CHR VOICE the. GrandRounds. CHR s Fall Travel Plans. The Center for Human Reproduction LOCAL NEWS. Also in this issue: monthly CHR UPDATE OCTOBER 2014

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1 OCTOBER 2014 CHR VOICE the The Center for Human Reproduction Clinical Care Research Education monthly CHR UPDATE CHR s Fall Travel Plans The Annual Meeting of the American Society for Reproductive Medicine (ASRM) is always the principal event of fertility specialists and reproductive endocrinologists in Image courtesy of picturesofhawaii.com October. The meeting this year takes place from October 18th through 22nd in Hawaii, and CHR investigators, as has become routine in the last decade, will again present a large number of accepted abstracts. In general, the fall is a heavy travel time for the physicians and scientists at CHR. This year is no exception. After ASRM in October, a number of other annual professional meetings are on the travel schedule: The Ovarian Club, an international meeting of the leading experts on ovarian physiology, with CHR s Medical Director and Chief Scientist, Norbert Gleicher, MD and CHR s Senior Scientist and Director of the Division of Laboratories, David Albertini, PhD, invited faculty speakers. The annual Controversies on Obstetrics & Gynecology (COGI) Europe meeting (in Paris, France) and COGI Asia meeting in Ho Chi Min City (Saigon, Vietnam) follow, both attended as faculty by Dr. Gleicher. LOCAL NEWS A lot is happening locally at CHR. All construction permits have finally been obtained from the City of New York Building Department and construction progress should kick in at a more rapid pace; CHR is continuing to expand its services. As noted in last month s VOICE, we are officially inaugurating our new Onco-Fertility Preservation Program on October 14th, with Prof. Dror Meirow, MD from Israel giving CHR s Annual Fertility Preservation GrandRounds. GrandRounds October 2014 Join us for our annual fertility preservation GrandRounds on Tuesday, October 14, 2014, in which Dr. Dror Meirow will present on methods of prevention for ovarian failure and infertility in young patients treated with chemotherapy for cancer, which destroys ovarian follicle stockpile. Dr. Meirow s lecture aims to increase awareness among physicians of fertility preservation for young cancer patients, particularly ovarian tissue cryopreservation and use of protecting agents. Can we rescue ovarian follicles from the toxic effects of chemotherapy to allow future reproduction? Dror Meirow, MD The evening will begin with cocktails at 6 pm, with presentations beginning at 7 pm, followed by a formal sit-down dinner. For more information and to register for the event, please visit: Updates on Clinical... 2 Progress at CHR Updating our readers on CHR s newest research endeavors. Also in this issue: Beyond Older Ovaries... 3 New Clinical Trials... 3 Against Blastocyst-Stage... 4 CHR s focus extends much further than the treatment of older ovaries. Updates on new trials going on at CHR - Embryoscope and HGH Embryo Transfer and PGS New evidence supports the well informed opinions of CHR physicians 1

2 Updates on Clinical Progress at CHR Regular readers of these pages know that much of CHR s research is translational; meaning that we are trying to pursue research, which if successful has immediate clinical relevance in how we treat patients. We previously reported in these pages that one of CHR s major concerns in recent years has been the rapid drop in IVF pregnancy rates after age 43. Very few other IVF centers in the U.S. (and around the world) even treat women above age 42. They are therefore not aware of this decline. CHR, however, routinely treats women up to age 47 and on some occasions even beyond that age. We are therefore acutely aware that our pregnancy rates up to age 43 are quite good. After age 43, even though we still pretty regularly establish pregnancies and achieve deliveries almost up to age 47, there is a considerable drop-off in pregnancy rates. As we reported in these pages, over a year ago we therefore decided to try to find out what may cause this sudden dropoff in pregnancy chances, while up to age 43 pregnancy rates decrease with age much more gradually. To find out more about our previous research into this sudden drop-off in pregnancy chances, go to: chrvoice_1403.pdf Our research revealed very convincing evidence that women after age 43 prematurely age their follicles during maturation in a biological process called premature luteinization. In younger women, luteinization starts only once follicles reach large sizes of approximately mm. In women above age 43, this occurs at much smaller follicle sizes. As a consequence, the eggs in these relatively small follicles already overcook at such small follicle sizes which, of course, results in poor egg and embryo quality and, therefore, poor pregnancy rates. This observation raised the immediate question, what might be done to prevent this premature luteinization from happening? The only realistic option CHR s investigators came up with was to remove (i.e., retrieve) eggs before this premature luteinization occurred. There was, of course, concern that earlier egg retrieval could increase the number of immature eggs (which also is not a good outcome), but considering CHR s recently developed expertise of in vitro maturation (IVM), we felt that we could safely handle this problem should it, indeed, arise. To read more about our recently developed expertise of in vitro maturation, go to: chrvoice_1406.pdf At the beginning of 2014, we changed the egg retrieval protocol for women above age 43 by giving the hcg shot, which induces ovulation, at 16 mm follicle size (rather than mm) and shortening the time between hcg administration and egg retrieval from 36 to 30 hours. We are now pleased to report that preliminary data we just analyzed, and are preparing for publication, demonstrate strong evidence that this strategy, indeed, improves pregnancy chances in women above age 43. It is important to note that these data are preliminary because considering how low pregnancy chances are at this very advanced reproductive age, we will likely need at least IVF cycles to reach statistically significant proof of improvements in live birth rates; but with almost 40 IVF cycles in women above age 43, we already have statistically sound evidence for the following: While we, indeed, slightly increased the number of immature eggs, because of our IVM s success in maturing eggs, we lost no embryos and, indeed, slightly increased embryo numbers available for transfer. Egg and embryo quality were improved significantly. Moreover, the number of artretic ( overcooked ) eggs was significantly reduced. While the number of so far completed cycles is still too small to have statistically significant results for implantation and clinical pregnancy rates, both of these primary outcome parameters showed strong trends toward improvement, with both almost doubling. Delivery rates will, of course, take even longer to establish, but the numbers so far suggest no increase in miscarriage risk. We are delighted about these preliminary results because CHR s patient population is continuing to increase in age as the number of older women trying to conceive is rising; yet, most other IVF centers still refuse treatment to older women. Because we are planning to submit these data for publication, we, unfortunately, cannot go into further details about outcomes. Only so much: Utilizing this new protocol in women above age 43, our clinical pregnancy rate so far has been in the double digits. We are currently discussing additional changes in our protocol for this group of patients, which we hope will further improve outcomes. These pages will immediately report on any further progress. 2

3 Beyond older ovaries Patients often ask us why we so rarely write in these pages about the treatment of younger patients, who, after all, represent the vast majority of infertility patients. The answer is that we, of course, by no means want to ignore patients who have other infertility problems, like polycystic ovary syndrome (PCOS), endometriosis, immunological infertility and repeated pregnancy loss, tubal infertility or male factor infertility. CHR treats women and men with these fertility problems every day, but so do most other fertility centers. Women with older ovaries, however, usually do not have such wide access to care since most fertility centers stop treating women once they reach the age of 42 years. Even if centers do not acknowledge doing so, they practically do so by cancelling IVF cycles if patients do not produce minimal follicle numbers or by insisting on culturing embryos to blastocysts stage (see above) and/or to performing PGS. Most of the time patients don t ever reach embryo transfer, even if they allegedly receive treatment. If they don t reach embryo transfer, IVF centers, then often do not have to report those patients in their IVF cycle outcome statistics. This, however, does not mean that CHR does not have special expertise in many of these areas. Indeed we do: You will hear very soon about some quite exciting research on PCOS going on at CHR. We are just summarizing and preparing a manuscript of a study that we believe will offer important new insights into the condition. Dr. Gleicher, CHR s Medical Director and Chief Scientist, was the first to describe endometriosis as a possible condition with (auto)immune components, and suggest appropriate treatment adjustments (Obstet Gynecol 1987; Fertil Steril 1990; Hum Reprod 1992; Brit J Obstet Gynecol 1995). He also was a principal in establishing the field of reproductive immunology and, indeed, in establishing the American Society for Reproductive Immunology, and served as founding editor-in-chief of the American Journal of Reproductive Immunology for close to 20 years. Because of Dr. Gleicher s long-standing interest in reproductive immunology, there are, likely, few fertility centers in the country (or even the world) where reproductive immunology is as actively practiced as at CHR, and, indeed, where as much reproductive immunology research is conducted, whether in association with efforts to improve IVF outcomes or reduce miscarriage rates. After old ovaries, immune problems likely represent the second most frequent reason why patients consult CHR physicians long-distance. CHR never got caught up in the war of roses between proponents and opponents of immunotherapy in reproductive medicine. CHR always viewed this subject within the context of the human embryo being a hemi-allograft, with half of its genetic background coming Continue reading on Page 5 3 New Clinical Trials at CHR CHR started a clinical trial of the Embryoscope at the end of September, in which we compare the efficacy of this widely touted new embryo culture system with old-fashioned standard embryology. This trial will last for four months and will be decisive in determining whether to integrate this new technology into CHR s routine embryology. CHR s human growth hormone (HGH) clinical trial in women up to age 45 is progressing well. This is a prospectively randomized study of women who produced two or fewer embryos in an IVF cycle utilizing CHR s standard treatment protocols for women with low functional ovarian reserve (LFOR). Women above age 45 do not qualify for the trial but can still opt for HGH off-label treatment under experimental consent. In that patient group we can therefore follow outcomes, which in a clinical trial cannot be done until analysis time, since randomization is unknown to treating medical staff. The off-label experience in women above age 45 so far demonstrates clearly improved egg and embryo numbers and quality, as well as a trend toward better pregnancy rates. We, of course, will continue offering updates on this experience as it is developed. Though with mixed results, HGH has at a number of centers around the world for quite a number of years been used in association with IVF. It, therefore, is important to reemphasize that use of HGH in the clinical trial and in the off-label use in women above age 45 at CHR differs from how HGH has been used historically elsewhere. While most other centers add HGH to their routine IVF stimulation protocol, CHR uses HGH in preparing the ovary for stimulation for IVF by pretreating for at least six weeks before IVF cycle start. Based on our understanding of ovarian physiology, we anticipate that maximal effect of HGH (via IGF-1 induction) on follicles occurs at their small growing stage, rather than at preovulatory stages during IVF cycles. Those are the same early growing follicle stages, where DHEA supplementation has proven so effective in earlier research at CHR. In addition, CHR committed to a major role in a new multicenter clinical trial of a recently newly patented treatment, which is alleged to improve implantation and pregnancy rates in association with in vitro fertilization (IVF). This study will be conducted in three U.S. centers (including CHR), Israel s leading Ob/Gyn department at Sheba Medical Center of Tel Haschomer and a leading IVF center in Ukraine, where this treatment was developed. The study protocol that will be submitted to the Food and Drug Administration (FDA) is in final stages of development, and the trial will hopefully be clinically initiated before year s end. For more information about all of our currently ongoing clinical trials, go to: html

4 Against Blastocyst-Stage Embryo Transfer and PGS in women with LFOR CHR never made it a secret that we oppose blastocyststage embryo transfer and PGS in women with LFOR. In our opinion, if FSH levels are abnormally high and/or AMH levels are abnormally low, women should avoid both of these procedures because we have believed for a long time that both of these interventions in women with LFOR actually reduce pregnancy chances. CHR never made it a secret that we oppose blastocyst stage embryo transfer and PGS in women with LFOR Colleagues who support the use of blastocyst-stage culture and/or preimplantation genetic screening (PGS), on the other hand, have argued that embryos that do not survive culture in the laboratory to days 5/6 (blastocyst stage), also cannot have pregnancy potential on day-3. We have argued based on our center s clinical experience that this was not true. We have seen quite a significant number of pregnancies in women who at other centers either never had embryos that survived to blastocyst stage and/or never had any chromosomally normal embryos for embryo transfer after PGS, but here at CHR still ended up conceiving with day-3 embryo transfers without PGS and delivered healthy babies. To read more about CHR s opinions on blastocyststage embryo transfer and PGS, go to: on_peer_review_bias_in_pgs_ html Our position is strongly supported by the medical literature. In a careful review of the world literature Gluyovski et al. in 2012 very convincingly demonstrated in a Cochrane Review that implantation and pregnancy chances per transferred embryo slightly increase in favor of blastocyst-stage transfer in comparison to day-3 embryo transfer. However, cumulative pregnancy chances (i.e., the sum of all pregnancies achieved by a cohort of embryos from a single egg retrieval achieved) are significantly higher with day-3 transfers (see figure). Cumulative pregnancy chances from a single embryo cohort obtained through a single egg retrieval, however, decline with extended embryo culture. Consequently, women with relative small embryo numbers will lose cumulative pregnancy chance if embryos are cultured to blastocyst stage and, therefore, should be transferred on day-3 or even earlier. What this means is that young women who have lots of embryos to choose from for embryo transfer may benefit from embryo selection that blastocyst-stage transfer offers. If in such good prognosis patients a few embryos die off on the way to day-5 culture, it does not matter much. In addition, 4 Pregnancy/embryo Cumulative pregnancy chance Day 1 Day 2 Day 3 Days 5/6 Gluyovsky et al. Cochrane Database Sept.Rev 2012; 7:CD Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology This figure demonstrates how pregnancy rates per transferred embryo improve as embryos are cultured longer in the IVF laboratory, with blastocyst stage embryos demonstrating the highest pregnancy chances. In contrast, cumulative pregnancy rates decline with longer embryo culture to days 5/6, clearly demonstrating loss of healthy embryos with extended culture. they receive selection benefits and, therefore, improve their pregnancy chances. Women with small embryo numbers will, however, lose embryos, which, with day-3 embryo transfer, might still give them pregnancy chances. Those women, however, cannot afford unnecessary embryo loss. Blastocyststage transfers therefore reduce pregnancy chances in poor prognosis patients because of such embryo loss. Pregnancy chances are further decreased if such patients undergo PGS in addition to blastocyst-stage embryo culture. Women with relative small embryo numbers will lose cumulative pregnancy chance if embryos are cultured to blastocyst stage CHR s Medical Director and Chief Scientist, Norbert Gleicher, MD, just returned from the Annual Meeting of the Middle Eastern Fertility Society in Abu Dhabi, United Arab Emirates, where he had been asked to talk about this subject. Current Open CHR Positions: Clinical IVF Coordinator, RN or equivalent, prior fertility experience a plus If you, or someone you know, would like to apply, contact Jolanta Tapper at jtapper@thechr.com

5 OPINIONs Independent Voices on Reproductive Endocrinology, Medicine and Society On the Promising but Experimental Nature of Cryopreservation to Preserve Female Fertility CHR s OPINIONs commentary series, which began over the summer, has been the subject of considerable discussion in the reproductive endocrinology community. The latest piece, published last month, deals with the rapid commercialization of egg freezing for social reasons. We in this OPINION discuss the concept of fertility preservation. It is based on the facts that (i) women are born with a limited number of follicles/eggs in their ovaries, which constantly decline from birth; (ii) as women age, the quality of their eggs also declines, leading to fewer pregnancies and more chromosomally abnormal pregnancies and miscarriages. The concept of fertility preservation evolved from attempts to interrupt this ticking time bomb by freezing eggs, embryos or ovarian tissue. Once frozen, eggs, embryos or follicles within frozen ovarian tissue no longer age. When thawed out years later, if they survive the thawing process, these eggs, embryos or ovarian tissues, therefore, represent similar pregnancy potential as they would have offered at time of cryopreservation (freezing). Fertility preservation is currently offered for two principal reasons: In so-called medically indicated fertility preservation, medical treatments Continued from Page 3 from the father. Consequently, implantation and pregnancy are immunological processes. Unless they are understood as such, how can either one be appropriately treated? We, therefore, never understood our many colleagues who categorically deny the relevance of immunology in reproduction; yet, we also disagree with those on the opposite extreme of the spectrum, who over-treat everybody who needs fertility treatment with remedies directed at the immune system. Investigators at CHR publish immune-related studies on a regular basis. Indeed, quite a number of potentially important immune studies are currently underway, and will be featured in these pages once there is something to report. As far as we know, CHR is the only fertility center in the U.S. with its own x-ray facility to assess tubal anatomy. It is probable that no fertility expert in the U.S. (or elsewhere) has the same level of experience in assessing hysterosalpingogram (HSGs) as CHR s physicians, starting with Dr. Gleicher, because he has maintained such an x-ray unit in house for almost 30 years. Every physician at CHR is not only trained in reading HSG films but also in performing painless HSG procedures in-house. In contrast to other fertility centers, CHR is not dependent on the interpretation of HSG studies by our radiology colleagues. 5 (usually required as lifesaving procedures) threaten the integrity of ovarian tissue, usually resulting in the premature loss of follicles and eggs, leading to early menopause. Examples are chemotherapy or radiation therapy for cancers, but other treatments may also be toxic to ovaries. So-called social fertility preservation is different: here the reason for the procedure is that women are not ready to conceive but fear aging of their ovaries. They, therefore, want to preserve eggs, embryos or ovarian tissue in time. These two reasons for fertility preservation are based on distinct motivations and risk-benefit considerations. In some circumstances fertility preservation is, therefore, no longer considered an experimental procedure, while under other circumstances it is still classified as experimental. This OPINION will review in detail the concept of fertility preservation, with special emphasis on what CHR currently perceives as appropriate indications for female fertility preservation. To read the whole OPINION piece on fertility preservation, go to: on_social_cryopreservation_ html Because for radiologists, the HSG is in principle a test to determine patency of fallopian tubes, while for competent fertility specialists it should be a tool in determining normalcy of fallopian tubes, CHR s diagnostic capabilities in this area are likely unmatched. It is also frequently forgotten that Dr. Gleicher, in principle invented the concept of recanalizing fallopian tubes with transvaginal tubal catheterizations under x-ray control (Am J Obstet Gynecol 1988; JAMA 1990; Hum Reprod 1992). This has since become a routine procedure, now almost exclusively performed only by radiologists, except of course at CHR, where tubal catheterizations are performed in house. When IVF pregnancy rates were still much lower, Dr. Gleicher and colleagues performed hundreds of these catheterizations annually. Since IVF results have greatly improved, these procedures are much less utilized. CHR is, however, still the only fertility center in the country where these procedures are done in house. Finally, CHR is working with some of the best urology colleagues specializing in male factor infertility. We, therefore, routinely treat the most difficult cases of male infertility, usually by closely integrating the best of male urology care and the best of IVF laboratory expertise. -The CHR Fighting for every egg and embryo!