CHR VOICE the. Upcoming changes at CHR for the new academic year 2017/2018. The Center for Human Reproduction. monthly CHR UPDATE.

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1 The Center for Human Reproduction June 2017 CHR VOICE the CHR s June newsletter traditionally announces our intended summer break in publishing the VOICE during July and August, unless, of course, urgent matters must be communicated, as indeed often happened in past years. We, therefore, want to take this opportunity to wish all patients, colleagues and other readers a wonderful summer, and are planning to return with the next issue of the VOICE at the latest in September. With the expansion of the facility almost complete, we are now able to host seminars and even reasonable lecture attendance in our own facility. It, once again, appears time to reconsider how CHR will offer continuous medical education (CME) to colleagues in the field and related specialty areas. The last big reorganization in CHR s CME activities occurred a little over five years ago, when we decided to change from offering general Ob/Gyn topics in CHR s monthly GrandRounds to more specialized and concentrated offerings, in reproductive biology and clinical reproductive endocrinology/infertility. This decision was not only based on the fact that CHR in clinical practice and research is dedicated to these areas of medicine, but also on the recognition that within the context of regular CME activities in New York City and surrounding areas, other areas of reproductive medicine, like general gynecology, obstetrics and oncology, usually garner more attention than reproductive biology and endocrinology. Our intent was to supplement this omission. Since these changes were implemented, gracious support from the Foundation for Reproductive Medicine in co-sponsoring these events offered CHR the opportunity to continue the monthly GrandRounds, even though extramural support from pharmaceutical companies, which in earlier years used to be the mainstay of financial support, completely disappeared due to new federal funding guidelines for the pharma and 1 medical device industries. Clinical Care Research Education monthly CHR UPDATE We are looking with considerable excitement forward to the start of the new academic year in the fall because we are planning several significant changes to longstanding routines. Some changes will become apparent to visitors already after July 1, because that is when the construction at the center will, finally, be completed, allowing us for the first-time full use of all new facilities. Upcoming changes at CHR for the new academic year 2017/2018 We pride ourselves over the last five years to have hosted as speakers many, if not most, of the leading scientists in reproductive biology and reproductive clinical endocrinology (and related areas). In reflection of truly breathtaking and revolutionary work currently going on in many laboratories in this country and elsewhere, we have consciously pivoted toward more basic science rather than clinical talks. CHR has always pursued two distinct formats of CME: A steady flow of visitors to CHR, on occasion scientific collaborators or even formal Visiting Scientists at CHR, have been enriching CHR s knowledge base for years. There is only so much one can glean from published papers, and nothing replaces the direct contact with investigators. Small in-house seminars, usually exclusively for CHR staff, have, therefore, been a frequent tradition at CHR for many years. Continue reading on page 2 In this issue, we cover: Can you believe what happened?... 3 Endometriosis and infertility: Monthly case report... 4 Dr. Gleicher is NY Magazine's best doctor... 5 Nothing more controversial than PGS... 6 New GrandRounds... 9 In Focus Not one, but two gifts: Letter from a patient CDC's IVF outcome reporting still misleading... 11

2 New academic year: Continued from Page 1 At the same time, as CHR s three main areas of activity, Clinical Care, Research and Education (i.e. CME) well demonstrate, since its original inception in Chicago in 1981, CHR has always considered CME of colleagues one of its three main activities and responsibilities. Most educational activities were, therefore, channeled through CHR s monthly GrandRounds program. Especially over the last three years, CHR s GrandRounds have offered a constant flow of talks by many of the most exciting basic scientists working in the field, presenting some of the most groundbreaking research, at times even before publication. Indeed, a 2016 Nature paper from the laboratory of Ali Brivanlou, PhD, at Rockefeller University, that later became finalist for Nature Paper of the Year 2016, was presented to the public for the first time at CHR s GrandRounds. In recent years, the pivot toward more basic science subjects in CHR s CME activities also had several additional reasons: A very important one was, of course, increasing emphasis at CHR on basic laboratory research after recognizing that only better understanding of basic reproductive biology through progress in basic biological research would lead clinical reproductive endocrinology and infertility out of the field s current stagnation. Various recent issues of the VOICE addressed CHR s concerns about several clinical practices that have entered IVF practice over the last decade and, not only failed to contribute to better IVF outcomes but, likely, were responsible for the worldwide decline in live birth rates (including in the U.S.) during this time period, resulting in lower live birth rates in 2014 than Ineffective additions to practice are a frequently observed side effect of stagnations in medical specialty fields. When real progress takes place, resources go toward such progress rather than ineffective treatments. Decline in IVF live birth rates: CHR s ability to pivot toward more basic research was also supported by increasingly close cooperation with several leading research laboratories. The first formal such collaboration was established with the mouse laboratory of Aritro Sen, Ph.D. at Rochester University School of Medicine and Dentistry, in Rochester, NY It immediately demonstrated the mutual advantages and the translational potential 2 of such a collaborative strategy between clinical research and basic science laboratories by providing the necessary experimental understanding how dehydroepiandrosterone (DHEA) supplementation (or testosterone supplementation directly) improves treatment outcomes in women with low functional ovarian reserve (LFOR). Providing such experimental evidence in animal laboratories is especially important when clinical trials in humans are difficult to conduct, as is the case in women with LFOR. Because women with LFOR often refuse participation in clinical trials that require randomization (and we cannot blame them, considering the limited time they often have left to conceive), animal models in such situations offer crucial evidence for likely effectiveness of treatments. We, therefore, can state with absolute certainty that DHEA supplementation of women with LFOR, which was clinically initiated at CHR, would never have received the wide acceptance all over the world, were it not for these collaborative efforts with Dr. Sen s laboratory that allowed us to define how DHEA exerts beneficial effects on ovaries. DHEA for LFOR: CHR s current collaboration with this laboratory regarding clinical use of anti-müllerian hormone (AMH) as a potential therapeutic agent will, hopefully, be clinically equally successful. It already led to three patent applications. Likely CHR s most potentially consequential current collaboration are several projects with the Stem Cell Ineffective addition Biology and Molecular Embryology to practice are a Laboratory of Ali Brivanlou, PhD, frequent side effect at Rockefeller University in NYC. of stagnations in If successful, they will not only medical fields..." greatly affect our understanding of early human embryo development but, will also offer potential for truly revolutionary future infertility treatments. In addition, CHR maintains collaborations with the world-famous Gene Expression Laboratory of Juan Carlos Izpisua Belmonte, PhD, at the Salk institute for Biological Studies in La Jolla, CA, with the laboratory of Dietrich Egli, PhD, in the Department of Pediatrics at Columbia University in NYC and with the Department of Obstetrics and Gynecology at Vienna University School of Medicine, Vienna, Austria. Related: Read "The new CHR GrandRounds" on Page 9

3 Can you believe what happened? The number of healthy babies born around the world after transfer of so-called aneuploid embryos (now at times called euploidmosaic ) is steadily growing. Even a reproductive endocrinologist in NYC advised us very recently of the birth of his own perfectly healthy daughter after transfer of allegedly aneuploid embryos. Altogether, we are now aware of nearly 50 healthy births after such transfers worldwide, with the total number, likely, being even higher. Already in late 2014, transferring selected alleged ly aneuploid embryos, CHR was the first IVF center in the world reporting to immense attention at the Annual Meeting of the American Society for Reproductive Medicine (ASRM) in October of 2015 three healthy births. It, however, took until 2016 before the Preimplantation Genetic Diagnosis International Society (PGDIS) reinforced this practice in new guidelines. The Ethics Committee of the ASRM, finally, did so recently as well (Ethics Committee of the American Society for Reproductive Medicine. Transferring embryos with genetic abnormalities detected in preimplantation testing: An Ethics Committee Opinion. Fertil Steril 2017;107: ) report at ASRM: PGDIS announcement: patients that such services may be available through other medical providers. Though such professional behavior, fortunately, is generally the norm in our specialty, on occasion there are exceptions, as we recently were reminded, when a couple with residence in another U.S. city presented to CHR for a Second Opinion Consultation. They had undergone three IVF cycles at another nationally prominent center, which almost routinely utilizes PGS in association with IVF and, therefore, equally routinely cultures embryos to blastocyst stage. After three IVF cycles at that center, they ended up with only three blastocyst-stage embryos, which all after PGS were reported as aneuploid. Colleagues at that center then categorically refused to even consider transferring any of these embryos, even though such transfers are now accepted as a potential treatment option for couples with no euploid embryos after PGS (see also the CHR Opinion on page 5). At that point, the couple decided to reconsult with CHR (they had previously consulted with a CHR physician long-distance prior to their IVF cycles at the other center but then decided to stay local for their IVF treatments). CHR physicians reviewed the couple s history, including the genetic analyses of their embryos, and concluded that at least some of their still cryopreserved, allegedly aneuploid, embryos could be transferred. This, of course, does not mean that all colleagues have endorsed this practice. Indeed, several are still totally opposed to transferring any aneuploid/ mosaic embryos, whatever their classification under whatever nomenclature. While we obviously disagree, and believe that available evidence strongly supports transfer of many, if not most, aneuploid/ mosaic embryos, we accept their right to refuse a treatment, which they (rightly or wrongly) believe may be damaging to their patients. We, indeed, strongly feel that no physician should ever be forced to apply treatments against better judgment or over moral objections (an opinion also supported by the above noted Ethics Opinion of the ASRM). In reverse, physicians, however, also do not have the right to represent personal beliefs, not shared by others, as undisputed medical facts and, thereby, impose their personal opinions on patients. Indeed, ethics standards require that physicians who refuse to provide certain medical services, still advise Based on this opinion, the couple contacted their local IVF center, trying to move out their embryos to CHR. Such transfers of embryos between IVF centers are quite common, and are usually processed by the respective embryology teams at the two centers in a rather routine fashion. Not so, however, this time: To patients and CHR s surprise, their local IVF center refused to transfer the embryos to CHR under the explanation that they do not transfer abnormal embryos to other centers. The couple s argument that those embryos under the law were their property and, therefore, subject to their and not the center s decisions, was also unsuccessful in changing minds at the IVF center. It took the intervention of a lawyer on behalf of the couple before their local IVF center, suddenly, agreed to release the embryos. The IVF center s lawyers, very obviously and quickly, read their clients the riot Continue reading on page 9 3

4 Monthly Case Report: Endometriosis and Infertility In this section, we report brief case summaries we believe may be educational for patients and colleagues. We invite colleagues to participate in this monthly feature by contributing interesting cases. Submitted cases should be described in not more than 500 words, and suggested treatment and outcome should not exceed 250 words. If accepted for publication in the VOICE, CHR will add a commentary. If you think that you may have an interesting case to report, please contact this newsletter s editor, Yu Kizawa, at ykizawa@thechr.com. Case: A 32-year old woman without prior pregnancies presented for initial consultation. She was diagnosed via laparoscopy at age 16 with mild endometriosis, and was started on OCPs. The laparoscopy was only diagnostic. By age 28, she had undergone 3 additional laparoscopies, all describing increasingly severe endometriosis, and all 3 involving fulguration of endometriotic surface lesions on fallopian tubes, ovaries, crucial ligaments and peritoneum in the cul-de-sac. In her final laparoscopy (4th) she, however, also for the first time demonstrated a small endometrioma, which was laparoscopically resected with no significant damage to the ovary per operative report. At age 29, concerned about her future fertility, she presented to another fertility center with intent to freeze her eggs to preserve future fertility. She underwent a cycle of ovarian stimulation with gonadotropins. The cycle was, however, abandoned because of poor ovarian response. After subsequent blood testing, she was advised that she was not a good candidate for fertility preservation because her FSH was high and her AMH was low. Instead, she was advised to try to conceive as soon as possible because, otherwise, her only chance of conception would be with donated eggs. The patient at that point was engaged, and she and her fiancé decided to proceed with infertility treatments. Over the ensuing 3 years, the couple underwent 4 IVF cycles in two different IVF centers. Oocyte yields were between 1 and 4, with only 2 cycles leading to embryo transfer of 1 and 2 embryos, respectively. The last advice she had received was to have surgery on both of her ovaries. She was warned that such surgery may castrate her, subsequently mandating use of donor eggs. 4 Analysis: This was a childless young woman who for most of her adult life had suffered from endometriosis. She now presented with at least stage III endometriosis and clear evidence of premature ovarian aging (POA), based on severe ovarian resistance to stimulation, high FSH and low AMH for her young age. The patient was advised that, considering her young age, CHR s published experience suggests that women with POA of here demonstrated severity with appropriate preparation and IVF cycle treatments still have excellent pregnancy and live birth chances. This patient s case was, however, complicated by bilateral endometriomas, which created additional risks of leakage during egg retrieval that the patient had to be informed about. Moreover, presence of these endometriomas also, likely, reduced the number of oocytes that would be retrievable since some follicles would probably not be reachable during retrieval without risking entry by the retrieval needle into an endometrioma. Overall, the patient s chances of conception with use of her own eggs were, therefore, assessed as moderate, and she was advised that her pregnancy and live birth chances would be better with use of donor eggs, which would also avoid the abovenoted retrieval risks. Resolution: The couple, nevertheless, decided to proceed with continuous use of the female s own eggs. Following CHR s standard protocol for women with low functional ovarian reserve (LFOR), the patient was pretreated with DHEA and CoQ10 supplementation until her testosterone levels had risen into approximately mid-range and her SHBG had fallen, which took approximately 6 weeks. Only at that point was a microdose-agonist IVF cycle initiated under maximal stimulation. Eight oocytes were retrieved, of which 7 were mature and 6 fertilized, resulting in 5 day-3 embryos. Two were transferred on day-3 and the remaining 3 embryos were cryopreserved. At presentation to CHR, the patient demonstrated multiple endometriomas in both ovaries, the largest 1.8cm in diameter. Her FSH was 11.8 miu/ml and her AMH was 0.6ng/mL. Both ovaries, however, also Previous case with SHBG: demonstrates between 3 and 6 antral follicles. Free and total testosterone were both within the lowest The patient conceived and delivered a healthy 15th percentile of normal range, while her SHBG was female infant at term by Caesarean section (CS). relatively high at 115nmol/L. Continue reading on page 5

5 Case report: Continued from Page 4 Approximately nine months following her delivery, she underwent a frozen-thawed cycle with 2 surviving day- 3 embryos but did not conceive. At that point, her FSH was 12.2 miu/ml and her AMH had declined to 0.4ng/mL. Her ovaries were prepared once again with DHEA and CoQ10 until androgens and SHBG were in range and, now 34 years old, she was stimulated in identical fashion as in her earlier retrieval cycle. She this time produced 7 oocytes and 4 embryos; two were transferred on day-3, and 2 were cryopreserved. She again conceived a singleton pregnancy and delivered a healthy male by CS. Her 2 frozen embryos were thawed and transferred approximately a year later, leading to a third pregnancy and delivery, and a second female child. Conclusions: This case, maybe to some extreme, demonstrates many of the typical problems encountered in infertile women with severe endometriosis. This patient, unquestionably, was very lucky in achieving in relative short time so many pregnancies and deliveries. This, by no means, can be generalized, but it is also important to remember that pregnancy chances per embryo in young women are high and, therefore, young women do not need very large embryo numbers to achieve pregnancies. The literature is split on whether egg quality in women with endometriosis is normal or lowered. The CHR experience suggests that both can be the case: Poor egg quality in endometriosis patients is not usually associated with endometriosis itself but with the frequent co-morbidity of LFOR so often found in endometriosis patients, as in this case. If LFOR is properly addressed by preparing ovaries with DHEA and CoQ10 supplementation, egg quality can be surprisingly excellent, as this case also demonstrates. This patient (and her then fiancé and now husband) are to be congratulated on reaching the best possible decision once the LFOR diagnosis became apparent. The couple s IVF center, where this diagnosis was made after the patient did not respond as expected to stimulation of ovaries, is also to be applauded for abandoning egg freezing and advising the couple to try to conceive immediately. Unfortunately, time was wasted during their 4 IVF cycles without proper preparation of the patient's ovaries. One would think that the concept of supplementing hypo-androgenic women with LFOR with DHEA (or testosterone directly) for approximately 6 weeks before IVF cycle start has by now already reached wider acceptance. Except in emergencies (for example, leakage of an endometrioma), CHR also disagrees with any form of ovarian surgery in women with severe endometriosis who are still desirous of pregnancy because, often, such surgery to significant degrees further reduces already low FOR, at times putting patients into menopause. At least in this case, all ended well and, even though, as already noted, this couple was unusually lucky, their case is a good example for many important treatment principles that should be known by patients and physicians regarding endometriosis. Mitochondria Study DO YOU CARRY A MITOCHONDRIAL DISEASE OR KNOW SOMEBODY WHO DOES? If you do, please call us at for a free consultation in person, by phone or via Skype. CHR is searching for a way to prevent inheritance of these awful diseases in collaboration with colleagues at the famous Salk Institute for Biological Studies in La Jolla, CA. You may be able to help us find a way to prevent mitochondrial diseases in children! Contact us to learn more about the study: New York Magazine s Best Doctors CHR is very pleased to announce that Norbert Gleicher, MD, CHR s Medical Director and Chief Scientist (right), was once again elected by his peers as a Castle Connolly Top Doctor in the specialty of Reproductive Endocrinology for the year With 433 peer-reviewed publications, Dr. Gleicher is one of the most widely published individuals in the infertility field in the world, and one of the most soughtafter speakers at conferences. He currently holds professorial appointments at Rockefeller University in New York City and at the University of Vienna Medical School in Vienna, Austria. CHR congratulates Dr. Gleicher on this honor, and extends the center s appreciation to all colleagues who voted for Dr. Gleicher. 5

6 ADVERTISEMENT After a very successful 2016 meeting, we are very pleased to announce the dates for 2017: November The 2017 Conference promises to be even bigger and better than the 2016 Conference, which received glowing reviews from over 250 participants from nearly 50 countries. With 6 pre-conference workshops and main conference program showcasing the thought leaders of the field, the Conference offers a unique opportunity to visit New York City in the very popular pre- Christmas season to interact with colleagues, gain new ideas that will change clinical practice patterns and develop new research concepts. We look forward to welcoming you in New York City in November. Take advantage of the Early Bird registration until June 15! Workshops: Thursday, November 16 Maximizing access to fertility services Individualization of ovarian stimulation protocols Changing and enhancing genomes in human IVF Maximizing IVF outcomes for poor prognosis patients Social, medical and economic realities of egg donation The FMR1 gene in female infertility Conference Day 1: Friday, November 17 Welcome and announcement of the Young Investigator Award The "Breaking News" Lecture The future of assisted reproduction 1 I Successful reproduction is tolerance dependent Debate: Preimplantation genetic screening (PGS) in association with IVF Paradigm Change I: Polycystic ovary syndrome (PCOS), a multietiological epigenetic syndrome? The future of assisted reproduction 2 Conference Day 2: Saturday, November 18 Quintessential questions in assisted reproduction Paradigm Change II: Preventing rather than treating female infertility and other new concepts Debate: How important is the implantation window? Paradigm Change III: Avoiding in IVF practice "fashions of the moment" Paradigm Change IV: Reading the medical literature with appropriate skepticism Conference Day 3: Sunday, November 19 Ovarian physiology Quick updates on the "most interesting presentations at the 2017 ESHRE and ASRM meetings" The most exciting faculty of the year! Eli Y. Adashi, MD, MS, MA, USA David F. Albertini, PhD, USA David H. Barad, MD, MS, USA Juan Carlos Izpisua Belmonte, PhD, USA William J. Burlingham, PhD, USA Nancy C. Chescheir, MD, USA Barbara Collura, MA, USA Daniel Anthony Dumesic, MD, USA Dietrich M. Egli, PhD, USA Norbert Gleicher, MD, USA Kara Goldman, MD, USA James A. Grifo, MD, USA Katsuhiko Hayashi, PhD, Japan Aaron J. W. Hsueh, PhD, USA Joshua Johnson, PhD, USA David L. Keefe, MD, USA Vitaly A. Kushnir, MD, USA Diana Laird, PhD, USA Milton Leong, MD, DSci, Canada Shoukhrat Mitalipov, PhD, USA Raoul Orvieto, MD, Israel Lisa M. Pastore, PhD, USA Pasquale Patrizio, MD, MS, USA Alan S. Penzias, MD, USA Nigel E. Pereira, MD, USA Catherine Racowsky, PhD, USA Danny Schust, MD, USA Richard Martin Schwartzstein, MD, USA Zeev Shoham, MD, Israel Neeta Singh, MD, India Carlos Simon, MD, PhD, Spain Constantine A. Stratakis, MD, USA Andrea Weghofer, MD, PhD, MA, MBA, Austria Yan-Guang Wu, PhD, USA Magdalena Zernicka-Goetz, PhD FMedSci, UK Michael Zuccaro, PhD, USA For program and registration, visit the conference website: Foundation for Reproductive Medicine 551 Madison Avenue #700, New York, NY Attendee Inquiries: frm2017@foundationforreprodmed.com Sponsorship & Exhibition inquiries: ttan@foundationforreprodmed.com

7 CHR-OPINION Nothing more controversial than PGS Norbert Gleicher, MD, CHR s Medical Director and Chief Scientist was invited to give in September a talk under above noted title at the annual Ovarian Club Meeting, this year to be held in Barcelona, Spain. We here present a summary of his upcoming presentation as a CHR-Opinion. It has been estimated that in 2016 approximately 20% of IVF cycles in the U.S. were accompanied by preimplantation genetic screening (PGS). Assuming approximately 250,000 IVF cycles annually in the U.S., this would represent an added annual cost of ca. U.S. $200 million to IVF for a procedure that even PGS proponents no longer claim to improve pregnancy and live birth chances; but now is alleged to warrant effort and expense because it reduces miscarriage risks and time to conception. That, like prior claims by PGS proponents of improving pregnancy and live birth rates, these two new claims also are unsupported, should not surprise since the PGS industry, from its founding in the 1990s, based on the seemingly unassailable hypothesis that exclusion of aneuploid embryos prior to embryo transfer must improve IVF outcomes, never hesitated to make unsupported claims. As PGS has amply demonstrated, even seemingly unassailable hypotheses do, however, not always work out in clinical practice. When an earlier form of PGS (PGS 1.0), performed on cleavage-stage embryos, was, finally, declared ineffective by professional societies like the American Society for Reproductive Medicine (ASRM), the solution for the PGS industry was simple: It instantly created PGS 2.0, with even bigger promises of IVF outcome improvements and, therefore, not surprisingly, with even higher cost and wider utilization. But, like with PGS 1.0, there, again, were no validation studies to confirm the industry s hypothetical claims before PGS 2.0 was brought to market. Remarkably, despite the obvious earlier failure of PGS 1.0 to meet expectations, IVF community and patients accepted renewed promises by the PGS industry with even greater enthusiasm. Like it took years to overcome opposition from the PGS industry before PGS 1.0 was formally declared clinically useless, again strongly opposed by the PGS industry, opposition to PGS 2.0 has been growing for years. The burden of proof that PGS 2.0 did not work was, however, once again placed fully on opponents rather than, as one would expect, proponents of PGS, who would have to prove that PGS 2.0, indeed, did 7 improve IVF outcomes. When more recently evidence became irrefutable that trophectoderm at blastocyst stage was much more mosaic than represented by the PGS industry, and that, therefore, false-positive rates of trophectoderm biopsies had to be substantially higher than the industry has claimed, without any meaculpa, the industry once again, literally overnight, radically changed course, simply declaring all prior pronouncements and the prior reporting system nil and void, and establishing brand-new diagnostic criteria for PGS: Suddenly, embryos were no longer either normal (euploid) or abnormal (aneuploid), but embryos (likely in a majority of cases) could fall into a third diagnostic category of being mosaic and, even more remarkably, such embryos could also, selectively, be transferred (we, going forward describe this change as the introduction of PGS 3.0). What makes the overnight appearance of PGS 3.0 so remarkable is not only that publication of newly recommended guidelines for diagnostic laboratory criteria and clinical practice by the Preimplantation Genetic Diagnosis International Society (PGDIS) in late 2016 did not comment on why the PGDIS, so suddenly, radically changed how PGS was to be reported out (i.e., recognition that the high prevalence of trophectoderm mosaicism did not allow for only diagnostic criteria of euploid and aneuploid and, at minimum, mandated a third category of mosaicnormal ) but that the PGDIS (in speaking for the PGS industry) did not have the courage to acknowledge that under the prior PGS 2.0 criteria, likely tens of thousands of potentially transferrable embryos had been erroneously discarded and, with it, pregnancy chances for thousands of women. PGDIS announcement: In a typical marketing strategy for recovery of a commercial product that has fallen into disrepute, and to separate it from its two prior incarnations, Continue reading on page 8

8 Nothing more controversial: Continued from Page 7 this now allegedly again renewed PGS product we call PGS 3.0 has in recent publications (May issue of Fertility and Sterility) been given the completely new acronym, preimplantation genetic diagnosis for aneuploidy screening (PGD-AS). Despite these marketing efforts, it is, however, once again only yet another unvalidated diagnostic test with completely unsupported claims by evidence: According to new PGDIS guidelines, embryos with up to 19% aneuploid cells (per biopsy, meaning ca. 1.2 cells in an average 6-cell biopsy) are normal-euploid and should be the preferred embryos for transfer. Embryos with 20-80% aneuploid cells ( cell in an average 6-cell biopsy) are euploid-mosaic, and are potential candidates for transfer, following a hierarchical selection process. Embryos with over 80% aneuploidy ( embryos) are considered fully aneuploid, and should not be transferred (i.e., should be discarded). May issue of Fertility & Sterility: are no data to support the new guidelines" The new PGDIS guidelines, however, do not address where these cut offs come from. Indeed, there are no data in the literature to support them. The 20% cut off between euploid and euploid-mosaic is obviously based on high-resolution next generation sequencing (hr-ngs), the only diagnostic platform capable of detecting mosaicism with reasonable accuracy, though only above 20% (The new PGDIS guidelines claim that only NGS should be used in testing embryos under their guidelines). The PGS industry, thus, does not separate normal-euploid from normal-mosaic based on clinical validations of differences in IVF outcomes but solely based on technical limitations of hr-ngs, which cannot reliably detect mosaicism levels below 20%. An embryo with 19% aneuploid under PGDIS criteria is, thus, automatically transferrable, but an embryo with 20% or 21% aneuploidy (i.e., being designated as euploid-mosaic ) should only be transferred with considerable caution, and selectively. The same complete lack of clinical evidence also underlies the 80% cut off between euploid-mosaic and full aneuploidy, as defined by the PGDIS. 80% aneuploid embryos, therefore, can be selectively transferred but 81% aneuploid embryos should be discarded. The newly promoted PGS 3.0 (PGD-AS) is, therefore, as spurious a diagnostic product as PGS 1.0 and PGS 2.0 before. CHR does not see biological or clinical rationale in these new, yet again unvalidated PGDIS guidelines, as they will still lead to discarding of potentially healthy embryos in large numbers, and will not improve IVF outcomes. Increasing evidence supports that trophectoderm mosaicism at blastocyst stage is a completely normal physiological phenomenon. The extent of trophectoderm mosaicism, lack of congruency in ploidy between trophectoderm and inner cell mass and, finally, increasing evidence for significant selfcorrection of embryos downstream from blastocyst stage, make it biologically and technically highly unlikely that the ploidy of blastocyst-stage embryos can reliably be determined by a single trophectoderm biopsy. PGS in all forms, therefore, should be clinically abandoned. ADVERTISEMENT The ultimate supplement to augment fertility care for women with DOR, from Fertility Nutraceuticals, LLC FERTINATAL DHEA FERTINATAL DHEA is endorsed by Center for Human Reproduction (CHR) #, the fertility center in New York City that holds the only U.S. patents on DHEA supplementation, egg quality and female fertility*. The DHEA for women under infertility treatments*, FERTINATAL supports healthy egg development via an androgen-rich ovarian environment*. hhprovides 25 mg of DHEA per tablet, micronized according to CHR s published protocol* hh Tested by third-party laboratories to ensure consistency in potency and micronization levels *These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. # Fertility Nutraceuticals, LLC, pays licensing fees to CHR. info@fertilitynutraceuticals.com

9 The New CHR GrandRounds Center for Human Reproduction CLINICAL CARE RESEARCH EDUCATION As readers of these pages will be aware, the Foundation for Reproductive Medicine started sponsoring an annual conference on Translational Reproductive Biology and Reproductive Clinical Endocrinology every November in NYC, which CHR has had the honor of co-sponsoring. Last year s conference was a smashing success, not only in attendance but also in the number of commercial sponsors and, most importantly, in the quality of conference faculty. Conference evaluations by attendees were unprecedented in their approval of this four-day event. This year, the Conference will take place November 16-19, Because the Foundation for Reproductive Medicine is primarily a (not-for-profit) research foundation, and because it in its philosophy fully aligns with the above-described CHR opinion that close translational collaboration between clinical fertility centers and leading research laboratories is now essential if significant progress is to occur in clinical reproductive endocrinology and infertility, the Foundation after last year s conference success, designated this annual conference as its funding priority for future years. This means a significant financial commitment to this project by the Foundation. Though this decision means less available funding for CHR s GrandRounds in coming years, we philosophically fully agree with the Foundation s decision, which, therefore, requires a radical restructuring of how, and where, CHR GrandRounds, starting in the new academic year, will be conducted. Here is what remains the same and what will change: CHR s GrandRounds will continue as before: monthly, except during holiday seasons in the winter, and vacation breaks between academic years in the summer. GrandRounds will continue to be co-sponsored by the Foundation for Reproductive Medicine and CHR. Participation in GrandRounds will remain free of charge for individuals who become Members of the Foundation for an annual donation to the Foundation of at least $1, Donations to the Foundation are tax-deductible according to the law. Membership in the Foundation and attendance is also open to CHR patients and potential commercial sponsors. Scenes from the Translational Reproductive Biology & Clinical Reproductive Endocrinology Conference 2016 For non-members, there will be, going forward, a $ charge for participation in GrandRounds events, charged at reservation time, and nonrefundable, unless reservations are cancelled at least 48 hours prior to the event. Because food and other values received at these events exceed the price of attendance, these charges, even though paid to the Foundation, will likely not be tax-deductible, unless considered a business expense. (Please do not consider this tax advice; we recommend that you consult your accountants.) Going forward, CHR will also sporadically announce In-House Seminars at CHR, which to date were only open to CHR staff. They will now also be open for free to Members of the Foundation for Reproductive Medicine, while there will be a $25.00 charge to non-members. Total attendance at GrandRounds will be restricted to 70, while attendance at In-House Seminars will not exceed 30. Reservations will be accepted on a first come-first serve basis. In partnership, CHR and the Foundation for Reproductive Medicine, will continue to present the most interesting and path-breaking speakers in our field. We here at CHR hope that friends and colleagues will continue supporting our CME activities under this new framework, and are looking forward to welcoming you to the new academic year in September. 9

10 Can you believe: Continued from Page 3 act, and explained to them that they simply had no legal leg to stand on. Physicians entrusted with their patients embryos should, however, know better in the first place! PGS debate. Both sides of the debate, very obviously, must learn to objectively assess biological and clinical evidence and move away from convictions of absolute certainty since nothing in science is ever absolutely certain. As we are describing this episode in these pages, the embryos are on the way to CHR. We, of course, have no idea whether their transfer will lead to a pregnancy and birth. But we do know that what happened to this couple was not only illegal (because under the U.S. law, embryos are considered property of the parents) but also highly unethical. If we are lucky, a pregnancy and live birth from here discussed embryos may just do that for at least the colleagues in that other city. But can you believe what happened! In Focus It is simply inappropriate for any physician to usurp a patient s (or in this case, a couple s) responsible, and well thought-out, clinical decision-making process. It is even more inappropriate when physicians presume to possess decision-making rights over embryos produced by patients. The last time (and fortunately only time we are aware of in the history of IVF) physicians in our field erroneously felt entitled to insert themselves into parental ownership of gametes and embryos, it led to the by now infamous University of California Fertility Scandal in This feature presents microscopic images from CHR s laboratories, edited by our Director of the Division of Laboratories and Senior Scientist, David F. Albertini, PhD. We by no means want to equate the unauthorized use of eggs in creating embryos for other women/couples (which is what happened in 1995 in Irvine, CA) to the experience of heredescribed couple, but there is a degree of analogy in the impertinence of physicians in presuming they have the right (whatever the reasons) to usurp the absolute rights of mothers and fathers to embryos created with their own gametes. Even most radical ideological beliefs in the validity of PGS as a diagnostic procedure and, therefore, even most strenuous opposition to transfer of embryos, by PGS determined to be aneuploid/mosaic, does not excuse such behavior. Differences of opinions are common and play an important role in quality control and progress in the medical field..." This image shows a small portion of a mouse ovary with many follicles developing, each of which contain a green circle: the zona pellucida. One of our collaborators, Aritro Sen, PhD, at University of Rochester School of Medicine and Dentistry, was recognized recently for the work he has done using the mouse ovary as a model for understanding the role of AMH. Differences of opinions between practicing physicians are common in all medical specialties. Such differences, indeed, play an important role in quality control and progress in the medical field. All such benefits are, however, lost when zealousness turns opinions into ideologies and/or dogmas, and alternatives are viewed as moral sins. CHR research spans many aspects of female reproductive biology in humans, but as in many of the premier research institutions around the world, animals like the mouse have become an invaluable resource for making discoveries that will eventually aid in the diagnosis and treatment of infertility. One example was the effects of DHEA via androgen receptors in the maturation of oocytes, which we also mention on page 2. Following this recent experience, we here at CHR have started to wonder what it will take to avoid the obvious zealousness that has crept into the ongoing 10

11 a "dumb" question, or the same question a few times. Letter from a Patient Through my course of treatments I felt like I had the entire CHR rooting for me. When i got pregnant with both my current child and the baby i am expecting now, every staff member who I saw was thrilled for me. When I did experience some road blocks getting to those points, they were there for me and sympathized with me. The doctors, like the nurses, care about each and every patient they see. They want the best for everyone. You are not just another faceless person in a waiting area that seems like a factory. CHR has not only given me one of the best gifts but two! As a young newlywed diagnosed with DOR, learning how to navigate the world of infertility could have been difficult and lonely, but at CHR I developed a family. I had been to two other fertility centers previously and both clinics were not a right fit for me. I had my initial consultation with Dr. Gleicher. He listened with a kind ear, took his time going through my chart and asked me numerous questions so that he can pinpoint my exact issues and the best way to overcome them. We started right away with additional blood work and I started taking DHEA and Coq10. After meeting with Dr. Gleicher I met the nurses, who always get back to you right away, and with the option of ing them, it's even quicker. They answer all your questions with the utmost patience and never make you feel belittled for asking what may seem like No other doctor I had seen before going to CHR was able to get me pregnant once, and here I am carrying my second child. I was told many times before coming to CHR that I would never get pregnant with my own eggs. Well, CHR proved all those other people wrong and I could not be more happy or thankful! - Rachel Simon CDC Reporting of IVF Outcomes Still Misleading IVF outcomes reported to, and made public by, the Center for Disease Control and Prevention (CDC) are highly inflated in some cases, and can be misleading, according to an analysis by the CHR researchers. The study, recently published in the medical journal Reproductive Biomedicine Online, found that of the 458 IVF centers reporting outcomes to the CDC under congressional mandate, 27 report a disproportionately high number of "embryo banking" cycles. By excluding "embryo banking" cycles in poor-prognosis patients from their statistics, the 27 centers were able to report IVF success rates far higher than the rates that include these banking cycles. CHR's analysis found that the 27 Read the full press release outlier centers' live birth rates would actually be below the median of the rest of the centers if the banking cycles were not excluded from their reporting. As these outlier centers include some of the most prominent IVF centers with large market shares, CHR researchers in their paper urge the CDC to to ensure that patients have access to accurate information about IVF centers' real competencies. -The CHR Fighting for every egg and embryo! Visit CHR on Facebook: Follow CHR: 11 Check out our video resources: CenterForHumanReprod

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