CHR VOICE the. Inflammation and the Immune System. Welcome to 2018! The Center for Human Reproduction. monthly CHR UPDATE.

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1 January 2018 CHR VOICE the Welcome to 2018! Now that most of us have made our annual New Year's resolutions, we also have to acknowledge that most are, unfortunately, as quickly forgotten as they were made. Since the start of a new year often involves decisions surrounding family planning, we in this first 2018 issue of the VOICE want to take our readers on a little journey through some of the basic realities of contemporary fertility care, as CHR sees them. Regular readers of these pages, of course, by now know that fertility treatments at CHR often differ from approaches followed by other centers to significant degrees. We here at CHR see this less as being different but, more so, as being ahead of the curve. Since its founding, CHR (originally in Chicago) has in many ways always been a little ahead of most other centers. To name just a few major innovations in the fertility field that originated at CHR, this center was the first IVF center in the world to perform and publish ultrasound controlled vaginal egg retrievals, when the routine The Center for Human Reproduction 1 Clinical Care Research Education monthly CHR UPDATE still was to retrieve eggs surgically in the operating room [Gleicher et al., Lancet 1983;2(8348): ], and the first to open obstructed fallopian tubes with transvaginal tubal catheterizations [Confino et al., Am J Obstet Gynecol 1988;159(2): ) and JAMA 1990;264(16): )]. CHR investigators greatly contributed to reproductive immunology [Gleicher and Friberg, JAMA 1985;253(22): ], and were the first to report animal models for uterine transplantation [Confino et al., Int J Gynecol Obstet 1986;24(4): ], only now a very hot topic in the field. CHR brought androgen supplementation of women with poor ovarian reserve into clinical practice [Barad and Gleicher, Fertil Steril 2005;84(3):756 and Hum Reprod 2006;21(11): ], now utilized all over the world, and CHR investigators were the first to point out the potential importance of the fragile X mental retardation (FMR1) gene for ovarian function [Gleicher et al., Fertil Steril 2009;91(5): ], now widely acknowledged and intensively investigated in a number of laboratories. Continue reading on page 5 Inflammation and the Immune System We recently in the VOICE announced CHR s new Reproductive Immunology Initiative, pointing out that recent research in other areas of medicine induced CHR to make reproductive immunology, once again, a priority of the center s research and clinical practice since many findings in other areas of medicine had potential clinical implications for reproductive biology and reproductive medicine. Reproductive Immunology Initiative: How correct a decision this was became apparent at the recent Ovarian Club meeting in December of 2017 in Hong Kong, when Canadian colleague Marc-André Sirard gave a wonderful talk on the three main reasons for poor ovarian response and poor oocyte quality in IVF cycles. Remarkably, in a complex genomic analysis of failed IVF cycles, his research group identified inflammatory genetic pathways among the most important key contributors to adverse IVF outcomes. In other words, it s the immune system, stupid! For CHR investigators this, of course, does not come as a big surprise. After all, we identified inflammatory markers as predictors of IVF outcomes quite a while ago, with elevated C-reactive protein (CRP) denoting decreased pregnancy chances in IVF and elevated interleukin-6 (IL-6) associated with significantly increased miscarriage rates following IVF (Barad et al., unpublished data). Continue reading on page 5 In this issue, we cover: Highly Individualized Egg Retrieval (HIER)... 3 In Focus: Images from the CHR lab... 4

2 ADVERTISEMENT Introducing CONFLAM Forte, new from Fertility Nutraceuticals, LLC The only comprehensive inflammation-modulating nutritional supplement, designed specifically to improve female fertility* Causes of excessive inflammation Obesity Infections Autoimmune diseases Allergies Others Effects of excessive inflammation on female fertility Excessive inflammation can make the immune systems hyperactive, negatively affecting women s fertility. Infertile women also demonstrate a higher prevalence of excessive inflammation, which can reduce pregnancy rates and increase miscarriage risks. Physicians and patients are often unaware of immune system hyperactivity, because it can be completely asymptomatic. ] CONFLAM Forte is the only comprehensive female fertility supplement designed to calm down immune systems that have become hyperactive due to inflammation*. ] CONFLAM Forte was designed in consultation with the Center for Human Reproduction (CHR), a fertility center in New York City with special expertise in immunology of reproduction. CHR also endorses the product. ] Every batch undergoes a rigorous triple-step quality assurance process. Also from Fertility Nutraceuticals Trusted by leading specialists Fertility-specific designs* Endorsed by Center for Human Endorsed by Robert F. Reproduction (CHR) # Casper, MD # 75 mg/day of micronized DHEA supports egg development via an androgen-rich ovarian environment* ANDROENERGEN TMT DHEA for Women CoQ10 for Women CoQ10 for Men Widely recommended by leading urologists 999 mg/day of CoQ10 in oil-suspended softgels provides antioxidant protection and supports robust mitochondrial energy metabolism in healthy gametes* Rx pad orders & wholesale inquiries: (212) info@fertilitynutraceuticals.com 21 E 69th Street, New York, NY USA Available Help your directly patients: & exclusively 5% off with from coupon Fertility code Nutraceuticals FNS Nutraceuticals for the next generation *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 and Dr. Casper. 2

3 Highly Individualized Egg Retrieval (HIER) Highly individualized egg retrieval (HIER), unquestionably, is CHR s most important recent innovation brought to the practice of IVF, and we are absolutely convinced that, like many other CHR contributions to IVF before, it will quickly be picked up by IVF centers all around the world. HIER started a number of years ago, when CHR noted that, as one would expect, the center s IVF outcomes progressively declined with advancing age up until age 43. After that age, the slow progressive decline, however, significantly accelerated, with almost no pregnancies and live births accomplished (most IVF centers till today believe that women above 42 should be automatically advanced into egg donation). CHR investigators at that point speculated that the cause for this sudden decline had to lie with the quality of eggs, and egg quality, of course, had to depend on what was happening within follicles. They, therefore, decided to investigate the molecular biology of the follicular microenvironment at time of egg retrieval in healthy controls (i.e., young egg donors), middle-aged IVF patients and IVF patients above age 43. The findings were nothing but... investigators astonishing, and were described decided to enhance in a publication in a prestigious egg retrievals in medical journal [Wu et al., J women above age 43, and ended up with significantly improved pregnancy rates." Endocrinol 2015;226(3): ]: Women above age 43 were found to have overwhelming evidence for what medically is called premature luteinization of follicles. In practical terms this means that, as women get older, the biological processes within follicles speed up. As a consequence, if the timing of egg retrieval in older women is maintained like in younger women, the eggs one obtains are hard-boiled rather than softboiled, or in medical lingo atretic rather than mature and, therefore, unusable. Based on these findings, CHR investigators decided to enhance egg retrievals in women above age 43 and, lo and behold, ended up with more transferrable embryos and significantly improved pregnancy rates. But this was not the end of the story for HIER. In the initially published study, the target population of patients were women above age 43, and CHR investigators had arbitrarily chosen a range of 16mm 3 as lead follicle size (in place of the routine range of 18-22mm) to trigger the follicles with human chorionic gonadotropin, hcg). Since this study was published, CHR investigators also established that women with POA, similarly to older women, also accelerate their intra-follicular metabolisms. With early retrievals, benefits to pregnancy rates in POA patients were even larger than in older women above age 43. Moreover, 16-18mm lead follicle size was, indeed, confirmed to offer best results, with smaller and bigger follicle sizes at time of hcg trigger resulting in clearly lower pregnancy chances. Likely, the most remarkable discovery made by CHR investigators, however, was that 16mm follicle size at trigger was also not the last word yet: They since learned that, as patients age, follicle sizes at which hcg triggers have to be given must continue to shrink in parallel. Considering that CHR now quite routinely treats women between ages 45 and 49 with use of their own eggs, hcg triggers at 12mm lead follicle size are no longer uncommon. CHR s oldest woman ever to conceive and deliver with use of her own eggs at age 47 and 10 months, was, indeed, triggered at 12mm lead follicle size. Report of our "oldest" IVF pregnancy: Early retrievals affect IVF cycles in additional ways: They, of course, shorten stimulation cycles and some patients have to be triggered after only 2-3 days of gonadotropin stimulation. Because cycles are dramatically shortened, there is no longer a need to Continue reading on page 4 Mitochondria Study DO YOU CARRY A MITOCHONDRIAL DISEASE OR KNOW SOMEBODY WHO DOES? If you do, please call us at for a free consultation. CHR is searching for a way to prevent inheritance of these awful diseases in a collaborative research project 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:

4 HIER: Continued from Page 3 prevent premature ovulation. Neither agonist nor antagonists are, therefore, needed in such cycles. In summary, HIER is really what this acronym stands for, highly individualized egg retrieval. Its significance also carries over into the embryology laboratory, where CHR investigators have also started individualizing how oocytes are treated that come from HIER cycles. Specifically, since early retrievals can be expected to mildly increase the number of premature eggs, CHR embryologists now in many HIER cycles do not automatically strip oocytes of their cumulus cells, as is routine practice in IVF. Instead, again based on highly individualized criteria, they may culture those oocytes with the cumulus cells still attached overnight, strip the cumulus cells the following morning, and fertilize the eggs with intracytoplasmic sperm injection only then, rather than on the previous day. Because of all of these changes introduced to CHR s IVF program since 2013, the center s IVF population and IVF cycle outcomes have quite significantly changed. Our patient population is getting older and older, and pregnancies and live births are no longer limited to women under age 43. As already noted, we, indeed, established last year at almost age 48 what, likely, represents the oldest autologous IVF pregnancy ever reported that resulted in a healthy birth. Pregnancy rates, and more so live birth rates, at these very advanced ages are, of course, still quite low but they are clearly better than they were only a few years ago before we introduced HIER. We are convinced you will hear more about HIER in coming years. Remember, however, like so many other infertility innovations, you heard it here first, coming from CHR! ADVERTISEMENT Help your eggs's maturation process with OVOENERGEN CoQ10 for women*. hh 333 mg of oil-suspended CoQ10 to protect eggs from oxidative stress and supply them with energy for normal development* hh Pharmaceutical-grade CoQ10 suspended in oil for optimal absorption hh Endorsed by Dr. Robert F. Casper, a Canadian specialist of antioxidants and female fertility *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 Dr. Casper. In Focus 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. Our image this month is an example of the new technology scientists at the CHR are employing to make the best eggs possible for our patients. Shown here is a human egg that has not yet completed the process of maturation needed before it can be fertilized. Many human eggs that are retrieved remain immature and it is our ongoing and future aim to establish conditions that will allow us to avail as many mature eggs as possible for our patients. Under the direction of David F. Albertini, PhD, an expert on biomedical imaging, CHR is launching a research program with the latest technologies that should allow us to evaluate the quality of each and every egg we retrieve for our patients. The image here represents a human egg that we subjected to in vitro maturation. After it was retrieved, it was placed into culture in hopes that it would finish the maturation process. Using special techniques, we were able to determine that this egg had not completed the process, enabling us to identify reasons why this occurs. Here the chromosomes in the egg are apparent in the lower right hand corner (blue); the red coloration refers to special proteins we can visualize that hold the egg cell and its surrounding cells together. Continue reading on page 6 4

5 Inflammation: Continued from Page 1 The finding of Sirad and colleagues are, nevertheless, important because they offer totally unbiased, and for the investigators actually very surprising information, confirming how essential a normally functioning female immune system is for normal conception. We have made this point before many times over in these pages, and consider CHR s emphasis on understanding pregnancy as an immunologically-mediated temporary state of immunological tolerance as yet another very important contribution of our center to reproductive medicine, as most of the field over the last two decades has been rather dismissive of reproductive immunology. This attitude is, fortunately, changing. Discoveries in organ transplantation and, even more so, discoveries in how malignant tumors evade recognition by the host s immune system, have major potential significance for normal human pregnancy but also for implantation failure and increased miscarriage risks. A recent study demonstrated almost eerie similarities in the genomics of the microenvironment of invading tumors and pregnancy [Nehar-Belaid et al., J Immunol 2016;196(2): ]. CHR s Medical Director and Chief Scientist, Norbert Gleicher MD, was recently invited to write a commentary in LeapsMag, an online life sciences publication (below), in which he noted that he started his research career in the late 1970s researching common immunological denominators between pregnancy and malignancy, only to return to exactly the same theme approximately 40 years later. The cycle, thus, closes but also demonstrates how much our understanding of the immune system has improved. It now appears high time to put this knowledge to work in clinical reproductive medicine. Welcome to 2018: Continued from Page 1 In more recent years, CHR has pioneered the treatment of older women with use of their own eggs, who at most other centers usually are automatically referred into egg donation. CHR was recently, indeed, able to report the healthy birth of a daughter to a woman who, at 47 years and 10 months at time of her embryo transfer, likely, was the oldest IVF patient ever in the world to achieve a successful delivery after using her own eggs. See our original report: CHR s remarkable progress in treating older women [and younger women with premature ovarian aging (POA)] has been a slow but consistent process, based on two principles: By investigating the basic molecular physiology of aging follicle in the laboratory, CHR investigators learned important clues about what damages oocytes (eggs) in older follicles. This knowledge then could be applied to highly individualized cycle management of patients, for which CHR has coined the term Highly Individualized Egg Retrieval or HIER (for further detail see the article on HIER in this issue). What CHR refused to subscribe to, while other centers embraced it, may, however, have been even more responsible for CHR s clinical successes than the center s quite remarkable research achievements. By not jumping on the bandwagon with every fashion of the moment, often more propagated by economic interests than scientific evidence, CHR has also become a worldwide-recognized force in correcting some very important wrongs in the fertility field. The, likely, most prominent example has been preimplantation genetic screening (PGS), now also called preimplantation genetic testing for aneuploidy (PGT-A), likely the most frequent target of CHR s wrath over the last few years. Our criticisms of PGS promotion: Dr. Gleicher's commentary: Though at times pretty viciously attacked by proponents of the procedure, CHR is proud to have stood its grounds, as the pendulum is quickly moving into the right direction. We were especially gratified to recently learn that one of the biggest commercial genetic laboratories and manufacturer of genetic testing equipment, in recognition of the shortcomings of the procedure, has quietly decided to deemphasize PGS/PGT-A in its marketing efforts. We wish, others exhibited he same honesty! 5 Continue reading on page 6

6 Welcome to 2018: Continued from Page 5 Another area where in CHR s opinion many wrongs require corrections, is the rapidly growing egg freezing industry. We addressed this concern in last month s VOICE, and are also raising again some important issues in our journey through the field of infertility in this issue. But before we do so, a more prosaic point, namely time: New Year's resolutions involving fertility must consider the importance of time in human reproduction. Female age is, in principle, the most important predictor of pregnancy chances, whether in spontaneous conceptions or in fertility treatments. The importance of not wasting time Nothing makes us prouder than the trust patients express in CHR when, after (often repeatedly) failing elsewhere, they still muster the will and strength to give it one more chance at CHR. Over 90% of CHR s new patient have failed IVF previously at other centers (CHR also serves the by far oldest patient population of any U.S. IVF center, reporting to national data banks at CDC and SART). At the same time, we, however, also always wonder how much more effective we could have been, had these patients presented to CHR only six months or a year earlier. Time is of great importance when it comes to fertility treatments, and the beginning of a new year is a good moment in time to be reminded of that. Especially at older ages or in women with significant POA, even just a few months can make a big difference. Egg freezing Nowhere is time, however, of more importance than when women freeze eggs for fertility preservation purposes because, as we in last month s VOICE in detail reviewed, the earlier eggs are frozen, the better can they be expected to thaw out, and the more likely will they lead to pregnancies. For those readers whose New Year resolutions included the potential of egg-freezing during 2018, the message, therefore, is this: The earlier you do it, the better! New egg freezing program: where to freeze your eggs, making the right choices matters! CHR s newly expanded Egg Freezing Program started on January 2 with a bang, offering the services of CHR s world-renowned clinical and laboratory staff at remarkably low packaged cycle costs. As we also noted in last month s VOICE, CHR decided to expand its Egg Freezing Program after noticing during 2016/17 a considerable increase in women who reported very disappointing thawing rates for their eggs frozen elsewhere. We know that we can do better! Diagnosing POA early Thinking ahead, the beginning of a new year is also a good time to remind young women (and parents of young women) that ca. 10 percent of all women, independent of race and ethnic background, end up suffering from POA. This means that, often starting at quite young ages, so-affected women have fewer eggs left in their ovaries than the other 90 percent. Since POA is an insidious (i.e., asymptomatic) condition, these young women have usually no way of knowing that they are in the process of developing POA. Especially if they are on hormonal contraception of any kind, they will not even notice menstrual irregularities, which often are the only clinical symptoms of POA. At younger ages, a diagnosis of POA may not matter much since, even though affected women will have fewer eggs, they still are well above a threshold that denotes infertility. But once they get into their 30s, this threshold is often reached, and expensive fertility treatments become the only option. As offered here at CHR and over the Internet at www. whatsmyfertility.com, What s My Fertility? is a second opinion program, which allows for definition of whether young women are or are not at risk for POA or already demonstrate evidence of POA. Most women, of course, are not at risk and, mostly, can stop worrying once they have been cleared by What s My Fertility?. Also, where you freeze your eggs matters; but where you thaw them once you need them, matters even more! Freezing of eggs is not a social event, as it is marketed at egg freezing parties by some. It is a costly and serious medical and laboratory procedure, where patients potentially entrust their future fertility to either a serious and reputable IVF center or a flyby-night commercial outfit. When it comes to choose 6 Roughly 20-25% of women will, however, demonstrate risk factors. This does not mean that they all will develop POA (only ca. 10% do); it, however, does mean that, going forward, these young women need to be monitored longitudinally, so those who really are on the verge of developing POA are diagnosed Continue reading on page 7

7 Welcome to 2018: Continued from Page 6 as early as possible. They then at still young ages can be given the choice of either completing their families early or freezing their eggs. As noted above, the younger eggs are at time of freezing, the higher their pregnancy chances. With better pregnancy chances per egg, fewer also need to be frozen. DISCLOSURE: CHR investigators developed this program and received a U.S. patent for the diagnostic algorithm feeding it. Some of CHR s physicians, indeed, screened their own daughters through this program. If you have daughters or granddaughters in their late teens or early 20s, you should, too! CHR sees almost daily new patients with POA who almost uniformly report stories like this: They initiated oral contraceptives during those late teens to early 20s, and never went off until recently, now in the mid- to late 30s, after reaching the conclusion that they wanted to conceive. When conception did not happen, their gynecologist s testing to everybody s surprise revealed high follicle-stimulating hormone (FSH) and/or low anti-müllerian hormone (AMH). In other words, a diagnosis of POA was made. Their uninterrupted longterm use of hormonal contraceptive had covered up even the occasional symptom that, otherwise, might have led to earlier diagnosis. Before placing young women onto hormonal contraceptives, we, therefore, always advise colleagues, either on their own or through What s My Fertility?, to assess their young patients for risk toward POA. Once a young woman is identified as at risk, we generally advise against hormonal contraceptives since they hide the even minimal symptoms of the condition. If there is no good alternative to hormonal contraceptives in a given patient, then her contraceptive coverage should be interrupted annually by a two-month wash-out period, and retesting of the woman s ovarian reserve to make sure her values have not fallen off her agespecific curve, should be performed. CHR offers physicians access to this program for free. Gynecology, adolescent medicine and general practice medical offices all around the world are welcome to apply at no cost for designation as What s My Fertility? centers by calling or writing to info@ whatsmyfertility.com. -The CHR Fighting for every egg and embryo! Visit CHR on Facebook: Follow CHR: Check out our video resources: CenterForHumanReprod ADVERTISEMENT The ultimate supplement to augment fertility care for women with DOR Only on our website: Get $9 off a 3-pack purchase 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* hhtested 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