CHR VOICE the monthly CHR UPDATE

The Center for Human Reproduction

Clinical Care • Research • Education

July 2017

In this issue, we cover:Watch out for "ovarian rejuvenation" claims ..... 3PCOS and future fertility: Monthly case report ..... 4PGS no more; long live PGT-A ..... 9In Focus ..... 12

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Yes, we know that, over many months now, almost every issue of the VOICE contained an article about PGS. Yet, here we go again, because the audacity of the PGS industry, simply, leaves us no other choice.

The industry’s misrepresentations, simply, cannot be made up, and just continue giving fodder for further commentary. Trying not to be repetitive, we already in last month’s issue outlined why the name change for PGS to PGT-A, recently parenthetically announced in Fertility & Sterility (the official organ of the ASRM), in our opinion just represented yet another marketing tactic, which (hopefully unsuccessfully) attempts to divert attention away from the increasingly obvious failure of PGS 2.0, as practiced over the last half a dozen years (see also on page 9, "PGS is no more...").

Readers of these pages, of course, know that PGS 2.0 replaced PGS 1.0 once (much too late), the latter finally declared ineffective by ASRM and other

professional organizations in improving pregnancy and reducing miscarriage rates in association with IVF. Effectiveness of PGS 2.0 was then touted with even bigger fanfares by the PGS industry, resulting in even wider utilization (and even more rapid growth of PGS laboratories and the industry as a whole).

The loudest proponents of PGS 2.0, with few exceptions, were, of course, the same “experts” who had previously argued in favor of PGS 1.0. None of them, however, appeared bothered in the least about having sold to the IVF community PGS 1.0 without prior clinical validation over many years. As we all finally learned, PGS was not only clinically useless

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Since there is important new information for infertility patients to be disseminated, we decided to shorten the summer hiatus for the VOICE by, after all, publishing a July issue. This issue will, therefore, among other subjects, address the seemingly never-ending saga of preimplantation genetic screening (PGS), now suddenly given the new name preimplantation genetic testing for aneuploidy (PGT-A) by the American Society for Reproductive Medicine (ASRM), and by us, simply, given the acronym PGS 3.0. We will also address a previously only marginally discussed subject in the VOICE, which in recent months in chat-rooms, however, received increasing attention: the so-called “ovarian rejuvenation.”

The ultimate evidence from leading proponents of PGS that flipping a coin is as good as PGS 3.0 in determining embryo ploidy

In addition, we also have to again note the issue of nuclear transfer (i.e., 3-parent IVF), this time in attempts to treat infertility in older women, since colleagues here in New York City have gone public by announcing the utilization of this technique (without prior approval by the Food and Drug Administration) through a newly-formed start-up company at the startling average price of $100,000 per in vitro fertilization (IVF) cycle. With so much truly challenging news to comment on, we, simply, could not stay quiet in the month of July!

3-parent IVF, previously in VOICE: http://kaywa.me/x6lNY

but, at least in poor prognosis patients, actually reduced IVF pregnancy chances [Mastenbroek et al., N Engl J Med 207;357(1):9-17].

Those supposed experts’ certainty that PGS 2.0 would succeed where PGS 1.0 had miserably failed before was so profound that, amazingly, they, again, brought the new PGS to market without proper prior validation studies. A small group of PGS skeptics on both sides of the Atlantic (including CHR) called for caution, and warned that the IVF community may be repeating the mistakes made in association with PGS 1.0, but were “out-marketed” by proponents of PGS, some of whom are undoubtedly honest and true believers in the procedure, but others, unquestionably, primarily driven by more profit-focused commercial interests.

Inexplicably, as noted in the last month’s issue of this newsletter, the PGS industry received a surprising degree of support from a number of medical journals in the specialty, which clearly favored articles in support of PGS over those that attempted to critically examine its use. No team of editors in the field, indeed, acted in a more biased manner than the editors at Fertility & Sterility (F&S), the official journal of the ASRM, where proponents of PGS 2.0 were practically given free reign (the same had happened earlier for PGS 1.0 under a different team of editors), and ended up deciding which PGS papers would be accepted for publication and which would be rejected.

F&S, therefore, has been almost exclusively publishing manuscripts in support of PGS 2.0, while, almost universally, rejecting manuscripts critical of the procedure, including (without sour grapes) a good number of manuscripts from CHR investigators, which, fortunately, had no problems being accepted elsewhere. Some of these rejected manuscripts offered important new information. One, indeed, reported the first group of healthy live births in the world after transfer of allegedly “aneuploid” embryos. These data have since been confirmed by other investigators and, as will be discussed further, created the impetus for the major restructuring of PGS reporting by the PGS laboratory industry. Recitation of this background information is important because this CHR research became a crucial turning point in the recently observed demise of PGS 2.0 with publication of new reporting guidelines for PGS (i.e., creation of PGS 3.0).

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Flipping a coin: Continued from Page 1It all started with an oral presentation by Norbert Gleicher, MD, CHR’s Medical Director and Chief Scientist, at the October 2015 Annual ASRM Meeting in Baltimore, reporting the first three live births after transfer of “aneuploid’ embryos. His presentation, likely, was the most talked about of that meeting. It, unquestionably, became the starting point for changes in PGS practice, which ultimately led to the announcement of new practice guidelines for PGS by the Preimplantation Genetic Diagnosis International Society (PGDIS) barely a year later in 2016 and, therefore, to a switch from PGS 2.0 to PGS 3.0 (now also called PGT-A).

CHR’s initial ASRM report was followed shortly thereafter by a confirmatory report from Italian colleagues in a research letter in the New England Journal of Medicine, which further shook up the PGS establishment and by a report of the Bernabeu group in Alicante, Spain, at the ESHRE meeting in 2016.

Increasing numbers of healthy births from all over the world following transfers of allegedly “aneuploid” embryos are finally leaving the PGS industry with no other choice but to acknowledge that their many-years-long policy of defining embryos via PGS 2.0 as either euploid or aneuploid was no longer sustainable.

When CHR as the first center in the world (in association with some colleagues at other New York centers) in 2014/2015 announced a new program of transferring so-called “aneuploid” embryos in certain situations, the PGS establishment quite viciously attacked the program as unethical. By late 2016, the same PGS “experts” were no longer able to maintain the position of defining any level of aneuploidy as “abnormal,” and recommending the disposal of any embryo with even minute alleged chromosomal abnormalities.

Surprisingly high pregnancy and live birth rates, reported by CHR and other centers from transfers of allegedly “aneuploid” embryos only too obviously demonstrated that old PGS testing methods and reporting procedures were no longer sustainable. Like PGS 1.0 before, PGS 2.0 also had failed in improving IVF outcomes. Even more disturbingly, however, these new transfer data of allegedly “aneuploid”

Read the OPINION about hijacking: http://kaywa.me/x6lNY

Continue reading on page 7

PGDIS fiasco: http://kaywa.me/x6lNY

Abnormal transfer policy: http://kaywa.me/x6lNY

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You must have heard recently about "OVARIAN REJUVENATION"Having a significant presence on the Internet (www.centerforhumanreprod.com), CHR receives a large number of inquiries daily about all kinds of fertility-related subjects. One such subject has been floating toward increasing prominence over the recent months. The subject can be summarized under the term “ovarian rejuvenation.”

The idea of “rejuvenating ovaries” is nothing new. This concept has been under consideration since modern infertility treatments started in the late 50s and early 60s with initiation of gonadotropin therapy. It is based on the recognition that ovaries “age” as women advance in age. “Rejuvenation” of ovaries, therefore, implies the ability to reverse this ovarian aging process. To better understand whether such rejuvenation is really possible, it is essential to understand the physiological basics of ovarian aging.

What is ovarian aging?The ovarian age is determined by the ovaries’ principal product, their oocytes (eggs). Since women are, likely, born with all of their eggs in ovaries, and since these eggs are constantly lost in large numbers, the total number of eggs (i.e., the ovarian reserve) declines with advancing female age. Concomitantly, egg quality also declines. As woman grow older, they, therefore, experience in parallel two independent declines, in egg quantity and quality.

The decline in egg quality is still widely attributed to the fact that eggs are in ovaries from birth and, therefore, age. In contrast, males constantly produce fresh sperm into advanced ages, which, therefore, remains “fresh.”

While environmental aging over time may play some role in oocyte aging, CHR investigators have questioned this concept of ovarian aging. They proposed a number of years ago the hypothesis (the “CHR hypothesis of ovarian aging”) that increasingly poor oocyte quality with advancing female age may not be due to aging of oocytes but actually due to aging of the ovarian micro-environment, in which follicles and eggs after recruitment mature. Under this

hypothesis, primordial follicles, which contain the most primitive and immature eggs prior to recruitment into maturation cycles, sit in the outermost layer of ovaries, the so-called ovarian capsule. Their extremely immature state and minuscule size mean that those follicles have almost no metabolic needs and, practically, live in total isolation, and mostly without nutritional needs. In a way, they, therefore, can be considered “frozen in time,” like frozen eggs, sperm or embryos are, once they are cryopreserved. Consequently, these very immature eggs are well protected from environmental influences.

This changes immediately, however, once such primordial follicles are “recruited,” and start their weeks- to months-long journeys of maturation, during which they literally travel from the outer capsule toward the innermost parts of the ovary (the medulla), while rapidly growing in size. During that journey of maturation, follicles become extremely dependent on nutrition from their environment (stroma) and, therefore, do become exposed to influences from the ovarian micro-environment in which they mature.

The modified ovarian aging hypothesis developed by CHR investigators, therefore, suggests that the age of this ovarian-microenvironment, likely, greatly affects oocyte quality. In other words, while sitting in ovaries, often for decades, at very primitive primordial stages may have some negative impact, it, likely, is relatively small. A much larger impact can be expected

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Resting follicles are recruited into the maturation process, which takes place over a few months in the ovarian micro-environment.

Stages of oocyte maturation

testosterone levels and relatively low sex hormone binding globulin (SHBG). Her DHEAS level was in mid-range. Her AMH level was high for her age at 7.4 ng/mL. In addition, the patient demonstrated FSH/LH inversion, a fairly typical finding with the “classical” PCOS phenotype. Her vaginal ultrasound examination demonstrated multi-cystic ovaries but not a typical “pearl-string” PCO-ovarian phenotype.

Her fasting glucose levels were in normal range, though her insulin levels were marginally elevated, suggesting early insulin resistance. The patient also demonstrated evidence of immune system activation with elevated total IgM and IgE levels and of inflammation, with abnormally high IL-6 and CRP. Her TSH was in clearly hypothyroid range and she demonstrated low level TPO as well as TG antibodies, leading to a diagnosis of likely Hashimoto’s thyroiditis.

Analysis: This patient’s work-up led to two distinct, yet often interwoven, diagnoses: She very clearly reflected the typical “classical” PCOS phenotype, characterized by truncal obesity, hyper-androgenism, a history of oligo-amenorrhea, hirsutism, elevated AMH levels, FSH/LH inversion and early insulin resistance. She, however, did not demonstrate a typical ovarian PCO-phenotype. In addition, she suffered from overt hypothyroidism and, based on evidence of thyroid autoimmunity, from Hashimoto’s thyroiditis. A hyperactive immune system was also confirmed by IgM and IgE gammopathies and elevated inflammatory markers in IL-6 and CRP.

PCOS is a widely misunderstood condition; it is perceived by many as "a disease,” which it is not. PCOS really is a group of separate conditions, which for reasons we will address below in more detail, have historically been thrown together in the medical literature in one “syndrome” named PCOS. Over the years, it has become apparent that this syndrome consists of very different patient groups, and groups of experts have tried to divide PCOS into distinct “phenotypes.”

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Monthly Case Report: Consultation with Polycystic Ovary Syndrome (PCOS)

Diagnostic work-up: A limited diagnostic work-up was ordered, which resulted in the following relevant results: The patient demonstrated hyper-androgenism, characterized by relatively high

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 27-year-old childless, single woman presented to CHR. Though concerned about her future fertility, she was not interested in conceiving at the time. She was of Middle-Eastern Mediterranean background, mildly obese with mostly truncal obesity (BMI 33). She also demonstrated moderate acne scars in her face and appeared mildly hirsute, with some dark facial hair and significant amounts of black hair on her arms.

She reported irregular menses since menarche at age 14, characterized by oligo-amenorrhea. Over the year prior to presentation to CHR, she claimed weight gain of ca. 15-20 lbs, without noticeable changes in exercise and/or eating habits. As a teenager, she was placed on OCPs to “regulate her period,” more for heavy menorrhagia episodes than menstrual irregularity. Her bleeding episodes were so severe that, twice as a teenager, she was admitted to a hospital and was treated for anemia.

With OCPs, her menstrual pattern regulated itself, and she stayed on birth control till age 24. Once she discontinued OCPs, she experienced six months of post-pill amenorrhea but then fell into a semi-regular menstrual pattern of 32-34 days, with a occasional amenorrheic months.

Her past medical history was otherwise insignificant except for an appendectomy at age 14, apparently without overt rupture. She had periodic visits with gynecologists and nurse midwifes over the years, though in irregular intervals. She was never advised of a diagnosis of polycystic ovary syndrome (PCOS). Her family history was also insignificant, except for the fact that her mother suffered from systemic lupus erythematosus (SLE).

She presented to CHR with a request for advice about her future fertility.

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This has, however, been only partially successful, as “experts” have not been able to agree on how this PCOS pie should be divided into individual phenotypes. Therefore, no consensus exists and different classifications of PCOS phenotypes are used in the medical literature, resulting in confusion and limited ability to compare results reported in various studies because investigated patient populations do not match.

Here discussed case represents the “classical” PCOS phenotype, except for the lack of the typical ovarian PCO phenotype on ultrasound. Many erroneously consider the "classical" PCOS to be the most frequent and most “typical” PCOS phenotype. That is not really the case. The literature suggests that the “classical” PCOS phenotype represents only ca. 40% of all PCOS patients. Indeed, an approximately equal number of PCOS patients (under most current international criteria) are lean women, without evidence of obesity, hirsutism, acne and the metabolic syndrome, which is so frequently found later in life in women with the “classical” phenotype.

Recent research at CHR that concentrated exclusively on this lean PCOS phenotype strongly suggests that etiologies and pathophysiologies of these two most frequent PCOS phenotypes, likely, are very different. Whether it makes sense to keep them within one syndrome and under one diagnostic parapet, therefore, has to be questioned.

Also widely underappreciated is the fact that PCOS is not necessarily a static condition. It, in principle, is a condition of young women and lightens in its reproductive clinical expression as women grow older. This, however, is not the case in the “classical” PCOS phenotype when it comes to the expression of signs and symptoms of the metabolic syndrome, which actually increase with advancing age.

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Case report: Continued from Page 4Resolution: The patient was advised of her diagnoses, and was started on thyroid supplementation. She was also advised of her risks of developing the metabolic syndrome and of benefits of proper diet, exercise and weight control.

Because at least the “classical” PCOS phenotype is increasingly viewed as an inflammatory condition and because the patient demonstrated early signs of insulin resistance, she was also advised of anti-inflammatory and hypo-glycemic effects of Metformin but chose not to initiate treatment at the time. She, however, did start with a baby aspirin daily. PCOS has also been associated with increased risk toward autoimmunity, and especially thyroid autoimmunity. Here observed combination of diagnoses is, therefore, not unusual.

Regarding her future fertility, she was advised that her current ovarian reserve was normal, with her functional ovarian reserve, based on her high AMH, even being abnormally high. Any infertility treatment would, therefore, likely place her at some risks for ovarian hyper-stimulation as well as multiple pregnancy.

She also was advised that autoimmune thyroid disease (and other autoimmune conditions) statistically denote increased risk of premature ovarian aging (POA), which would be reflected in relatively quick declines in AMH values. She, therefore, was advised to undergo repeat AMH evaluations every 1-2 years. Finally, she was advised that, as a “classical” PCOS patient, she likely, was oligo-ovulatory, which meant that she may require help to conceive. Consequently, she should seek out help from a fertility expert if she did not conceive within 6 months with regular intercourse, and, if possible, should accelerate her pregnancy attempts.

The patient has not returned since that consultation.

Hypoandrogenic PCOS: http://kaywa.me/ZCR7a

Polycystic ovary on ultrasound

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embryos offered strong supportive evidence that embryos, declared unsuitable for transfer by PGS 2.0, could lead to healthy live births in surprisingly high rates. Especially for poorer prognosis patients, this meant that they apparently had discarded their last pregnancy chances when their IVF centers disposed of their allegedly “aneuploid” embryos.

History, thus, repeated itself like CHR and a small group of other colleagues had warned about for a good number of years: Like PGS 1.0 before, only after years of clinical use had been exposed as clinically ineffective and even harmful to poor prognosis patients, PGS 2.0 now had met more or less the same fate, and the PGS industry found itself, once again, faced with immediate need to rescue its testing business.

Many of the same “experts,” who so smoothly had managed their laboratories’ transition from PGS 1.0 to PGS 2.0, now, again, jumped on the bandwagon of the inevitable, suddenly claiming to be leading a perfectly

natural switch from PGS 2.0 to PGS 3.0. They are not to be believed and, indeed, are to be held responsible for fooling the IVF community twice before. Shame on us, if we allow them to fool us a third time!

Which, finally, brings us to the main reason for this lengthy introduction. That reason is a paper, so far published only in electronic format by (of course) F&S, with two of the world’s most prominent PGS proponents as senior authors (Munné and Fragoulis et al., Detailed investigation into the cytogenetic constitution and pregnancy outcome of replacing mosaic blastocysts detected with the use of high-resolution next-generation sequencing. Fertil Steril). Not surprisingly, some of the strongest proponents over three generations of PGS (and, concomitantly, representatives of some of the largest PGS laboratories in the U.S. and elsewhere), are apparently quite desperate to establish yet another indication for use of PGS 3.0. They, now fully accepting that many mosaic embryos can and should be transferred, in this paper are attempting to claim that, PGS 3.0 may be just the right tool to differentiate which mosaic embryos should receive priority for transfer. Like so many others before from the PGS industry, careful analysis of their manuscript, however, resolutely debunks this claim.

But let’s not get ahead of ourselves, and start from the beginning: Though a good number of authors on this paper were among the most outspoken opponents of transfers of allegedly “aneuploid” embryos when it was first announced by CHR investigators and colleagues, this group of PGS proponents from all over the world now, quite remarkably, reported on cycle outcomes of 143 allegedly “aneuploid” embryos (now under new PGDIS criteria called “mosaic”) that were, nevertheless, transferred, in their paper. Though our colleagues did not give us the professional courtesy of referencing our preceding published work in their manuscript, we do want to congratulate them on this combined effort, which represents the, so far, largest number of reported IVF cycles using aneuploid/mosaic embryos. We are, however, especially grateful for this publication because, contrary to the authors’ obvious intent, the data in their publication allowed us to reach very obvious conclusions, further demonstrating the futility of all PGS as a diagnostic procedure. Like in the two prior PGS marketing rounds for PGS 1.0 and PGS 2.0, claims for PGS 3.0 are, once again, false.

Here is why: In compliance with 2016 PGDIS recommendations, chromosomal analyses were performed with Next Generation Sequencing (NGS) in the study. Also in compliance, normal-euploidy was defined as below 20% aneuploidy (i.e., mosaicism) in a single embryo biopsy, aneuploid-mosaic as 20-80% mosaic, and outright aneuploidy as above 80% mosaic. We refer readers to the June issue of the VOICE for explanation why this classification biologically makes absolutely no sense. Aside from that fact, only normal-euploid and aneuploid-mosaic embryos by this classification were transferred. Embryos with over 80% mosaicism were still disposed of as “aneuploid” - a point we will return to later.

Overall a remarkable 41% of mosaic embryos (i.e., embryos, which, under the old classification of PGS 2.0, would have been discarded) produced an ongoing implantation (pregnancy). Single aneuploid mosaics had as high as 50% implantation rates. Monosomies did equally well as trisomies. Complex chromosomally abnormal embryos did more poorly but still resulted in ongoing pregnancies of ca. 10%.

Though this study does not report on live birth rates,

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Continue reading on page 8

Lack of biologicla basis: http://kaywa.me/x6lNY

PGS laboratories in the US and elsewhere are apparently quite desperate to establish yet another indication for use of PGS 3.0 in IVF..."

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Flipping a coin: Continued from Page 2

reported IVF outcome numbers are, nevertheless, remarkable, not only because they fully confirm CHR’s earlier reported pregnancy and live birth rates after transfer of allegedly “aneuploid” embryos, but also because they demonstrate once more how many potentially good embryos have been disposed of over many years by PGS laboratories during the PGS 2.0 period.

Yet, instead of acknowledging that despite quickly expanding utilization, PGS has remained a diagnostic test in search of a clinical purpose, the PGS industry is trying again to develop yet another rationale why PGS should be continued as the new PGS 3.0 (or PGT-A). Why anybody should or would order a test that, as this study by PGS proponents again demonstrates, cannot differentiate between embryos that can safely be transferred or should be discarded, is unclear. Here at CHR, where we are used to "fighting for every egg and embryo,” we assume that patients do not want to discard by mistake even a single healthy embryo that may still have pregnancy potential! Why, then, utilize a test in the first place that cannot reliably differentiate between embryos that do and those that don't?

Trying to invent yet another reason for continued use of PGS, the authors of above cited manuscript came up with only one conclusion: PGS 3.0 should be performed to determine which embryos should be given priority for transfer. They could not even muscle enough data, however, to make a logical argument in support of that conclusion because the PGS industry, still, has not learned from past failures: The study still generalizes outcomes obtained in favorable prognosis patients, while the utility of PGS, of course, varies at different ages and with different degrees of ovarian reserve.

Even putting this very obvious criticism aside, the authors’ conclusions are nonsensical: Let’s for a moment assume a patient’s embryo does have a single chromosomal abnormality, either a monosomy or trisomy (the most frequent abnormal findings in human embryos on PGS). Such an embryo, according to the study, has a 50/50 chance of implantation. In other words, a coin flip would give us an equal chance of assessing this embryo correctly! And, even assuming an embryo has a slightly higher or lower chance of implantation, would that really affect clinical IVF practice to significant degrees, worth an additional $4,000, tacked on to an already exorbitantly expensive IVF cycle? We do not think so!

What further shames this manuscript is, of course, that the authors, still, recommended discarding all embryos with over 80% of mosaicism. As PGDIS guidelines refer to this cut off without any supportive underlying data, so does the materials and methods section of this manuscript. There really is no published evidence whatsoever in the literature that embryos with over 80% aneuploidy in a single biopsy sample are really abnormal and incapable of developing into normal offspring. As we noted in the last month’s article on PGS in these pages, to presume that an embryo with 79% aneuploidy can be transferred safely but one with 81% cannot, makes absolutely no biological sense. It also demonstrates a lack of statistical knowledge!

Further undermining the validity of this cut off, CHR investigators, collaborating with investigators from Rockefeller University, have demonstrated that a single 6-cell trophectoderm biopsy, mathematically, simply cannot determine whether a trophectoderm is normal, mosaic or aneuploid, even at 100% aneuploidy if all 6 cells are aneuploid [Gleicher et al., Reprod Biol Endocrinol 2017;15(1)33].

By confirming unexpectedly high pregnancy rates from transfer of aneuploid-mosaic embryos in the so far largest published patient cohort, the authors of the above noted paper, despite their very obvious intent, actually bear witness to the clinical futility of PGS. The procedure cannot differentiate reliably enough whether an embryo is normal-euploid, mosaic or aneuploid and, therefore, whether an embryo can be transferred with reasonable expectation of pregnancy or should be discarded. The PGS-test has no clinical purpose!

The authors of the paper are, nevertheless, to be congratulated on this publication, though for obviously different reasons than they, likely, had hoped for. Offering in their manuscript considerable amounts of raw data, allowing detailed reassessments of their statistical evaluations, they provided additional opportunities. As these words are written, CHR investigators and statisticians are, indeed, already hard at work in reanalyzing their raw data in more detail. We are sure results will be interesting and will, of course, be shared in these pages in the future!

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Flipping a coin: Continued from Page 7

Is an additional $4,000 tacked onto an already expensive IVF cycle really worth it?"

“

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PGS is no more; Long live PGT-A!Nothing happens by accident, not even changes in how procedures in IVF are referred to. It now appears time to say good-bye to a term we have been using since the late 1990s, when European colleagues first coined it: Preimplantation genetic screening (PGS), then considered a small sub-category of preimplantation genetic diagnosis (PGD) that described chromosomal testing of human embryos prior to transfers. At least, American Society for Reproductive Medicine (ASRM) and Fertility & Sterility (F&S), the official journal of the ASRM, no longer considers PGS the appropriate term to describe a chromosomal analysis of human embryos.

Instead, the May issue of F&S, largely dedicated to the procedure, suddenly, and without further explanation, was instead referring to the procedure as preimplantation genetic testing for aneuploidy (PGT-A). And for those who considered that a coincidence, the recent preliminary draft of a Practice Committee Opinion of ASRM and Society for Assisted Reproduction (SART) had as its short tile, PGT-A for “aneuploidy.”

Since such drafts of Practice Committee Opinions are preliminary, and ASRM members are requested to keep them confidential until official publication, we will not further comment on the opinion itself here. The sudden name change is, however, peculiar enough to comment on because it surprises not only in its suddenness but also in its obvious coordination by the ASRM.

In this month’s lead article of the VOICE, we make

the point that the renaming of the procedure gives the impression of a typical rebranding marketing effort, which under the name PGS has failed twice and, in the process, has not only wasted incredible resources, added significant undue financial burden to IVF and, in many cases, has actually reduced patients’ pregnancy and live birth chances, while leading to the mistaken discarding of large numbers of perfectly normal human embryos.

We are hesitant about being so cynical but, despite maximal efforts by everybody here at CHR, we, simply, could not come up with another explanation for the sudden name change which, of course, follows just a few short months the equally sudden radical revamp of how the procedure is viewed by “experts,” analyzed and reported by the industry, in more detail discussed in this month’s lead article.

While we truly hope that our cynicism will be refuted by another, better explanation, should the name change really be primarily only a marketing ploy, then shame is, of course, on the PGS/PGT-A industry. But even bigger condemnation would have to be directed at the ASRM and its primary medical journal, F&S, for supporting such a charade.

The most important take-home lesson from this column is, however, that should anybody try in the future to promote something, either called PGS or PGT-A to improve your IVF experience, run, just run! We then suggest you use a tiny fraction of the money you saved from avoiding the procedure to buy a celebratory drink for having avoided to fall for version 3.0 of the same old ruse.

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Ovarian rejuvenation: Continued from Page 3during weeks and months of follicle maturation after recruitment, when the ovarian micro-environment really can negatively affect follicles and eggs and, therefore, produce poorer egg quality.

Differences between these two theories of ovarian aging are of great theoretical and practical importance because, under the traditional theory of long-term damage, follicles and eggs recruited into maturation are already damaged. Their ultimate fate, therefore, is already determined and no medical treatment will, likely, be able to improve already damaged eggs.

Under the CHR hypothesis of aging, however, the assumption is that eggs enter maturation after recruitment mostly undamaged. Consequently, if the ovarian micro-environment, in which they will mature, can be therapeutically improved, their maturation will take place under

improved environmental conditions, and oocyte quality at the end of folliculogenesis will be better. In other words, under the CHR hypothesis of ovarian aging, ovaries, indeed, can be medically rejuvenated by reconstituting the ovarian micro-environment as close as possible to where those micro-environments used to be at younger ages.

Rejuvenating the ovarian micro-environmentThat the ovarian micro-environment changes with advancing female age is well documented. Surprisingly, however, only very little is known about what changes and at what ages. What actually lead CHR investigators to the CHR hypothesis of ovarian aging was the recognition that androgen levels (i.e., male hormone levels) rapidly decline in the ovarian micro-environment after age 40. Since small growing follicles need good androgen levels in these very early stages of follicle and egg maturation, CHR investigators started reconstituting older women with androgens (in that case with dehydroepiandrosterone, DHEA, from which our bodied make testosterone). With improving testosterone levels, ovaries started producing better eggs; better eggs led to better embryos and higher pregnancy rates.

It was this observation that then led CHR investigators to develop their hypothesis of ovarian aging because it did not appear probable to them that better androgen

levels would be able to reverse existing long-term damage to oocytes. The only remaining alternative explanation for outcome improvements observed in older women and younger women with premature ovarian aging (POA) after DHEA supplementation was, therefore, that improvements in the ovarian micro-environment had led to better egg quality.

The success of DHEA supplementation can, therefore, be viewed as the first and, unfortunately, so far the only successful clinical attempt at ovarian rejuvenation. It is, however, reasonable to assume that, like androgens, other important ingredients of the ovarian micro-environment also change with advancing female age. It now would behoove us to learn what those are. The better we reconstitute the micro-environment in older women, the better will our fertility treatments fare.

Legitimate trialsThis is, however, not the kind of “rejuvenation” the Internet has been buzzing about in recent months. There were, of course, some legitimate reports of other potential approaches. For example, investigators in Japan and San Francisco reported a few years ago a form of ovarian rejuvenation, in which they removed ovarian tissue from women who had entered menopause prematurely (premature ovarian failure, POF, also called primary ovarian insufficiency, POI), treated that tissue in the laboratory with biologically active ingredients known to activate a certain pathway (i.e. the Hippo signaling pathway) in primordial follicles, and then surgically re-implanted the treated tissue into the patient. Primordial follicles activated by this treatment, in some cases, started growing and a very small number of so-treated women ended up conceiving, because even women in menopause still have follicles and eggs in their ovaries. The problem with those follicles is, however, that they no longer grow in response to fertility drugs (gonadotropins). The in vitro treatment of these women’s ovarian tissue, thus, in a way “rejuvenated” the ovarian tissues removed and reinserted.

Requiring surgery twice, this treatment did not prove very practical and does not appear destined for wide clinical application. It, nevertheless, generated considerable interest because it, of course, raised the potential of learning how to activate these dormant follicles in vivo (i.e., in the body). Because the Hippo pathway can be mechanically induced, investigators at CHR have started to investigate such an approach

Differences between the two theories of ovarian aging are of great theoretical and practical importance..."

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in a preliminary fashion. Unfortunately, others have not been as measured in their approach (see below).

Watch out for snake oilOvaScience, Inc. (NASDAQ:OVAS) is a biotechnology company, which presents itself as a “global fertility company, dedicated to improving treatment options for women around the world.” Its motto is “improving fertility through science.” After reaching an extravagant market cap in the hundreds of millions of dollars based on alleged treatments that could “rejuvenate” ovaries through “proprietary technology that leverages the breakthrough discovery of egg precursors cells,” OvaScience returned to a much lower market reality even more quickly, and now operates under new management. Its first treatment, called AUGMENT™, initially got wide publicity, but was never offered in the U.S. for regulatory reasons. Now, after years of being sold in Canada and the Middle East, the treatment still has no evidence of efficacy.

Indeed, the company has mostly moved on from this initial product line, and is now offering a successor product, called OvaPrime™. While AUGMENT™ was designed “to improve IVF outcomes,” the company claims that OvaPrime™ “could increase a woman’s egg reserve.” Whether it really does so is, of course, unknown, and a healthy degree of skepticism appears appropriate. The company is also developing OvaTure™, “a potential next-generation in vitro (IVF) fertilization treatment that could help a woman produce healthy, young, fertilized eggs without hormone injections.” That would be a very welcome addition to the currently available fertility treatment offerings, but we, again, advise caution in paying for unvalidated products.

Above, we noted the interesting work of Japanese and West Coast colleagues regarding the Hippo pathway, and noted that there was a scientific rationale for exploring the possibility of trying to activate this pathway in vivo in order to avoid the double surgery required under our colleagues’ protocol. Though the purpose was not activation of the Hippo pathway in ovaries (at least they did not describe their practice as such), the Internet has recently been flooded by reports, where women with POF/POI have, with allegedly favorable results, all kinds of biological substances injected into their ovaries.

A center in a Middle Eastern country reported success in POF/POI patients through injections of the patients’ own white blood cells into ovaries.

Though this approach was first reported over two years ago, the claim has, still, not been formally reported in the medical literature. It, therefore, cannot be verified and/or duplicated. Nevertheless, at least one center in NYC picked up on the report and has been offering this treatment to patients (of course, with full charges). We advise utmost caution!

Even more attention has been given on the Internet and in some articles on the Web to injection of platelet-enriched plasma into ovaries. This approach was first reported by a center in Athens, Greece, and was picked up by at least two centers in NYC and others on the West Coast, who have started offering these treatments, of course, for appropriate fees. Once again, we advise great caution because no validation studies on any of these products have so far been offered.

Platelet-enriched human plasma has gained notoriety in sports medicine, where well known athletes have been allegedly cured from joint and other skeletal problems by such injections. The hypothesis behind these treatments is that platelet-enriched plasma contains many immunologically active substances (which is true), which exert anti-inflammatory and other beneficial effects (which, at least as of this time, is unproven).

Our friends and steady readers of the VOICE, of course, know how interested we are here at CHR in research that advances fertility care and allows quick translational applications. We, therefore, would strongly hope that all of here described attempts at ovarian “rejuvenation” will be properly researched and reported. Unfortunately, this is currently not the case. Most of these “products” are introduced to the market without any prior validation. We consider this inappropriate, potentially dangerous and often misleading because uninformed patients often believe these to be established procedures.

They are not! And this is why we felt we had to write about them.

Commercializing three-parent babiesSince we are already writing about the unethical commercialization of unestablished infertility treatments, we cannot help but mention an Internet article by Emily Mullin on June 13, 2017, called "The Fertility Doctor Trying to Commercialize Three-Parent

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Ovarian rejuvenation: Continued from Page 10

Babies" (https:www.technologyreview.com/s/608033/the-fertility-doctor-trying-to-commercialize-three-parent-babies/).

As it turns out, one of our New York City colleagues, who a few months ago was in the news for helping a woman conceive a “3-parent baby” by what is called spindle-cell transfer, has again made the headlines. Readers of these pages may recall that this case was presented as an altruistic step in helping a mother avoid another affected child, who had lost prior children to a mitochondrial genetic disease which she transmitted to her offspring.

It now turns out that nothing is ever as altruistic as it is presented to the public. As this article disclosed, John Zhang, MD, PhD, quietly established a new company, (seriously!) called Darwin Life already in 2016 (we assume the Food and Drug Administration, FDA, will love the name), which on its website (http://www.darwinlife.com) proclaims “introducing human egg reconstitution in vitro fertilization,” i.e., the use of nuclear transfer technology to treat older infertile women by placing the woman’s (older) nucleus into young egg donor’s cytoplasm.

We previously discussed in these pages that the hypothesis behind such an approach of treating older women is the belief that in older women the mitochondria in the egg’s cytoplasm have run out of steam. Replacing them with mitochondria from a young egg donor, therefore, should improve the eggs' overall quality, while any resulting child will, overwhelmingly, still have all of his parents’ genes, though the child will also have a very small amount of genetic material from the egg donor (hence the name "3-parent" IVF).

Importantly, at current knowledge levels, all of this is still a hypothesis that needs to be proven. Once again, we strongly encourage well-conducted research to determine whether this hypothesis is correct or not. That, however, does not seem to be the goal of Darwin Life. As Emily Mullin reports, the goal is to charge a laughable $80,000-120,000 per

Visit CHR on Facebook:https://www.facebook.com/thechr

Follow CHR:http://twitter.com/infertilityNY

Check out our video resources:https://www.youtube.com/user/CenterForHumanReprod

-The CHRFighting for every egg and embryo!

Our previous reports on spindle transfer: http://kaywa.me/T9kCG

Three-parent IVF basics: http://kaywa.me/T9kCG

IVF treatment cycle with spindle cell transfer!

Interestingly, Zhang is planning to offer this procedure to women only between ages 42 to 47. Women at these ages here at CHR still quite routinely conceive with regular IVF. Maybe, we should invite Zhang to a prospectively randomized study in women at those ages, comparing not only how regular IVF outcomes at CHR compare to those with spindle cell transfers by Zhang, but also, what the cost difference ends up being.

Ovarian rejuvenation: Continued from Page 11

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In FocusThis feature presents microscopic images from CHR’s laboratories, edited by our Director of the Division of Laboratories and Senior Scientist, David F. Albertini, PhD.

Here is an image of a human blastocyst that has been labeled to demonstrate the contact points between cells making up the outer shell of the embryo, the trophectoderm. Trophectoderm biopsies are used to estimate the genetic composition of human embryos in preimplantation genetic screening (PGS), a matter of much debate here at CHR and around the world. (For a detailed discussion of PGS/PGT-A, see articles on pages 1 and 9 of this issue.)

This image was taken by Agata Durda during her summer research project at the CHR. Agata is a pre-med student at Pace University here in NYC.

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A new prenatal vitamin that combines the pregnancy-supporting benefits of complete prenatal vitamins with fertility benefits of FERTINATAL® DHEA, Prenatal Vitamins + Fertility DHEA is designed specifically for

normally fertile women above age 35 who are trying to conceive spontaneously.Upon pregnancy, women should switch to a prenatal vitamin product without DHEA.

www.FertilityNutraceuticals.comNutraceuticals for the next generation

Also from FNC: Prenatal Vitamins with Fertility DHEA, the only fertility-supporting prenatal vitamins designed for women over 35

For infertility* patients:

Trusted by leading specialists

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*

Endorsed by Robert F. Casper, MD#, a foremost researcher of CoQ10 in female reproduction, in Toronto, Ontario, Canada

Widely recommended by leading reproductive endocrinologists and urologists specializing in male infertility

Fertility-specificdesigns

The original DHEA for women under infertility treatments*Supports healthy egg development via an androgen-enhanced ovarian environment*

Provides antioxidant protection and supports robust mitochondrial energy metabolism in healthy eggs*

Provides antioxidant protection and supports robust energy metabolism in healthy sperm*

Formulations based on published literature

Delivers 25 mg of DHEA, micronized to the same particle size as used in CHR’s published clinical studies*

Delivers a 999 mg daily mega-dose of CoQ10, in oil-suspended softgels for maximal absorption*

Intuitive packaging Individually blister-packed, making the recommended 3-Times-Daily schedule easy to follow

Triple-tested Industry-leading rigorous quality assurance with batch testing at independent laboratories

®DHEA for Women

®CoQ10 for Women CoQ10 for Men

TMANDROENERGENTM

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