CHR VOICE. Our October GrandRounds will differ from the usual format as we welcome two of the world s leading experts on follicle/oocyte maturation:

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1 The Center for Human Reproduction Clinical Care Research Education September 2013 CHR VOICE the monthly CHR UPDATE Moving toward a season of growth Welcome to the fall season, which, here at CHR, promises lots of new excitement. As has become routine in recent years, the summer months have been clinically extremely busy. And this year it s not only our patients who are conceiving and delivering: The CHR family has grown as well, with our embryologist and Junior Scientist, Emanuela Lazzaroni Tealdi, MS, giving birth to a beautiful daughter with the poetic name Ottavia Viola Tealdi (and starting her maternity leave), while coordinator Huina Zhou, fortunately, is back from her maternity leave after over three months ago delivering an equally beautiful son. We are missing Ema already and can t wait for her return. And before we forget, Ema also deserved congratulations on completing her Masters degree. What a wonderful year 2013 has been for her so far! CHR is looking forward to an even busier fall season because not only is the second half of the year always our busiest time clinically, but it also is the time when most big Emanuela Lazzaroni Tealdi, MS Huina Zhou Congratulations Ema and Huina on your beautiful new babies! medical meetings take place. Therefore, our physicians and scientists are frequently on the road. The Annual Meeting of the American Society for Reproductive Medicine (ASRM), our specialty s most important meeting in the U.S., is taking place, like every year, in October. This year s meeting in Boston will be special because, by presenting 18 abstracts, CHR investigators are breaking all institutional records and will be extremely busy preparing in coming weeks. Continue reading on Page 2 GrandRounds: Cutting-Edge Ideas in Reproductive Medicine Special Seminar in Follicle & Oocyte Maturation in Vitro Our October GrandRounds will differ from the usual format as we welcome two of the world s leading experts on follicle/oocyte maturation: Aaron Hsueh, PhD, Professor of Obstetrics and Gynecology at Stanford University School of Medicine will offer a talk on Hormonal regulation of preantral follicle growth, followed by Evelyn Telfer, PhD, Personal Chair in Reproductive Biology at University of Edinburgh School of Biological Sciences, who will offer a presentation entitled Growing human eggs in vitro Combined, these two leading voices in the field are promising a state-of-thearts seminar on one of the most important subject in reproductive medicine. This event will be offered by invitation only. Preference will be given to long-standing clinical friends of CHR, investigators in the field, and colleagues in reproductive endocrinology and infertility from other institutions. If you are interested in attending, please let us know ASAP by contacting our CME office at bross@thechr.com. Please consider that this will be a more basic science-oriented and longer event than usual. We, therefore, would appreciate receiving registrations only from those who are really interested in the subject and certain they can attend. We reserve the right to select who will be confirmed by written invitation. Only individuals with printed invitation in hand will be seated. Because we expect to be oversubscribed, there will be no exceptions. Tuesday, October 8th 6:00 PM - 6:30 PM Cocktails and hors d oeuvres 6:30 PM - 7:30 PM 1st lecture 7:30 PM - 8:00 PM Appetizer course of dinner 8:00 PM - 9:00 PM 2nd lecture 9:00 PM Rest of dinner There will be no seating during lectures since the lectures will be recorded. We are looking forward to a great evening! 1 Presented by the Center for Human Reproduction and Infertilty University

2 Choosing donor eggs: the BIG questions For quite some time we have not covered egg donation in these pages. While donor egg recipient cycles still represent only a small minority of IVF cycles performed at CHR, they, nevertheless, proportionally represent the most rapidly growing IVF cycle format. The increase in demand for donor eggs is, indeed, remarkable. This is not a trend unique to CHR; egg donation cycles nationally have been growing proportionally faster than any other form of IVF they just have been growing even faster at CHR. There are, likely, two reasons for the rapid growth of egg donation at CHR: The center s very adversely selected patient population, of course, will disproportionately utilize donor eggs. Surprisingly, an increasing majority of CHR s donor recipients, however, are not prior infertility patients. They turn to CHR because of its very unique egg donor pool (more about that later). And this brings us to the primary topic we want to address today: How does a patient select donor eggs? On many prior occasions we have made the point in these pages that, in our opinion, many infertility patients are directed into egg donation too early. This is, however, not what we ll discuss today. What we do want to review is how patients, advised to proceed into egg donation (and agreeing with this advice), should go about finding their ideal donors. There, of course, is no such thing as an ideal donor because the only truly ideal donor would have to be a perfect clone of the recipient. Every donor selection, therefore, will require some compromise. The goal of a good egg donor selection is to keep those compromises to a minimum. negative happens to the child later in life, especially if it can be attributed to genetic predispositions (and what medical problem can t?). We constantly hear from patients that they were told you don t really want to see pictures of your donors or you don t really want to know too much about your donor. We Multiple and true donor disagree! Recipients usually selection opportunities want to know everything about their donors, and represent an absolutely they are right in wanting crucial step. as much information as possible. A donor s likes and dislikes, her hobbies and talents will, therefore, be as important for many recipient couples as the donor s looks, weight, height and education. In other words, we believe that multiple and true donor selection opportunities represent an absolutely crucial step for almost every recipient. They need to know that their choice of donor was based on selecting among a number of good candidates, and was not driven by nobody better being available. CHR places incredible importance on donor selection because we feel that, basically, two issues determine longterm patient satisfaction with the process: (i) Patients must be convinced that egg donation represents their only reasonable chance of becoming parents; and (ii) Patients must be convinced that their selected egg donor does not represent too much of a compromise. These two criteria are of utmost importance because a woman who is not convinced that egg donation is her only reasonable chance of maternity may later second-guess her decision every time she looks at her child and does not see herself in the child. And, similarly, a parent may secondguess her/his donor selection if, God forbid, something Continued from Page 1 Season of growth Indeed, CHR research is on record pace this year with, based on PubMed, already 16 (!) peer-reviewed publications listed as published in 2013, as of mid- August. Four additional articles are beyond proof stages and will be appearing in print within weeks, and at least an additional half-dozen papers are at various stages of peer review. Truly a record year, not only in quantity but also quality, considering the high impact factor of many journals where these publications appeared or will be published. 2 Donor selection, therefore, requires a number of principal initial choices from potential recipients: Should donor selection be a process restricted to the patient and her treating physician/center or should patients search for their ideal donors elsewhere as well? Should other IVF centers be involved or should one also involve donor agencies? Should patients search for so-called fresh donors, i.e., donors who will go through IVF cycles and make for their recipient fresh eggs available or should patients search for already cryopreserved (frozen) eggs? Should recipients select a donor exclusively for themselves or should they share a donor with another recipient? Should recipients consider egg donation in other countries? Continue reading on Page 3 There is, however, more to come: With three physician (MD) scientists and, now, four PhD-level scientists on full-time staff, and two more part-time Visiting MD/PhDlevel scientists from other institutions, research at CHR is destined to expand exponentially. At no time in CHR s history were there as many research projects underway as we have currently, and never before have there been as many active research collaborations with other institutions.

3 Continued from Page 2: Donor Eggs There are no right or wrong answers to these questions but we consider it essential that future recipients be fully informed about what the advantages and disadvantages are in choosing each of these options. Let us discuss them one by one. Where to look for a good egg donor? Most IVF centers in the world offer egg donation cycles these days. But very few IVF centers maintain their own donor pool; and even fewer maintain a pool of donors for fresh donations of adequate size. As a consequence, most IVF centers have rather long waiting lists for egg donation cycles. Indeed, many centers do not even start looking for an egg donor until a recipient presents, a process that can take considerable time. CHR is, therefore, unique in maintaining a very large pool of immediately available donors of almost all races and ethnic backgrounds. Indeed, we know of no other IVF center in the U.S. or anywhere else in the world with a comparable pool. There are multiple reasons why CHR, many years ago, decided to act differently from most of our colleagues. Most centers do not maintain large donor pools because such pools require enormous work and are very costly. Large numbers of donors have to be screened (CHR accepts less than 5% of applicants into its pool), a very expensive and timeconsuming process. And since not all donors will be matched with recipients, the screening costs for many donors are never recovered. Most IVF centers, therefore, have started to farm-out donor selection to donor agencies. This means that, rather than maintaining their own egg donor pool, they refer their patients to one or more of such agencies. Many of these agencies do a reasonably good job in selecting their donors; others are not that great. CHR always felt that donor selection is too important a process to farm out. This does not mean that we do not accept donors from donor agencies if that is the preference of one of our patients (a quite rare event at CHR); but we insist on re-interviewing these donors ourselves, and we will tell our patients whether this donor would have qualified under CHR-criteria or not. The final decision is, of course, always up to the patient, as long as the donor qualifies under guidelines of the Food and Drug Administration (FDA), the governing federal agency for egg donation in the U.S. CHR accepts less than 5% of applicants into its donor pool Another reason why we are not great fans of donor agencies is the associated cost. Egg donation is already a very costly process (for more on this, see below under fresh vs. frozen eggs ), and donor agencies significantly add to the costs. Here at CHR, we see the donor selection process as part of our overall responsibility to patients. But, likely, the most important reason why we prefer it when our patients work with our own program s donors is that, historically, we have always achieved better pregnancy rates with donors from our own pool than with those who came to us from the outside. CHR s very detailed donor selection is, likely, one of the principal reasons why the pregnancy rates in our egg donation program have been so excellent over the years. Indeed, 2012 rates were the best ever, with a 66.2% clinical pregnancy rate per embryo transfer. Since some Continue reading on Page 4 In the original print version of this newsletter, we featured a summer intern from Germany in this section. The feature has been removed from the online version to protect her privacy. 3

4 Continued from Page 3: Donor Eggs recipients receive only 1 embryo during recipient cycles (a majority receive 2), the pregnancy rate for a 2-embryo transfer was really over 70.0%, and this, of course, does not include additional pregnancy chances from frozen embryos. Cumulative pregnancy chances from a single fresh egg donor at CHR, therefore, are in the high 80s to low 90s. Fresh vs. frozen eggs? Approximately one year ago, CHR initiated a frozen donor egg program in parallel to our fresh Standard Donor Egg program (SDEP), and we gave it the name Eco-Donor Egg Program (EcoDEP). The principal reason for introducing this EcoDEP, as we then stated, was to create an economical alternative for patients who needed egg donation to conceive but were unable to afford the SDEP. CHR awarded two new patents Exploring ways to improve pregnancy chances for women with diminished ovarian reserve (DOR) has been a long-standing research focus here at CHR. One fruit of that research was our introduction of DHEA supplementation (almost a decade ago!), which truly revolutionized fertility treatments for such women. We are now pleased to announce that, in continuing that research, CHR recently received approval of two patent applications that describe how supplementation with DHEA or other androgens is able to improve various quality parameters of eggs and embryos, to shorten time to pregnancy, and to improve pregnancy rates in women with DOR evidence of which was described in two previously awarded CHR patents. The EcoDEP offers 5 frozen eggs from a quite small pool of egg donors, selected for this pool mostly based on their race. The donors come from our general donor pool, and are, therefore, equally well screened and selected before acceptance. Indeed, they often have donated eggs already in the SDEP. The costs of the EcoDEP are approximately half the costs of a SDEP cycle. EcoDEP, however, also has significant disadvantages: Likely, the biggest issue is that the use of frozen eggs is still widely considered experimental. This is not only our opinion here at CHR but also the opinion of ASRM. The only circumstance in which oocyte cryopreservation is no longer considered experimental is oocyte freezing in young women who cryopreserve to preserve fertility (prior to chemo-, radio- or other ovary-toxic therapies). This point, unfortunately, is widely misrepresented, as an industry has arisen around oocyte (egg) freezing in the U.S. and worldwide. These efforts have taken varying formats: Both in Europe and here in the U.S., a small number of major IVF centers have established frozen egg banks. We are somewhat troubled by these efforts because, in contrast to CHR where the EcoDEP is very clearly offered as an experimental program, some of these new egg banks are presented as de-facto commercial enterprises, not dissimilar to frozen sperm banks. There are good reasons why the use of frozen eggs is still considered experimental. It is true that the quality of egg freezing has dramatically improved over the last decade, and with it pregnancy rates using frozen oocytes. However, it is also true that widely heard claims that pregnancy rates with use of frozen eggs are practically equal to pregnancy rates with use of fresh eggs are highly exaggerated. The use of frozen eggs is still widely considered experimental. First of all, even centers with the largest number of frozen cycles have only limited experience and limited cycle numbers. Indeed, cycle numbers at 4 We, indeed, have been clinically applying the knowledge described in these two patents for quite some time, as we no longer believe that eggs age as women age, says Dr. Gleicher, who is listed as one of the inventors on the patents. What ages is the ovarian environment in which the eggs mature. Low androgen levels are one manifestation of that ovarian aging. By increasing the patients androgen levels with DHEA, we are restoring the ovary s androgen levels to where they should be at young ages. This is quite a departure from the long-held dogma that older women s eggs are irreparably damaged, and their fertility prospects cannot be improved with medical intervention. We congratulate Dr. Gleicher and the rest of the research team on these new patent approvals and will continue our commitment to improvements in pregnancy chances for women with DOR. these centers are too small to say what pregnancy rates are with eggs frozen at different female ages. The few data sets of reasonable size published in the literature still demonstrate significantly lower pregnancy rates than are achieved (at least here in the U.S.) by good centers with use of fresh donor eggs. Of course, a center with relatively poor pregnancy rates, using fresh eggs, may find it easier to produce similar pregnancy rate with frozen eggs; however, those rates will still be low in comparison to what a more competent IVF center can achieve with the use of fresh eggs. Currently, there is simply no data in the worldwide medical literature to support the claim that use of frozen oocytes equates pregnancy rates in donor egg cycles with use of fresh oocytes. Indeed, such data would surprise us because the worldwide literature, literally for decades, has shown that pregnancy rates with fresh donor eggs are always higher than with frozen donor eggs. Why that would or should be different in egg donation cycles, using frozen eggs from egg donor banks, is puzzling to us! CHR, therefore, currently considers the use of frozen oocytes as inferior to the use of fresh eggs. Indeed, aside from fertility preservation purposes, we currently see only two

5 ethically viable reasons to use frozen oocytes: affordability and donor choice. We noted already that our EcoDEP was, in principle, conceived to make egg donation affordable to more patients. Some U.S. IVF centers have aggregated around business models of multi-center frozen egg banks. Under such a model, each center maintains only a relatively small frozen donor pool (which carries only relatively limited advance costs). Programs, however, share their donors in a central donor pool, which is available to all participants. If a recipient in city X likes a donor in city Y, the participating center in city Y ships the frozen eggs to the IVF center in city X, receiving an agreed upon payment in return. Patients worldwide come to the U.S. to select from our diverse pool of egg donors. CHR was invited to participate in such commercial efforts but has chosen not to do so. We have a number of reasons why: First, we do not like the concept of dealing in human eggs; and, second, we would be greatly concerned about inequalities in egg donor selection and egg quality between IVF centers, ultimately, impacting pregnancy rates. As noted before, we here at CHR consider good egg donor selection as fundamental. Equally important, of course, is the quality of the center where the donor is stimulated and the eggs are cryopreserved. There are good reasons why we prefer to have control over all of these aspects of egg donation here at CHR! Egg donor sharing? Many IVF programs offer shared fresh egg donor cycles; CHR does not! We abandoned shared donor cycles many years ago because they make good matches between donor and recipient impossible. It is difficult enough to satisfactorally match donors with recipients one on one. The donor matching process is too important for us here at CHR to compromise it in any fashion. There is really only one good reason for egg donor sharing, and that is the lower cycle cost. Therefore, we refer patients who are looking for such cycles into our EcoDEP, which for all practical purposes is a donor-sharing program, though with use of frozen eggs. Traveling overseas? In many countries the need for egg donation is driving medical tourism. In many European countries, laws do not permit egg donation. Patients who need donor eggs, therefore, have no choice but to travel. Under Turkish law it is a criminal offense to contribute to any form of gamete donation to a Turkish citizen. Other European countries are less radical in their prohibitions but, nevertheless, make it impossible for their citizens to receive donor eggs in their home countries. European countries that permit egg donation have, therefore, become providers for most of the rest of Europe and the Middle East. Spain has evolved as probably the primary destination for egg donation in Europe but, of course, does not have the multi-ethnic population that would allow for a multi-ethnic donor pool. Moreover, even Spanish law is quite restrictive: Our Spanish colleagues, for example, are not allowed to show photos of the donors, nor are they permitted to provide recipients with anything but the most basic donor information. Many are, therefore, turning to the frozen egg banking process we described above. Other European countries where egg donation is permitted are Cyprus, The Czech Republic, Ukraine, and other former East Block countries. However, relatively little is known about the services provided in these countries, and some have been involved in some rather uninspiring scandals over recent years. Moreover, like Spain, their donor pools are, of course, very monochromatic, and donor information provided to recipients is usually sparse. In the United Kingdom, egg donation is, in principle, permitted, but since the law prohibits payment to egg donors, our British colleagues have very few egg donors available, resulting in unreasonably long waiting periods. Continue reading on Page 6 Congratulations are due! Teresa K. Woodruff, Ph.D., a CHR s GrandRounds speaker in 2009, was recently introduced as the Endocrine Society s President. She is vice chair for research in the Department of Obstetrics and Gynecology at the Feinberg School of Medicine at Northwestern University and universally considered one of the founders of the field of onco-fertility, which attempts to preserve fertility in young individuals, mostly stricken by cancers (but also other medical conditions), requiring treatments that are toxic to ovaries and testes. Congratulations! Stephen R. Hammes, MD, PhD, Chief of the Division of Medical Endocrinology and Metabolism in the Department of Medicine, University of Rochester Medical Center School of Medicine and Dentistry will in January 2014 assume responsibility as Editor-in- Chief of the prestigious medical journal Molecular Endocrinology, one of the official journals of the Endocrine Society. CHR is in the 2nd year of a formal and very successful research affiliation agreement with his division. We congratulate both of these individuals to their welldeserved appointments. 5

6 Continued from Page 5: Donor Eggs European patients also increasingly choose U.S. centers because of significantly higher IVF pregnancy rates in standard IVF cycles and donor egg cycles than our European colleagues report. The discrepancy in reported rates approximates almost 50%. These differences are not necessarily a reflection on the quality of care provided by our European colleagues but, at least to a significant degree, reflect the much larger donor choices we enjoy here in the U.S. Having so many more donors available to choose from, we can be much more selective in choosing our egg donors. As noted above, CHR accepts less than 5% of applicants, very likely a major reason for the center s excellent donor egg pregnancy and delivery rates. Canadian colleagues experience similar problems as our U.K. colleagues. Canada also does not allow appropriate payments to egg donors. Canadian patients, therefore, after U.S. patients, represent the second-largest recipient population at CHR. Considering all of these circumstances our colleagues and their patients in other countries face, who can be surprised that CHR s volume of recipient cycles for non-u.s. patients has been skyrocketing? Located in New York City, we have the obvious additional advantage of, likely, the most multi-ethnic and multi-racial donor population of any city in the world. CHR s egg donor pool, therefore, very likely, is really unmatched anywhere in the world. -The CHR Fighting for every egg and embryo! 6