of the Department of Reproductive Medicine and Gynecology, University Medical Center, Utrecht, Head of the management team of the Woman and Baby Division, University Medical Center, Utrecht, Saal van Zwanenberg Professor, Center of Reproductive Medicine, Free University of Brussels, Brussels, Belgium The difficult transition from inside-out to outside-in thinking Bart CJM Fauser The history of in vitro fertilization (IVF) has been characterized by intense ovarian stimulation and the transfer of multiple embryos to maximize pregnancy rates per cycle. Ovarian stimulation aims to generate as many oocytes as possible in an attempt to counterbalance shortcomings in oocyte fertilization in vitro, embryo culture conditions, and embryo selection for transfer. The paradigm, the more embryos to choose from, the better the pregnancy rate, has been supported by many observational studies. Although the true added value of the cryopreservation of embryos not transferred in the fresh cycle is limited, the need for spare embryos for storage is often put forward to justify intense ovarian stimulation. Over the years, stimulation protocols have become extremely complex, time consuming (particularly with oral contraception pretreatment and gonadotropin-releasing hormone [GnRH] agonist long-protocol co-treatment) and costly, and are associated with patient discomfort, side effects and complications. Newer treatment protocols incorporating products such as GnRH antagonists (e.g. ganirelix) can help to reduce the overall treatment burden (shorten treatment time, reduce side effects, reduce the interval between cycles) without adversely affecting live birth rates. In addition, the trend towards replacing fewer embryos reduces multiple pregnancy rates, and thus the high miscarriage rates, premature labor, and increased perinatal morbidity and mortality rates associated with multiple pregnancies. The potential long-term health risks to offspring should also be seriously considered when planning IVF protocols. Registries usually compare IVF outcomes in terms of pregnancy (birth) rates per cycle. In a commercial environment, these registries may develop into league tables that are subsequently used for marketing and pricing. For the patient, the prospect of a healthy child seems the most relevant endpoint of treatment. Achieving this goal should be viewed in the context of duration of treatment (rather than births per cycle), overall patient discomfort, risks, and costs, as is the case for many other medical interventions. Moreover, the chance of a healthy future life for the offspring should be optimized by aiming for singleton pregnancies, term deliveries and normal birthweights. If professionals and healthcare providers agree on this shift in thinking, novel outcome parameters may be defined that encourage rather than penalize mild ovarian stimulation approaches and the transfer of a single embryo. Proof-of-concept studies performed by our group have further explored this concept. We have shown that mild ovarian stimulation is associated with a reduced proportion of aneuploid embryos, as assessed by preimplantation genetic screening. Subsequently, a large effectiveness trial comparing a mild approach (mild stimulation/gnrh antagonist co-treatment along with single embryo transfer) and a conventional approach has been performed, showing similar cumulative term live birth rates associated with lower costs, less patient discomfort, and a dramatic reduction in multiple pregnancies. 6 7

5 Name Alan B Copperman American Reproductive Medicine Associates New York, NY USA BA, University of Pennsylvania, Philadelphia, PA, USA, 1985 MD, New York Medical College, Valhalla, New York, NY, USA, 1989 Internship and residency, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA, Fellowship, Division of Reproductive Endocrinology, Mount Sinai School of Medicine, New York, NY, USA, BA, MD Publications and Presentations Has published over 100 abstracts, peer-reviewed papers and textbook chapters in domestic and international journals Frequently serves as an expert on reproductive issues for local and national print and television media Present Positions Director of Reproductive Endocrinology, Mount Sinai Medical Center, New York, NY, USA Vice-Chairman of Obstetrics, Gynecology and Reproductive Sciences, Mount Sinai Medical Center, New York, NY, USA Co-Director of Reproductive Medicine Associates, New York, NY, USA Ad hoc Editor for nine scientific journals New therapeutic strategies to address the realities of an aging reproductive population Alan B Copperman Unlike many animals, humans are inherently inefficient at reproduction. This is mainly due to female reproductive aging, particularly in regard to oocyte quality. Over the past decade, public awareness of the decline in reproductive function has increased. Strategies to counteract the impact of reproductive aging have varied from simple methods such as improved patient education about childbearing, to complex laboratory procedures such as manipulation of subcellular structures and the elective cryopreservation of gametes and embryos in an attempt to reverse or suspend an otherwise inexorable decline in reproductive efficiency. Educational campaigns to improve awareness of the physiologic biological clock have been slow to take hold with the targeted audience. Politicization of this topic has falsely raised concerns of ulterior motives beyond questions of women s reproductive health. Ironically, some women s groups have cautioned against providing too much information to young women about the implications of age because of concerns that it could deter them from pursuing careers, fearing that such knowledge would subjugate women to roles of childbearers rather than freeing them to pursue economic equality. However, by touting advances in medicine as liberators from biological reality, these efforts may give an incomplete appreciation of the limitations of science, and may thereby do these women a greater disservice. For example, the highly publicized pregnancies of older celebrities have, by omission of the complete facts, given false impressions of reproductive immortality. More practically, others have encouraged women to gain control over the limit of their reproductive life span by preserving their reproductive potential through the freezing of their gametes. Given the recent success and popularization of oocyte cryopreservation technologies, social and scientific debate about this procedure has been pushed to the forefront. As reproductive techniques, lab quality and cryopreservation technologies have improved, the concomitant use and success of egg freezing have increased. There are currently at least two successful methods for freezing eggs: slow freeze and vitrification. Both have advantages and disadvantages. Societies, governmental agencies and support groups have expressed varying opinions on whether the available technologies are efficient enough to be offered to patients who are attempting to preserve their fertility on a clinical basis, both for medical and for elective reasons, or whether their use should be restricted solely to research protocols. All parties have urged the continued collection and analysis of data to determine the relative and potential success of these fledgling technologies. In the next decade, we will see differences among patients, centers and societies. Will the physical and financial costs of technologies decrease as we develop effective orally active gonadotropins or in vitro maturation techniques? All of these advances should usher in the popularization of gamete preservation and enhanced reproductive control for individuals. In addition, just as the US Food and Drug Administration has outlawed the use of anonymous fresh donor sperm, we may see fresh donor eggs become obsolete as they are replaced with banked and screened cryopreserved oocytes. Technological advances will inevitably surpass our ability to plan and prepare. Regulatory bodies and social frameworks will struggle with the unanticipated implications of these advances. The time has come to address the realities of an aging reproductive population and to pursue new and effective therapeutic options and strategies. 8 9

6 Name Bernadette Mannaerts Dutch NV Organon Oss Doctorate in medical biology (specialties: immunology, endocrinology, cell biology), University of Utrecht, Utrecht,, Research Associate (bovine embryo classification and karyotyping), Veterinary School, Utrecht,, Group Leader (preclinical development of Puregon /Follistim ), Biochemical and Pharmacological R&D Laboratory, NV Organon, Oss,, Medical Research Project Manager (clinical development of Puregon/Follistim), Medical R&D Unit, NV Organon, Oss,, Head of Clinical Projects Infertility (global clinical development of Orgalutran /ganirelix), Clinical Development Department, NV Organon, Oss,, International Medical Advisor for Fertility, Marketing Services, NV Organon, Oss,, MSc, PhD Publications and Presentations Author of over 50 scientific papers and book chapters Has presented many invited lectures on outcome of preclinical research, clinical research and development of (recombinant) gonadotropins, gonadotropin-releasing hormone analogs, and treatment regimens in controlled ovarian stimulation, ovulation induction and intrauterine insemination, at international scientific meetings/symposia Present Position Director of Clinical Projects Infertility, (global scientific responsibility for all phase I to IV infertility trials), Clinical Development Department, NV Organon, Oss, A patient-centered approach towards innovative infertility research and drug development Bernadette Mannaerts Patients undergoing in vitro fertilization (IVF) are known to suffer from anxiety, depression, frustration, distress and disappointment. The psychological impact of the IVF process includes treatment-related stress due to complex medical schemes and the need to prepare and administer treatments, as well as the long duration of treatment, and the frequency of injections. 1 Since the introduction of recombinant follicle-stimulating hormone (FSH) more than 10 years ago, a considerable effort has been made in the development of new fertility drugs and formulations that could simplify treatment. Whereas recombinant FSH was initially launched as a freeze-dried preparation for reconstitution, shortly thereafter, the same product was developed as a ready-to-use solution in a vial and a cartridge, the latter to be administered with a convenient pen device. The great breakthrough for patients, however, was the clinical development of gonadotropin-releasing hormone (GnRH) antagonists, which shortened treatment cycles by 2 3 weeks, largely reduced drug exposure, reduced menopausal side effects, and significantly decreased the risk of developing severe ovarian hyperstimulation syndrome. 2 Although patients prefer the convenience of this new treatment option over conventional regimens, the success rates with GnRH antagonist regimens were initially under debate. It is clear that confidence in GnRH antagonists has increased in general IVF practice, resulting in high pregnancy rates in patients with normal responses. 2,3 Mounting evidence from the literature suggests that endogenous luteinizing hormone (LH) in these short GnRH antagonist regimens remains sufficiently high in normogonadotropic patients to support recombinant FSH during the whole stimulation period. Thus, LH supplementation does not appear necessary in the application of GnRH antagonist protocols. 4,5 In addition, the assumption that LH supplementation might find its place in the treatment of a subset of patients undergoing pituitary suppression in a long GnRH agonist protocol remains under debate. 6 Although GnRH antagonist regimens are a major step forward, patients still require daily FSH injections, which could be reduced if a sustained follicle stimulant were available, capable of initiating and maintaining follicular development for at least several days, but preferably for 1 week. For that purpose, Org (corifollitropin alfa), Organon s new recombinant fertility drug is currently being developed. A single injection of Org has been shown to initiate and sustain multiple follicular growth for an entire week. Following a large dose-finding trial, 7 two doses of Org (100 µg and 150 µg) have been selected for further clinical development in a 1-week regimen, followed by daily recombinant FSH injections from stimulation day 8 onwards. Whereas large double-blind, phase III trials are currently ongoing to prove the efficacy and safety of Org compared with daily recombinant FSH, an open-label, repeat-cycle trial is ongoing to demonstrate the non-immunogenicity of this compound in patients undergoing IVF. The reduction of daily injections and the simplicity of the Org regimen will be another step forward in the development of a more patient-centered treatment regimen, which will reduce the psychological burden of ovarian stimulation for IVF. References 1. Cousineau TM, Domar AD. Psychological impact of infertility. Best Pract Res Clin Obstet Gynaecol 2007;21: Kolibianakis EM, Collins J, Tarlatzis BC, et al. Among patients treated for IVF with gonadotrophins and GnRH analogues, is the probability of live birth dependent on the type of analogue used? A systematic review and meta-analysis. Hum Reprod Update 2006;12: Heijnen EMEW, Eijkemans MJC, De Klerk C, et al. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet 2007;369: Kolibianakis EM, Collins J, Tarlatzis B, et al. Devroey P. Are endogenous LH levels during ovarian stimulation for IVF using GnRH analogues associated with the probability of ongoing pregnancy? A systematic review. Hum Reprod Update 2006;12: Baruffi RL, Mauri AL, Petersen CG, et al. Recombinant LH supplementation to recombinant FSH during induced ovarian stimulation in the GnRH-antagonist protocol: a meta-analysis. Reprod Biomed Online 2007;14: Oliveira JB, Mauri AL, Petersen CG, et al. Recombinant luteinizing hormone supplementation to recombinant follicle-stimulation hormone during induced ovarian stimulation in the GnRH-agonist protocol: a meta-analysis. J Assist Reprod Genet 2007;24: Devroey P, Koper N, Mannaerts B. A randomized dose-finding trial to establish the ovarian response to a single injection of Org for sustained follicular stimulation. Hum Reprod 2006;21(Suppl 1):i68(abstract O-172)

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