VOICE NOV-DEC

THE VOICE November - December 2025

CHR

The Foundation for Reproductive Medicine Conference (FRMC) Issue See Program & Schedule Inside

In This Issue

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To Our Readers

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FRM Conference Program

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A Piece of My Mind

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The Business of Infertility

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The Quick Reads

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News From The CHR

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General Medical News

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Reproductive Medicine News

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To our readers, Welcome to the November–December issue of the CHRVOICE — our annual Conference Issue, released just ahead of the Foundation for Reproductive Medicine Conference (FRMC) in New York City. As always, this edition will be distributed at the meeting and made available to patients and visitors in the CHR waiting room, ensuring that our broader community can engage with the same timely insights shaping the field.

This issue highlights several of the scientific and clinical themes featured at this year’s FRMC. We analyze the broader commercialization of fertility care, using Kindbody as a case study in how profit-centric models can lead to significant financial instability. We also examine the ASRM’s latest guideline on subclinical hypothyroidism, including new evidence that contradicts parts of the Opinion, and explore updated data on thyroid autoimmunity, miscarriage risk, and ART outcomes.

Other sections address key developments in PCOS genomics, male infertility (including agerelated sperm mutations, Accutane in azoospermia, and lingering effects of androgen misuse), and placental chromosomal instability, which continues to reshape how aneuploidy in miscarriage is understood. From the aging sciences, we include new findings on organ-specific biological aging, early menopause as a driver of systemic aging, and evidence that multilingualism meaningfully extends healthy lifespan.

Importantly, this issue also engages with one of the central themes of FRMC 2025: the rapidly evolving landscape of embryo genetics and gene editing, including the recent Nature profile of Manhattan Genomics and the broader debate over correcting monogenic diseases at the embryo stage.

We hope this year’s Conference Issue provides clear, evidence-driven context for these fast-moving developments and serves as a useful companion to the discussions taking place at FRMC.

The Editorial Team We still love eggs

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A PIECE OF MY MIND

WHAT THE HELL IS GOING ON WITH PGT-A?

By Norbert Gleicher, MD, Medical Director and Chief Scientist, at The Center for Human Reproduction in New York City. He can be contacted though the CHRVOICE or directly at either ngleicher@thechr.com or ngleicher@rockefeller.edu.

BRIEFING: We start this issue with an article by the CHR’s founder, Medical Director, and Chief Scientist Norbert Gleicher, MD, which—as will quickly become apparent—was not only a piece of his mind, but also a product of his heart. Being blessed with several different areas of interest, which he explored in his over 500 peer-reviewed publications in many of the leading medical and science journals in the world in a career that by now has spanned over 40 years, the issue of preimplantation genetic testing (PGT) of embryos has clearly been a main subject of his interest over the last two decades. After attending ASRM 2025 in San Antonio, he came back with the distinct feeling that, for the first time in many years, something good may be happening in the IVF field regarding PGT for aneuploidy (PGT-A). Considering his track record, we have stopped second-guessing “suspicions.” He clearly has proven to be much more often right than wrong, and, therefore, we predict that—while readers may not agree with all of his opinions on PGT-A, they—with considerable certainty— will find food for thought in this article on PGT-A.

Some background If you attended ASRM-2025 San Antonio, you, with great likelihood, visited the exhibition hall; and, if you did, you must have noticed the change from last year (and several years before that) in the number of exhibitors trying to sell laboratory services for preimplantation genetic testing for aneuploidy (PGT-A). Until last year, they were everywhere and had some of the biggest booths in the hall; this year, they were almost nowhere to be seen, mostly replaced by companies peddling artificial intelligence (AI) products. And—if still exhibiting— their booth sizes had significantly shrunk.

And a similar disappearance act was also noticeable among oral presentations and posters on PGT-A, and among the relatively small number of abstracts in comparison to

prior years, there was clearly little remaining enthusiasm for the test/procedure. Even if you did not attend the conference, you may already have browsed through accepted abstracts.1 The decline in submissions seemed substantial and, after years of mostly glowing reports claiming all kinds of imaginary outcome benefits for PGT-A on IVF, the mood appears to have changed toward a much more skeptical assessment of PGT-A effects, a message we, here at the CHR, have been communicating for almost 20 years: It simply is no longer deniable, PGT-A, indeed, does not improve IVF cycle outcomes in many—if not most—patient populations and under almost all clinical circumstances. It, therefore, is also increasingly difficult to find excused for proponents of PGT-A who, despite constantly increasing evidence to the contrary, continue to claim to claim such benefits

in support of continuous routine utilization of PGT-A. Evidence has, indeed, also become overwhelming that, in several distinct patient populations, PGT-A, indeed reduces pregnancy and live birth chances in IVF cycles.

We, therefore, are asking our readers for forgiveness for the somewhat provocative heading of this Opinion article, which, as of this point, we feel is warranted, considering the accelerated pace of changes we have been witnessing regarding PGT-A, especially over the last year. Remarkably, they are happening so quietly that we are asking ourselves whether anybody but us here at the CHR is really noticing, but maybe—it is more appropriately to ask, does anybody really want to notice?

So, what has been changing?

Don’t worry, we do not want to

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rehash here the 20-plus-yearlong history of PGT-A (under different names), using steadily improving technologies and changing the timing of embryo biopsy from the cleavage stage to the blastocyst stage. Nor do we want to waste space and time on outlining the CHR’s very wellknown opposition to the routine utilization of chromosomal embryo testing since approximately 2006, after a Belgian colleague had published two small—and by many fiercely criticized - prospectively randomized studies of what then was called preimplantation genetic diagnosis (PGD) which failed to demonstrate widely expected outcome benefits in IVF cycles.

Like almost everybody else in the field, the CHR, indeed, at that time also questioned the validity of the Belgian studies. In an effort to confirm our opinion, we, indeed, decided to double-check our Belgian colleagues’ reported number in the two papers and, to our chagrin at the time, not only confirmed their analyses, but also had to conclude that PGD, likely, even adversely affected IVF cycle outcomes in older women.2 Because this conclusion so much contradicted what literally everybody in IVF at the time believed, we, for over a year, were unable to get a paper published in which we reported the reanalysis of the Belgian data and our new conclusion that PGD, indeed, in older women may actually reduce pregnancy and live birth chances.

Several of the leading fertility and general medical journals often outright rejected the submission even without review. Others rejected the submission after review

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since reviewers simply refused to believe our report.

Only after Mastenbroek et al. published their milestone paper in The New England Journal of Medicine (it previously was one of the journals that had rejected the CHR’s submission without review) which conclusively demonstrated that PGD, indeed, negatively affected IVF pregnancy rates in older women,2 did the editor-inchief of Fertility and Sterility recall our paper it had previously rejected and ended up publishing it.3 So, without too much further detail, let us here only summarize positive as well as negative milestones in the clinical evolution of PGD/PGT-A, which, in the CHR’s opinion, many years too late—finally have led to a point in time when the utility of this test/procedure for the first time is seriously questioned. (BOX 1 below).

BOX 1. HISTORICAL KEY-MOMENTS IN THE EVOLUTION OF PGD/ PGT-A Late 1990s—When first proposed, the PGD hypothesis was that deselection of “aneuploid” (chromosomal-abnormal) Embryos from an IVF cycle’s embryo cohort would improve pregnancy and live birth rates for the remaining “euploid” (chromosomal-normal) embryos, reduce miscarriage risk (because a majority of miscarriages are chromosomal-abnormal pregnancies), and would speed up time to pregnancy and delivery.

Early 2000s—Two small prospectively randomized studies

by Belgian investigators suggested that none of these expected IVF outcome improvements, indeed, were being achieved.

2007—Mastenbroek et al. confirmed the lack of improvement in IVF cycle outcomes and reported actual declines in pregnancy and live birth rates in older IVF patients.

ALL THREE ABOVE NOTED PUBLICATIONS WERE VICIOUSLY ATTACKED BY PGD PROPONENTS AND FAILURE TO DEMONSTRATE OUTCOME BENEFITS IN THESE THREE STUDIES WAS EXCLUSIVELY AND INCORRECTLY ATTRIBUTED ONLY TO POOR TECHNOLOGY, as at that time embryo biopsies were performed at cleavage-stage (day-3) at which time 1-2 blastomeres were removed from a 6-8-cell embryo and ploidy only was determined in the 6-8 chromosomes most often found to be abnormal in miscarriages.

Late 2000s—Switch from day3 to day-5 (blastocyst-stage), which accelerated after 2010, with diagnostic accuracy for aneuploidy testing from on average 5-6 trophectoderm cells improved, because of more DNA availability, for more accurate DNA diagnoses of all 46 chromosomes.

PROPONENTS ARGUED THAT THIS “IMPROVED” METHOD OF CHROMOSOMAL EVALUATION OF EMBRYOS WOULD, FINALLY, DEMONSTRATE OUTCOME BENEFITS IN IVF CYCLES THAT USED PGD/PGT-A. BUT THAT 13

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DID NOT HAPPEN. THOUGH THE UTILIZATION OF PGD IN THE US AND ELSEWHERE STEADILY INCREASED, LIVE BIRTH RATES AFTER IVF BETWEEN 2004 AND 2016 ACTUALLY WORLDWIDE CONTINUED DECLINING.4 2015—First, the CHR5 and shortly after that, Italian colleagues6 reported healthy euploid births after transfer of embryos by PGD as “aneuploid-abnormal” reported embryos.

AS OLDER CLAIMS OF PGDPROPONENTS IN VIEW OF THESE TWO REPORTS WERE NO LONGER SUSTAINABLE, PROPONENTS OF THE TEST/ PROCEDURE UNDERTOOK ANOTHER MAJOR RESTRUCTURING, WHICH THIS TIME ALSO INCLUDED A NAME CHANGE FOR THE TEST/ PROCEDURE FROM PGD TO PGT-A. 2016—Aside from the renaming, this additional important change was made: binary reporting of embryo ploidy as “euploid” and “aneuploid” was replaced by adding a third diagnostic category, “MOSAICISM.” AS IT TURNED OUT, THIS CHANGE COMPLICATED THE REPORTING OF PGT-A DIAGNOSES FOR TWO REASONS TO SIGNIFICANT DEGREES: (i) Laboratories chose different percentages of the second DNA lineage amounts for the definition of “mosaicism” (initially a range from 21% to 80%, but different laboratories later used different ranges, some a range as narrow as 40-60%).

(ii) To this day, PGT-A laboratories uniformly define “mosaicism” incorrectly. The correct and universal biological definition of “mosaicism” has for decades been the PRESENCE OF MORE THAN ONE CELL LINEAGE IN A COMPLETE ORGANISM DERIVED FROM A SINGLE CELL. This is, however, NOT the definition of “mosaicism” adopted by the PGT-A testing industry.

Basically inventing its own definition, PGT-A laboratories, to this day, deviate from the worldwide definition in a crucially important point: Instead of defining “mosaicism” as the percentage of DNA from a second cell lineage in a total organism (i.e., in this case blastocyst-stage embryo), the PGT-A industry defines “mosaicism” as THE PERCENTAGE OF DNA FROM A SECOND CELL LINEAGE IN A TROPHECTODERM BIOPSY OF ONLY 5-6 CELLS. In other words, in place of a percentage among over 150 cells, the definition of “mosaicism” now depends on whether a second cell lineage exists in only 5-6 cells of an embryo.

It does not take special math or statistics knowledge to understand the difference: the generally accepted definition of “mosaicism” makes biological sense, the PGT-A industry definition, in contrast, is a crapshoot (depending on where a biopsy is taken) and, therefore, biologically, makes absolutely no sense.

Because of the increasing confusion surrounding “mosaicism” diagnoses, many IVF clinics have asked laboratories to return to only binary “euploid” vs. “aneuploid”

reporting. Moreover, some clinics have started transferring so-called “low mosaic” embryos (with the definition of “low” once again varying between laboratories and clinics), though a majority still do not. EXCEPT FOR THE CHR (SELECTIVELY), ALMOST NO OTHER IVF CLINIC IN THE US CURRENTLY TRANSFERS SO-CALLED “HIGH MOSAIC” OR EVEN AS OUTRIGHT “ANEUPLOID” REPORTED EMBRYOS BY PGT-A. After 2015—Over the following 10 years, significant additional evidence that PGT-A does not improve IVF outcomes have been accumulating, in September of 2024, finally leading ASRM (and its daughter society, SART) toward issuing the formal guidance that PGT-A in all these years of ever-increasing clinical utilization has completely failed to establish any clinical utility.7 CONSIDERING, HOWEVER, THAT PGD/PGT-A IN OVER 20 YEARS OF INCREASING UTILIZATION HAS BEEN UNABLE TO OFFER ANY OF THE PROMISSED IVF OUTCOME BENEFITS, IT IS DIFFICULT TO UNDERSTAND WHY THIS GUIDELINE DID NOT ALSO REACH THE ONLY ETHICALLY AND CLINICALLY ACCEPTABLE CONCLUSION THAT PGT-A, THEREFORE, NO LONGER SHOULD BE OFFERED AS A ROUTINE CLINICAL TEST/ PROCEDURE. This conclusion is, indeed, further supported by considerable evidence in the literature in recent years suggesting that PGT-A in selected subpopulations not only fails to

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improve IVF cycle outcomes, but actually reduces pregnancy and live birth chances. This fact is probably best borne out by PGT-A mandating blastocyststage culture (rather than cleavage-stage transfers) as well as cryopreservation of all embryos and then subsequent thaw-cycles.

With cryopreservation, loss of at least some embryos is practically unavoidable. This fact alone, therefore, irrefutably demonstrates that cumulative pregnancy and live birth chances for any IVF cycle’s embryo cohort will, at least to a minor degree, adversely affect this cohort’s cumulative outcome chances.

2023—Class Action Suit against IVF clinic chain regarding PGT-A settled in Australia.

costly IVF practice.

BOX 2. THE CHR’S CURRENT CONCLUSIONS Different from traditional best ABOUT PGD/PGT-A •

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•

2025—Several Class Action Suits are underway against selected US PGT-A laboratories, in principle claiming incorrect outcome claims and/or informed consents

by PGT-A laboratories.

How is PGD/PGT-A best summarized up to this point in time, when most recently available data still suggest that, at least until very recently, the clinical utilization of PGT-A has continued to increase, and over half of all US IVF cycles (including donor egg cycles, using carefully selected and young egg donors) currently utilize PGT-A. In several IVF clinics and clinic networks, utilization of PGT-A, indeed, is a condition for starting an IVF cycle. BOX 2 attempts to offer answers.

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•

PGT-A—in contrast to years-long representations by its proponents—does not improve routine IVF cycle outcomes7 and, indeed, in several subpopulations of infertile women, adversely affects pregnancy and live birth chances in IVF. The hypothesis of PGT-A, and yes, PGD/PGT-A was never more than an unproven hypothesis, was based on a poor understanding of genetics and an even poorer understanding of embryology and reproductive biology in general.

That an unproven test/ procedure like PGD/ PGT-A, which determines daily decisions about the fate of thousands of human embryos, has not only been allowed in practice for over 20 years, but is still allowed to be actively promoted and clinically utilized, is, in its ethical and clinical relevance, unprecedented in medicine, and must be further studied in causality to prevent similar clinical missteps in infertility practice.

Current analysis suggests the following contributing causes to the current PGT-A fiasco:

PGD/PGT-A has seen increasing clinical utilization over more than 20 years, even though its basic hypothesis was never confirmed, it never fulfilled promised outcome improvements in IVF, and it added significant cost to already very

clinical and ethical medical practice, the onus of proof was never put on proponents of PGD/ PGT-A to confirm their hypothesis, but was demanded from opponents who were asked to disprove the hypothesis.

Lack of adequate communication between the research bench and clinical practice in reproductive medicine has, unquestionably, greatly contributed.

Instead of turning to reproductive biologists and embryologists for “expertise,” the field mistakenly identified the required “expertise” among geneticists who, indeed, had genetic expertise, but lacked understanding of reproductive biology.

Consequently, as noted in BOX 1, whenever opponents of PGD/ PGT-A reported findings that contradicted beneficial outcome claims of proponents of PGD/ PGT-A, (genetic) “experts” attributed these findings to technical shortcomings of assays in the detection of embryo aneuploidy, rather than considering potential errors in their understanding of basic biology of preimplantation-stage embryos. This excuse of the genetics community permeates PGT-A advocacy to this day (i.e., “your laboratory is just not good enough”), simply not understanding that the biology of preimplantation-stage embryos is the real explanation of PGT-A’s failures. Aneuploid cells at the blastocyst stage must be considered as “normal”, with many embryos 15

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self-correcting downstream in the embryonic lineage, though not in the extra-embryonic lineage (the trophectoderm) from where PGT-A biopsies are taken.8 Yet the infertility field ceded to unqualified geneticists significant control over the IVF process, as, for example, demonstrated by ASRM guideline documents repeatedly referring to (and relying on) professionally truly incompetent guidelines from a small and highly conflicted genetics society, the Preimplantation Genetic Diagnosis International Society (PGDIS).9,10 Important secondary consequences of routine PGT-A utilization in IVF have so far, moreover, not been addressed, yet can be expected to be highly significant: PGT-A, for example, is, of course, closely linked to routine blastocyst-stage transfer, which has become standard of care in IVF as well as to routine single embryo transfers.

PGT-A, moreover, with considerable likelihood (in association with routine blastocyststage culture and too broadly used single embryo transfer), has since 2010 been the principal culprit in steadily declining pregnancy and live birth rates in US autologous IVF cycles (as well as in other regions of the world), first reported in 2019.11 •

Current conclusions, therefore, mandate the following:

Having now, with considerable unnecessary delay, finally concluded that in over 20 years of clinical utilization, PGD/PGT-A has not established any clinical utility,7 it is difficult to understand 16

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why ASRM has not reached the only logical conclusion that can be derived from this opinion, that the routine utilization of PGT-A practice must be discontinued. It simply makes no sense to spend money and effort on something that, as everybody now finally agrees, doesn’t do anything good in an IVF cycle. The same obligation, of course, also applied to ESHRE and other fertility societies.

responsible for many of the false representations regarding PGD/ PGT-A—has initiated a marketing drive for a new and once again completely unvalidated test also requiring embryo biopsy, so-called polygenic risk scoring (PGRS, also called PGT-P). It behooves the infertility field not to fall once again for what can only be described as an even more absurd marketing drive than PGD/PGT-A ever was.

That such an opinion will, for economic reasons, be strenuously opposed by the genetic testing industry and—it must be acknowledged—by some (maybe even many) IVF providers who basically split the income from PGT-A with PGT-A laboratories by charging for the embryo biopsy, can be expected, but fertility practice must finally “come clean” on this issue.

A word about responsibility

If fertility practice will not lead this effort, fertility clinics will— ultimately—be dragged into the currently already ongoing class action litigation against PGT-A laboratories.

With large numbers of post-PGD/ PGT-A embryos currently still cryopreserved in the US and around the world, it must be openly communicated to the public that many embryos currently refused transfer by IVF clinics may—with only minimal risk—still have varying degrees of likelihood of pregnancy and live birth chances.

Finally, as repeatedly noted by the CHR in its publications (CHRVOICE and The Reproductive Times), the genetic testing industry— promoted by many of the same genetic “experts” who have been

Considering the fact that that many thousands of human embryos are daily produced in IVF cycles in the US (and many more, of course, around the world), are tested and judged with PGT-A regarding their alleged chromosomal complement, and then are, based on this judgment, transferred, cryopreserved, or even discarded, one must ask where is the special consideration and moral status basic science and medicine has always claimed to be giving human embryos and, more recently, even so-called” embryo-like-structures” 12 when it comes to the daily practice of IVF. Let us, therefore, address here the responsible parties for the mess PGT-A currently finds itself in:

We physicians It, of course, all starts with the ethical obligation of us physicians to serve our patients to the best of our abilities when infertility patients seek out our help with, in principle, only one desire, to conceive and deliver a healthy offspring!

If it is, indeed, our duty as health

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care providers to advise and help our patients to the best of our abilities, where else in medicine have physicians been not only passively providing, but actively and at times aggressively, promoting, an unproven medical service at quite significant costs (and outside of insurance coverage) that in over 20 years of clinical utilization has been unable to offer any outcome advantages?7 One, indeed, has to wonder how colleagues who to this day routinely recommend PGT-A to their IVF patients explain this not only to their patients, but to themselves?

Having likely been the longest— but certainly the loudest and most outspoken—provider of IVF services in the US opposing the routine utilization of PGT-A in IVF, the CHR (and all of its staff) do not revel in sentiments of “victory” in the decades-long, at times quite uncomfortable, conflict with proponents of PGT-A; but we have to acknowledge that we find ourselves at times questioning the reality of the situation when meeting some of the most aggressive proponents of PGT-A in the past, who always dismissed every single criticism of the test/ procedure out of hand, but now, suddenly, claim to have always questioned “how PGD/PGT-A was performed.”

Where were they when patients were refused access to IVF unless they agreed to PGT-A? Where were they when huge numbers of falsepositive embryos after PGT-A were either not used or even discarded?

Have they ever wondered how many of their patients ended up with third-party donor eggs and embryos because good eggs and

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embryos were not used because of their PGT-A results? Or have they ever asked themselves how many of their patients, based on their recommendations, gave prematurely up on having children at all?

From not even one of those vehement proponents of PGT-A, and they know who they are, have we ever heard a mea culpa!

And neither have, of course, their patients. Yet, based on a very reliable source, one of the most outspoken and most prominent proponents of PGD/PGT-A was the first to contact the plaintiff lawyers who filed the US class action suits against PGT-A laboratories in 2024, offering, of course, not out of goodwill or remorse alone, his services as an expert witness.

Considering all the damage caused

by PGD/PGT-A to so many of our IVF patients worldwide, the responsibility, of course, starts with us physician providers of IVF services because, without our recommendations, in many cases strong encouragement, and in some IVF clinics even mandates, only very few patients would voluntarily choose to add the significant costs of PGT-A to the already often almost unaffordable costs of IVF. And there is no excuse for us physicians because we should have known better, and over 20 years of PGD/PGT-A utilization is simply too long for any kind of excuse.

Government authorities But we providers of fertility services are by no means alone: Patients harmed by the use of PGD/PGT-A have also to thank our government: It is interesting

to read in the lay press, whenever the subject of infertility comes up, how “unregulated” IVF is in the US in comparison to, for example, the UK and many other developed countries. But that is incorrect!

In many ways, the US is, when it comes to IVF practice, indeed the most overregulated country in the Western world. The problem is not under-regulation, but extremely poorly over-regulation!

Here is a quintessential example: Under Congressional mandate, all IVF clinics in the US must report to the CDC all started IVF cycle and their outcomes. At the CDC, it takes a group of government bureaucrats, ca. three years to publish a report (data from the most recently available year at the time of this writing are from 2022).

One, of course, cannot be too surprised by this ridiculous delay because it, of course, also takes our federal government several months to get final election results, when even some third-world countries can do this on the day of the election. In short, with this group of government bureaucrats under the protest of some of our professional societies allegedly laid off by the Trump administration’s Department of Health and Human Services amid recent job cuts at the department, it is currently unclear where, when, and how the CDC will continue publication of these annual clinic-specific outcome data.13 And why has this been done in the first place? First of all, we assume because Congress mandated these reports (and who knows why, considering the fact that, over decades, Congress has

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demonstrated absolutely no interest in these results). And secondly, one cliché, of course, being as good or bad as any other one, likely, with the intent to inform the public.

At least on first impression, both of these motives seem like reasonable motivations, but neither, in fact, is. And here is a good example why these reports are, indeed, a major problem: For example, the 2022 median age for all US IVF clinics reporting to the CDC was 36.2 years, when at the CHR the median age at that point was 43 years (it in 2024 reached 45).

And older patients, of course, also means lower pregnancy and live birth chances. Clinic outcomes at a clinic with a median age of 36 will, therefore, always be better than outcomes with a patient population with a median age of 43 or even 45.

But here is the absurdity: Every annual report published by the CDC is preceded by the absolutely correct statement that the report (for above outlined reasons) should not be used to compare IVF clinics.

And if neither Congress nor the public can judge individual IVF clinics based on these reports, what is then their purpose? These reports, indeed, invite cheating in which clinics treat because the goal is no longer providing patients with the best treatments, but how to make the clinic’s cycle outcomes look the best, because the only reason for patients to look at these reports is to compare clinics.

And what are the consequences?

Difficult cases are often discouraged from pursuing IVF, are discouraged from using their own eggs, and are prematurely advised that their only “realistic chance” is with the 18

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use of third-party egg donations.

Consequently, the number of autologous IVF cycles after the ages of 42-43 in the US has remained minuscule (of course, except at the CHR, where they represent more than half of all patients).

Consider, however, what opportunity for true quality assessment this CDC registry could offer if the CDC just wanted to make the effort. In view of current computing and AI abilities, the amount of valuable quality of care information that could be extracted from these data with appropriate analyses is, of course, remarkable, and those data are currently completely wasted because nobody—neither Congress nor the bureaucrats at the CDC— really gives a damn about the data.

To statistically appropriately adjust these data is not that difficult. But why do that, when doing nothing is so much easier? After all, isn’t the Congressional mandate already warranted by just knowing how many IVF cycles every IVF clinic performs?

extremely valuable data source for outcome research in IVF. And while CDC bureaucrats on some rare occasions have published studies, none were ever of major significance, and some were outright ridiculous due to a lack of even the most basic clinical understanding.

But Congress did not pass the reporting mandate because it really cared about IVF outcomes or how well or poorly IVF clinics were performing. Congress passed the law as a purely demonstrable political act to show that Congress was “watching” the IVF field. To the best of our knowledge, IVF is the only clinical medical practice in all of medicine for which Congress has passed such a reporting mandate.

And then there is, of course, also the Food and Drug Administration (FDA) with regulatory function over the IVF field. But, once again, this aspect of government supervision addresses only a small portion of what IVF clinics do, in this case, supervision over third-party gamete donations (I.e., Lack of quality control at individual semen and oocyte donations).

IVF clinics is, however, not the Approximately every two years, only missed opportunity stemming therefore, one morning an from the enormous data set the unannounced FDA officer in CDC receives from most US clinics uniform suddenly shows up at all (despite Congressional mandate, IVF clinics and—depending on the a small number of US clinics do size of the clinic—usually spends not report to the CDC but, to one to two days inspecting medical demonstrate the poor quality of this charts and clinic policies regarding government’s supervision effort, all third-party donor activities.

Congress passed the mandate without outlining an enforcement The administrative costs for IVF effort. clinics to support these government mandates are not insubstantial and The CDC, therefore, does not even are not the only efforts and costs have an instrument to enforce because most states, through their the mandate. Such a huge data set respective health departments, also could, of course, also become an have an IVF-related review process.

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In New York State, this process, too, involves usually an inspection visit every two years but in clinics like the CHR, which in a majority serves patients from out of state, often also involves one-on-one consultation with senior staff at The New York State Department of Health, usually involving permission to move gametes (eggs or sperm) or embryos into and out of New York state.

The technical review of PGT-A The FDA as the agency that approved diagnostic tests The process of PGT-A, whether viewed as a test or as a procedure, has never undergone review by the FDA or any other authoritative body of government and, therefore, was never approved by the FDA or any other regulatory authority.

None of the existing PGT-A laboratories has, indeed, undergone any kind of inspection by the FDA or any other government organization. Who, therefore, can be surprised about the clinical mess PGT-A finds itself in, attacked from several sides, of course, including in these pages, by the CHR. And how unbelievable does it sound that a test/procedure responsible for the fate of hundreds of thousands of human embryos generated every year in IVF cycles, now, for over 20 years of steadily increasing utilization in the US, has never undergone any government scrutiny, either conceptionally or technically. In other words, while the American College of Pathology checks whether the thermometers in our IVF laboratory are regularly and correctly controlled, no government agency and/or, for that matter, professional body has

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ever asked over more than 20 years whether PGD/PGT-A can even differentiate accurately enough between euploid and aneuploid embryos.

Had this been done, it is reasonable to assume that—at minimum—it would not have taken 20 plus years to discover that PGD/PGT-A never was, indeed, able to make this distinction accurately enough to positively affect IVF cycle outcomes. At maximum, however, large numbers of human embryos which were wrongly excluded from transfers and/or even discarded, would have led to autologous pregnancies, large numbers of women who gave up on their own eggs in favor of third-party donor eggs would still have had children with autologous eggs, and many women who threw in the towel on maternity would be mothers, often already looking forward to becoming grandmothers.

What in many ways can be viewed as one of the biggest tragedies in modern health care could, in other words, have been largely avoided, had the government, in this case, the FDA, as the primarily responsible agency to approve diagnostic tests, done its job!

One then may ask, how was it possible that PGT-A was allowed to conquer the IVF process without any FDA approval? The answer is simple: PGT-A is sold to the public by the genetic testing industry as a so-called laboratory-developed test (LDT) and the FDA just—one day several decades ago—simply decided that LDTs did not have to be certified by the FDA like most other diagnostic tests and/ or procedures. BOX 3 (below)

explains the difference between routine in vitro diagnostic tests (IVDTs) and LDTs.

BOX 3. THE DIFFERENCE BETWEEN IVDTs AND LDTs In vitro diagnostic tests (IVDTs) • REQUIRES FDA APPROVAL • For sale to diagnostic laboratories, health clinics, consumers • Requires standardized instrument qualification procedures and commensurate training • Test must be pre-validated with data analyses and bioinformatic report • Must also be CLINICALLY VALIDATED Laboratory-developed tests (LDTs) • DOES NOT REQUIRE FDA APPROVAL* • Developed by a laboratory for only its own use • Only the laboratory has to establish instrument qualifications and staff training requirements • Often, no standard assay is available • Must be CLINICALLY VERIFIED • Can be implemented quickly for emergency use *Until recently, the FDA chose NOT to review LDTs, even though the agency always claimed to have the right. The FDA in 2024 announced a change of policy in that it would start selectively reviewing certain LDTs, but was stemmed by a court decision.14

The concept of LDTs arose from the offices of country doctors and was never really meant to be

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applied to corporate laboratories serving a nationwide (and often international) patient population.

Moreover, the FDA always claimed to have the legal right to approve LDTs in a similar way to how IVDTs are being reviewed, but chose not to do so. Unsurprisingly, a large laboratory corporation jumped at the opportunity to circumvent FDA approval by simply listing a test (like PGT-A) as an LDT. Considering the multidirectional importance PGT-A carries in the IVF process, we cannot think of a test that is more deserving of FDA review than PGT-A. Yet, interestingly, PGT-A was not among the LDTs that the FDA in 2024 announced as candidates for initial review. Obviously not happy with the decision of the FDA to—at least selectively—start reviewing LDTs, the laboratory industry went to war and sued. And the US District Court for the Eastern District of Texas, indeed, vacated the newly published FDA rule with the argument that the FDA lacked authority to do so.14 Though this very likely will not be the last word regarding the FDA’s ability to regulate LDTs, it appears reasonable to assume that PGT-A will not become a target of the FDA in the foreseeable future, even if the courts in the end may decide in this matter in favor of the FDA. In practical terms, this means that, from a regulatory standpoint, not much can be expected regarding PGT-A from the US government.

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More on professional societies And then there are ASRM and its sister society SART, with SART managing a voluntary parallel registry of slightly fewer US IVF cycle outcomes than the CDC, if one can call something “voluntary” on which membership in ASRM is dependent. For the same reasons as the CDC registry, the ASRM/SART registry also cannot be used for comparisons between individual IVF clinics.

In a much too complex and long application process, the ASRM, however, at times grants researchers access to this data bank for research projects that allow at least selected adjustments for co-variables, and the CHR’s researchers have on occasion applied and received access to this data bank for certain study purposes. ASRM and SART also review outcomes of individual clinics and initiate inquiries and sometimes even inspections (for which the clinic has to pay) if certain IVF outcomes of a clinic for several years in a row fall outside of national statistics.

And finally, most IVF clinics undergo a bi-annual in-house inspection of the American College of Pathology for all aspects of embryology laboratory management, which, usually over two days, is the most intense and detailed of all visiting inspections; and these inspections occur in addition to regular mailed trial samples for laboratory tests performed in-house.

In short, the claim that IVF practice in the US is un- or under-regulated is obviously simply incorrect. How poorly and illogically IVF, however, is currently regulated in the US, is not only demonstrated by the here presented description of the various review processes IVF clinics have to deal with independently,but is probably best demonstrated by the simple fact that PGT-A, whether viewed as a test or as a procedure, has never undergone review by FDA or any other authoritative body and, therefore, was never approved by the FDA or any other regulatory authority.

None of the existing PGT-A laboratories, therefore, has undergone any kind of inspection by the FDA or any other federal agency. Who, therefore, can be surprised that, a the CHR and others reported years ago, different PGT-A laboratories often will report different PGT-A results in blinded studies involving the same embryos.

In short, a test/procedure responsible for the fate of hundreds of thousands of human embryos generated every year in IVF cycles, now, for over 20 years of steadily increasing US utilization, has never even been looked at by any government agency! In other words, while the American College of Pathology checks whether the thermometers in our IVF laboratory are regularly and correctly inspected, no government agency and/or professional body has ever asked over more than 20 years ever asked whether PGD/ PGT-A can even differentiate accurately enough between euploid and aneuploid embryos. If such a question had ever arisen, the

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answer would have been obvious: PGT-A, after all of those years of use and very obvious technical improvements, still cannot reliably distinguish between a truly euploid or truly aneuploid embryo. One, therefore, is left wondering, why do IVF clinics still use this test—often routinely—and why is this test still on the market?

Had a formal review by either a qualified professional society and/ or federal agency taken place, it is reasonable to assume that, at a minimum, it would not have taken 20 plus years to discover that PGD/ PGT-A never was able to make this distinction accurately enough to positively affect IVF cycle outcomes.7 At maximum, however, large numbers of human embryos which were wrongly excluded from transfers and/or even discarded, would have led to autologous pregnancies, large numbers of women who gave up on their own eggs in favor of third-party donor eggs would still have had children with autologous eggs, and many women who threw in the towel on maternity would be mothers, often already looking forward to becoming grandmothers. What in many ways can be viewed as one of the biggest tragedies in modern health care could, in other words, have been largely avoided, had the government, in this case the FDA, as the primarily responsible agency to approve diagnostic tests, done its job, and/or had, frankly, our professional organizations done their job.

References 1. ASRM. Abstracts of the Annual Meeting. Scientific Oral & Poster Sessions Program Supplement. Fertility and Sterility 2025.

2. Mastenbroek et al., N Engl J Med 2007;357:9-17 3. Gleicher et al., Fertil Steril 2008;89:780788 4. Gleicher et al., Hum Reprod Open 2019;3:hoz017 5. Gleicher et al., Fertil Steril 2015;104:e59 (e1-e387, September 2015) 6. Greco et al., N Engl J Med 2015;373:2089-2090 (November 19, 2015) 7. Practice Committees of the ASRM and SART. Fertil Steril 2024;122(3):421-434 8. Yang et al., Nat Cell Biol 2021; 23:314321 9. Gleicher et al., Reprod Biol Endocrinol 2020;18(1):57 10. Gleicher et al., J Assist Reprod Genet 2023;40(4):817-826 11. Gleicher et al., Hum Reprod Open 2019(3):hoz017 12. Writing Group of the ESHRE Ethics Committee. Hum Reprod 2024;39(11):2387-2391 13. CDC National ART Summary 2022.

14. CONGRESS.GOV. Library of Congress. LSB11312

AD

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THE BUSINESS OF INFERTILITY

INSIDE KINDBODY: How a billiondollar fertility empire sacrificed patients for profit

By Chloe Haack, BS, BS, is a writer and editor at the VOICE and The Reproductive Times. She can be reached through the editorial office of the VOICE or at social@thechr.com

BRIEFING: A national, venture-backed clinic network promised to “reinvent” fertility care by owning the stack: employer benefits, clinics, labs, EMR, and add-ons. Reporting from Bloomberg documents embryo-handling mistakes, production-style targets tied to physician pay, and revenue pressure that bled into clinical judgment. The core problem isn’t one brand—it’s the US vacuum between surveillance and licensure. The CDC validates reported outcomes, ASRM/SART collects self-reported data, and FDA oversight focuses mainly on donor eligibility and tissue practices, not day-to-day IVF with patients’ own gametes. The result: glossy growth stories atop inconsistent safety systems, soft-evidence add-ons, and patients footing the risk. Real reform would mean federal licensure, routine inspections, mandatory nearmiss reporting, and transparent incentives.

The sales pitch had the polish of a lifestyle brand applied to medicine: glass-box clinics with café lighting and minimalist lounges, an app promising instant updates, and a venture-capital narrative about “reinventing” a field that hadn’t caught up with its own technology. The company doing the reinventing was Kindbody, a US fertility clinic network and employer-benefits provider founded in 2018 by Gina Bartasi. By March 2023, Kindbody announced $100 million in new financing—$290 million in total— at a reported $1.8 billion valuation: the sort of number that can turn a medical service into a growth story overnight.¹ The disruption thesis relied on vertical control. Rather than refer patients to outside providers, Kindbody aimed to control the entire process—operating its own clinics and embryology labs, an in-house genomics arm (Kindlabs) for preimplantation and carrier testing, a proprietary electronic 22

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medical record (KindEMR) to accelerate workflow, and even adjacent ventures such as KindEOS for donor and surrogacy services and KindRx and Kind360 for pharmacy and “whole-person” care. By providing employer benefits and offering care within its own facilities, Kindbody claimed it could reduce costs by about 25 percent while enhancing the experience and outcomes.² In 2025, the ambitious narrative of merging software with embryos and intertwining scale with hope crumbled under the immense pressure of its own aspirations.

Bloomberg’s five-part investigative series, “IVF Disrupted: The Kindbody Story,” reconstructed the rise and fall, detailing missteps, staffing strain, and financial pressure that were felt in exam rooms and labs.³

A startup’s rocket fuel meets biology’s limits The gamble was simple: if you could standardize IVF and market it like a consumer service, the resulting growth would justify the unicorn-level valuation. In the early days, the branding carried the weight. Clinics looked more like boutique hotels than hospitals.

For patients long frustrated by unpredictable scheduling and impersonal protocols, the experience finally felt more human.

But biology resists hurry. In October 2023, Bloomberg documented multiple embryohandling errors—mislabeled specimens, lost or destroyed embryos—across Kindbody sites over three years. Former and current employees described understaffed labs and inconsistent safety protocols they believed contributed to the setbacks; the company acknowledged incidents but said its error rate matched that

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of comparable programs.⁴ The podcast expanded on that reporting with firsthand accounts: a transfer canceled after a nearmiss labeling error, a thaw gone wrong, a couple discovering that an embryo was unaccounted for.

Behind each story lay a policy void—no universal protocols for labeling or chain-of-custody, and a patchwork of malpractice insurers and nondisclosure agreements (NDAs) that conceal patterns of misconduct.³

When profit targets enter the exam room Just before the 2023 holiday season, a pivotal collision between growth and care came to light. At a physician retreat that September, executives reportedly told more than 30 reproductive endocrinologists to raise monthly egg-retrieval counts by 12—a target that, for some, meant doubling procedures. Quotas were tied to pay and investor projections; several doctors warned the goal was “unreasonable” and could push IVF on patients who might succeed with less invasive care.

Kindbody defended the practice as an industry standard.⁵ Anyone who’s sat in on a fertility consult knows how subtle that pressure can feel. A 35-year-old with normal labs and a year of infertility might try ovulation induction with IUI before IVF. But if a dashboard treats retrievals as the key performance metric, “we should move quickly” becomes “we should move to retrieval.” By late 2025, Bloomberg reported patients being nudged toward costly cycles and add-ons with little evidence

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that they improve live-birth rates.⁶

The economics behind the white coats It wasn’t just culture—it was cash.

In November 2023, Bloomberg revealed Kindbody had cut its revenue forecast from $240 million to $186 million while seeking another $50 million and burning about $7 million a month.

Leadership churn and layoffs, according to insiders, reduced patient-facing staff just as the company was growing fastest.⁷

By June 2025, industry veteran David Stern became Kindbody’s third CEO in just seven years, stepping in to steady the company after years of rapid expansion and mounting scrutiny. Titles significantly influence perception, and staffing ratios influence outcomes. The crucial question now is whether bonuses are linked to retrieval counts or to patient experience and audited live-birth data, including cases that did not require IVF because they weren’t necessary.⁸

America’s fertility wild west Kindbody’s defense—that its incident rate matches competitors’—may or may not be true, but—even if correct—that’s hardly reassuring. It points to a regulatory vacuum. In the US, assisted reproduction exists in a gray area between consumer services and medical practices, with fractured oversight. Uniquely, federal rules require clinics to report all IVF cycle outcomes to the CDC’s National ART

Surveillance System; those data are validated against medical records and codified in the Federal Register.

In parallel, the American Society for Reproductive Medicine (ASRM), through its affiliated Society for Assisted Reproductive Technology (SART), collects IVF outcome data from member clinics on a voluntary basis and reviews outliers in reported results. But even that surveillance stops short of licensure.

It’s often said that no national body inspects or enforces standards in fertility care. That’s only partly true. FDA does inspect reproductive tissue establishments under its HCT/P framework—with frequency determined by risk and findings—but this oversight focuses on donor eligibility and tissue practices. Routine IVF using a patient’s own eggs and sperm largely falls outside that scope, leaving day-to-day lab safety to state rules and voluntary accreditation. New York State’s Department of Health maintains one of the stricter review processes, though even there the emphasis remains primarily on donor selection and the licensing of sperm and egg banks used by IVF clinics.

Across the Atlantic, a semigovernmental agency, the UK’s Human Fertilisation and Embryology Authority (HFEA) licenses the UK’s IVF clinics, inspects them, and publishes patient-friendly ‘add-on’ evidence ratings (traffic-light system, updated in recent years), which often do more harm than good.

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The US has no equivalent authority.⁹⁻¹⁰ Though some quality systems exist in the US to a certain extent through the FDA, which regulates donor eligibility and tissue safety under HCT/P rules,13 and labs can pursue voluntary accreditation, they do not equate to a legally binding license. Recent FDA guidance shows how narrow and procedural US oversight remains— far removed from the frontline clinical practices where labeling or storage failures actually occur.¹¹⁻¹² Meanwhile, courts have become blunt instruments of accountability.

After a 2018 cryotank failure at Pacific Fertility Center in San Francisco destroyed embryos and eggs, a federal jury awarded five patients $15 million in 2021—a landmark verdict that prompted later settlements. Litigation punishes, but it doesn’t prevent.14

thousands of dollars in out-ofpocket expenses, that provide no demonstrated benefit over limited testing and only rarely influence clinical management.

Few topics have drawn more scrutiny from CHR investigators than the rise of costly genetic screening tests known as preimplantation genetic testing for aneuploidy (PGT-A). Marketed as a safeguard that brings “peace of mind,” PGT-A promises to weed out embryos with chromosomal abnormalities before transfer.

In practice, it rarely delivers actionable insights—and, in many cases, may actually lower the chances of conception within an IVF cycle. Still, more than half of all IVF cycles in the United States now include PGT-A.

The test is just one of many so-called “add-ons”—a term coined by British researchers to describe the growing menu of unproven procedures tacked The market for hope onto fertility treatment. Others include endometrial scratching, To understand how an industry the intentional injury of the converges on high prices and soft uterine lining, promoted as a way evidence, picture a couple in their to boost implantation. Many of late 30s after a second miscarriage or a single 34-year-old debating egg these interventions show limited or no benefit for most patients, freezing as savings run low. Time and some may carry risks without pressure draws patients in, and improving live-birth rates. In the limited information keeps them United Kingdom, the Human there.

Fertilisation and Embryology Authority (HFEA) at least ranks Most Americans pay out of pocket such “innovations” by their or via employer benefits, meaning scientific credibility. In the United traditional insurers don’t police States, by contrast, they enter low-value care. In the absence of the marketplace unchecked—no clear guidelines, various “addreview, no regulation—then are ons” gain popularity among aggressively sold to patients and patients and providers. These physicians alike by clinics and evaluations may involve extensive immune panels, frequently costing industry partners.

Increasing evidence suggests that these tests and treatments not only do not reliably lead to higher live-birth rates but also often reduce pregnancy and live birth chances. This raises questions about their efficacy and value in fertility treatments. While the UK’s HFEA ranks the efficacy of these “add-ons” and makes evidence public, the US leaves it to doctors’ discretion and patients’ guesswork.15-16 The newest frontier, polygenic embryo screening (PGT-P), ranks embryos by polygenic scores to promise small lifetime risk reductions. A 2024 review in Human Reproduction Update found that marketing claims far outpace data and that discarding viable embryos poses ethical and clinical risks. The danger: what begins as a boutique and trendy option can normalize into routine practice long before science catches up.15

Vertical integration—with a caveat Kindbody’s best argument has always been that fragmentation breeds cost and confusion. By uniting benefit administration, clinics, labs, and EMRs—and offering donor and surrogacy services—Kindbody says it can streamline care and cut employer costs. That may help coordination, but it also concentrates conflicts of interest. When the same company designs the benefit, defines “covered” add-ons, and controls the clinic recommending them, it’s hard to tell where medicine ends and margins begin.²

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compliance rather than certified inspection.⁹⁻¹² Ethically, there’s no gray area. The ASRM Ethics Committee mandates full transparency when errors— or even close calls—occur with embryos or gametes. In a practice where life itself is the outcome, disclosure isn’t courtesy; it’s the condition of consent.17

The human ledger

Human Fertilisation and Embryology Authority (HFEA) traffic light ratings of commonly used IVF add-ons (Table courtesy of Armstrong, et al., 2019)

To make vertical integration truly patient-first, incentives must change. Retrieval quotas and revenue-linked pay are misguided, along with the quiet normalization of unproven add-ons that provide reassurance but deliver no measurable benefits.

What “standardization” should mean Everyone agrees on standardization—just not the kind tied to revenue dashboards. To achieve true standardization, it is essential to verify labels twice during transfers, continuously monitor cryostorage conditions, and have clear, practiced corrective action plans. Additionally, a system for reporting near-misses should be implemented to share these incidents nationally, promoting safety and preventing future errors. The US has inched forward through CDC validation updates, but still depends on voluntary

Behind every metric is someone staring at another negative test, someone hearing that transfer day is canceled, someone debating another cycle they can’t afford. For queer couples and single parents by choice, assisted reproduction isn’t elective—it’s the only route to a genetic child. For patients facing cancer treatment, the option of freezing eggs or embryos offers a precious opportunity to preserve their future. When investor updates take the spotlight, medicine transforms into the essential conduit for a growth strategy.

Kindbody’s story matters because it reveals the system’s design: what occurs when venture capital dictates clinical practices that regulation cannot keep up with.

If the company’s defense that its error rate is typical holds, the next step isn’t public relations damage control; it’s collective reform. Patients should not be treated as a revenue class. They deserve clinics where “disruption” describes paperwork, not the chain-of-custody of their embryos.

Real oversight—federal licensure, routine audits, mandatory nearmiss reporting, and transparent

financial disclosures would not impede scientific progress. It would slow sales. IVF is one of modern medicine’s most consequential advances. It deserves systems that protect its integrity as both science and service, not as a market to be scaled.

REFERENCES 1. Kindbody. Our New Funding and Reinventing Fertility Healthcare.

March 2, 2023.

2. Kindbody. Fertility Pioneer and Kindbody Founder Gina Bartasi Returns as CEO. PR Newswire. June 11, 2024.

3. Davalos J. IVF Disrupted: The Kindbody Story [podcast + series].

Bloomberg, 2023–2025.

4. Davalos J. Embryo Errors, Flooded Clinics: Kindbody and IVF’s Risky Business. Bloomberg. Oct 13, 2023.

5. Davalos J. Kindbody Pushes Doctors for More Egg Retrievals. Bloomberg. Dec 22, 2023.

6. Bloomberg News. Kindbody Doctors Push Expensive IVF Procedures, AddOns. Sept 26, 2025.

7. Davalos J. Startup Kindbody Cuts Sales Outlook, Seeks $50M. Nov 29, 2023.

8. Kindbody. Kindbody Names David Stern CEO. PR Newswire. June 10, 2025.

9. CDC. Reporting of Pregnancy Success Rates from ART Programs. Federal Register. Aug 29, 2024.

10. HFEA. How We Regulate.

11. FDA. Donor Eligibility for HCT/Ps. Jan 7, 2025.

12. HFEA. Treatment Add-Ons: Evidence Ratings.

13. FDA. Regulation of Human Cells and Tissues: Small Entity Compliance Guide.

2022.

14. Hawkins D. $15M Jury Award in Embryo Tank Failure Case. Washington Post. June 11, 2021.

15. Lensen SF et al. Endometrial Injury in IVF. Cochrane Review. 2021;6(6).

16. Capalbo A et al. Polygenic Disease Risk in Embryos. Hum Reprod Update.

2024;30(5).

17. ASRM Ethics Committee. Disclosure of Medical Errors Involving Gametes and Embryos. 2024.

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THE QUICK READS BRIEFING: Our editorial staff in this section offers brief and to-the-point summaries about specific medical conditions, fertility treatments, and/or other medically-related subjects that patients suggested to us as topics they wanted to be addressed in the CHRVOICE or which our staff identified as having recent received special attention in social media. Meant to be summaries, they, in contrast to most of the VOICE’s other content, are not routinely referenced or contain a reading list. They may be written by CHR editorial staff or may be the product of a single writer, in which case he/she will be identified. In other words, if the article has no author listed and has no references or reading list, you may just have to believe us!

THE ENEMY FROM WITHIN—When the maternal immune system turns against the paternal genome

By Lara Guijarro-Baude, MD, Research Intern at the FRM and the CHR, and Sonia Gayete-Lafuente, MD, PhD, Clinical Research Fellow at the FRM and the CHR. Both can be reached through the editorial office of the CHRVOICE.

BRIEFING: Among the many potential causes of pregnancy loss, immune mechanisms remain among the most complex and, at the same time, the most revealing. One particularly intriguing pathway involves the maternal immune response to male-specific antigens, known as anti-HY. The presence of antibodies against these Y-chromosome–encoded proteins (known as anti-HY antibodies) has been associated with recurrent pregnancy loss (RPL) and secondary infertility. Understanding this immune recognition helps explain why some women, after previously successful pregnancies, may later face unexpected reproductive challenges. In this article, we

The immunologic dialogue of pregnancy Pregnancy is, immunologically speaking, a controlled and highly specialized form of tolerance. The maternal immune system must distinguish without compromising protection between what is “self ” and what is paternal and, therefore,” semi-foreign.” This balance, maintained through countless molecular checkpoints, can, however, with relative ease in subtle ways can be disrupted, which then potentially can affect implantation, placentation, and fetal development.

Reproductive immunology and especially the immunological tolerance of the products of conception have been an important research subject at the CHR since its inception, and have led to innumerable published papers. The CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, was, indeed, already in 1978 appointed as the founding editorin-chief of the American Journal of Reproductive Immunology (a position he held for almost 20 years) and the founding Vice President of the American Society for Reproductive Immunology.

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The importance of reproductive immunology for reproductive success has, therefore, been deeply ingrained in research and clinical practice at the CHR since its founding in 1981 in Chicago. When the required balances in the maternal immune system are disrupted, a spectrum of reproductive dysfunctions can emerge, from implantation failure to repeated pregnancy loss (RPL) and even secondary infertility.

New insights into immunological miscarriage: Understanding the HY system HY antigens are proteins encoded by genes on the Y chromosome and expressed only in male fetuses.

When cells from a male fetus enter the maternal circulation, as fetal cells normally do, the mother’s immune system—even if her immune system otherwise has reprogrammed itself properly to make fetus and placenta immunologically invisible - may still recognize these Y-derived antigens as foreign. In some women, this immune recognition then leads to the production of anti-HY antibodies or the activation of HY-specific T cells.

Such a sensitization can only happen after a previous male pregnancy or after prior exposures to male

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antigens through blood transfusions from male donors, but sometimes also through inseminations and paternal lymphocyte transfusions (in the US, therefore, and for other reasons prohibited by the FDA, but in Mexico, Canada, and several European countries still offered). Consequently, most women experiencing this problem have had at least one prior (usually successful) pregnancy. Once established, anti-HY immune memory may influence all future pregnancies, but especially those with male fetuses.

From observation to clinical relevance The association between anti-HY immunity and adverse reproductive outcomes has been demonstrated in several studies. Women who experienced secondary RPL were more likely to test positive for anti-HY antibodies, particularly when their first child was a male.

At CHR, we view such findings not as isolated matters or curiosities, but as part of a broader immunologic continuum affecting reproductive function. AntiHY antibodies, like other immune markers we usually study in our patients, represent a tangible manifestation of how immune reactions intersect with reproduction, and offer a valuable insight into the mechanisms by which immune memory can interfere with implantation and tolerance.

Clinical implications and the CHR perspective Although standardized testing for anti-HY antibodies is still largely confined to research settings, the CHR has, especially in patients with “unexplained” RPL, long emphasized the clinical importance of immune evaluations. Although the presence of anti-HY antibodies is a significant risk factor for reproductive failure and, therefore, can be meaningful in specific contexts, these antibodies are not by themselves diagnostic and, therefore, are not by themselves predictive of miscarriage. It, indeed, appears that immune factors adversely affecting reproductive success often become clinically relevant not in isolation, but when several of them converge in the same patient. At the CHR, we use the idiom “hyperactive immune system” to describe such circumstances, which always requires that a patient

demonstrate more than just one laboratory test suggestive of immune system hyperactivity, whether reflective of autoimmunity, inflammation, and/or a hyper-allergic state. In all these circumstances, a hyperactive immune system has been demonstrated to induce poorly the necessary tolerance pathways an implanting embryo requires to already be in place when trying to implant, and then, without any input and support from the mother whatsoever for at least 10 days, as observed by Deglincerti and Brivanlou in their 2016 study (see reading list), successfully develops.

Anti-paternal immunity tends to have a stronger clinical effect when it coexists with other unfavorable immune conditions, such as HLA similarity between the parents, a so-called KIR AA haplotype paired with fetal HLA-C2, which reduces proper placentation (a still somewhat controversial topic); a pro-inflammatory Th1-skewed (rather than Th2) immune profile, or even other autoantibodies.

Some investigators have also suggested that certain thrombophilic variants may play a role in cases of RPL. Still, thrombophilia, in the CHR’s opinion, does not play a significant role in RPL because at least one well-designed study relatively recently demonstrated absolutely no outcome advantages from the use of anticoagulants in women with RPL. The CHR, therefore, has in such patients discontinued the use of anticoagulants, unless other medical indications exist.

What all of this, therefore, in principle means is that when multiple potentially detrimental mechanisms overlap, producing a” hyperactive” immune system, they can reinforce each other and create a setting in which otherwise viable pregnancies are rejected by the maternal immune system.

Therefore, understanding a patient’s immunologic profile comprehensively allows for more individualized management. Modulating immune activity (through numerous interventions, ranging from corticosteroid treatment to intravenous immunoglobulins (IVIg) or other immune-modulating therapies, like newer socalled biologicals) may restore the balance necessary for successful implantation and sustained pregnancy.

The key lies in recognizing immune dysregulation as a dynamic process rather than a fixed condition.

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A broader reflection on immunologic memory The case of anti-HY immunity is a compelling reminder that the immune system’s ability to remember is both a gift and a liability. In fighting infection, immune memory protects us. In reproduction, however, the same memory can sometimes interfere with tolerance toward the semiallogenic fetus, leading to harm. It in this context is also important to remember that in cases of egg donorrecipient pregnancies and when gestational carriers (GCs) carry a couple’s pregnancy, the pregnancy is not a semi-allograft but a full, 100%, allograft. This is, indeed, the likely reason for recent reports in the literature pointing out surprisingly high pregnancy complications in GC pregnancies (see reading list).

To date, Rh(D) incompatibility remains the classical model of maternal sensitization to fetal antigens (as well as sensitization to other erythrocyte antigens such as anti-Kell, etc.), but these mechanisms primarily affect the fetal circulation in later stages of pregnancy rather than implantation and early gestation. By contrast, HY-antigens currently represent the bestcharacterized example of antigen-specific immune memory that can directly disrupt maternal-fetal tolerance and contribute to RPL. Yet, it is unlikely that HY-antigens are the only relevant epitopes detected by the maternal immune system. It is plausible that many other paternal or fetal antigens (still undefined) may trigger similar immune responses in susceptible women, particularly after a previous pregnancy. Future research should therefore expand beyond broad immune markers to explore specific antigenic targets and how the maternal immune system responds to them.

Nevertheless, understanding these mechanisms is only the first step. If we aim to translate immunologic insights into clinical care, we also need accessible diagnostic tools. At present, even well-established assays for HY immunity are difficult to obtain in practice. Developing standardized, routinely available testing platforms will be essential to identify high-risk patients more accurately and to guide personalized treatment.

Finally, identification and characterization of clinically relevant antigens could open the door to preventive strategies aimed at modulating maternal immune sensitization. In such a scenario, even vaccine-like interventions might become feasible, similarly to how anti-D prophylaxis revolutionized the management of Rh-negative pregnancies. Such ideas may seem ambitious today, but could potentially become standard of care in selected cases of RPL, expanding targeted therapies in reproductive medicine.

READING LIST Christiansen OB, Steffensen R, Nielsen HS. The impact of anti-HY responses on outcome in current and subsequent pregnancies of patients with recurrent pregnancy losses. J Reprod Immunol. 2010 May;85(1): 9-14.

Christiansen OB, Steffensen R, Nielsen HS. Anti-HY responses in pregnancy disorders. Am J Reprod Immunol. 2011 Jul;66 Suppl 1:93-100.

Deglincerti A, Croft GF, Pietila LN, Zernicka-Goetz M, Siggia ED, Brivanlou AH. Self-organization of the in vitro attached human embryo. Nature. 2016 May 12;533(7602):251-4.

Kolte AM, Steffensen R, Christiansen OB, Nielsen HS. Maternal HY-restricting HLA class II alleles are associated with poor long-term outcome in recurrent pregnancy loss after a boy. Am J Reprod Immunol. 2016 Nov;76(5):400-405.

Masjedi AD, Mandelbaum RS, Erickson KV, Anderson ZS, Matsuzaki S, Ouzounian JG, Matsuo K, Paulson RJ. National-level assessment of gestational carrier pregnancies in the United States.

J Assist Reprod Genet. 2025 Jan;42(1):201-211.

Nielsen HS, Steffensen R, Varming K, Van Halteren AG, Spierings E, Ryder LP, Goulmy E, Christiansen OB. Association of HYrestricting HLA class II alleles with pregnancy outcome in patients with recurrent miscarriage subsequent to a firstborn boy.

Hum Mol Genet. 2009 May 1;18(9):1684-91.

Nielsen HS, Wu F, Aghai Z, Steffensen R, van Halteren AG, Spierings E, Christiansen OB, Miklos D, Goulmy E. H-Y antibody titers are increased in unexplained secondary recurrent miscarriage patients and associated with a low male: female ratio in subsequent live births. Hum Reprod. 2010 Nov;25(11):2745-52.

Nielsen HS. Secondary recurrent miscarriage and H-Y immunity.

Hum Reprod Update. 2011 Jul-Aug;17(4):558-74. doi: 10.1093/ humupd/dmr005. Epub 2011 April 11.

Velez MP, Ivanova M, Shellenberger J, Pudwell J, Ray JG. Severe Maternal and Neonatal Morbidity Among Gestational Carriers: A Cohort Study. Ann Intern Med. 2024 Nov;177(11):1482-1488. doi: 10.7326/M24-0417. Epub 2024 September 24. Erratum in: Ann Intern Med. 2025 Mar;178(3):456.

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OPINION: ETHICS IN THE TREATMENT OF INFERTILITY – Knowing when to stop and finding peace in the decision

By Sonia Gayete-Lafuente, MD, PhD, Clinical Research Fellow at the FRM and the CHR. She can be reached through the editorial office of the CHRVOICE.

BRIEFING: The Center for Human Reproduction (CHR) has, over many years worldwide, been recognized for pushing the boundaries of what is biologically possible in human reproduction. For decades, our mission has been to challenge the widespread belief that advanced maternal age necessarily means the end of fertility.

Indeed, we are proud to serve what with great likelihood is the oldest population of infertility patients in the world (median age in 2024 was 45 years vs. 36 years for all US IVF clinics). Many of our scientific contributions have emerged from this very pursuit–understanding, extending, and redefining the limits of reproductive aging.

Being at the frontline of reproductive medicine, however, daily brings us face-to-face with one of the most profound questions in medicine: when is it the right time (or the wrong time) to stop treatments?

Understanding reproductive futility In reproductive medicine, “futility” does not refer to the absence of effort or care, but to the point where the likelihood of achieving a live birth becomes so low that continuing treatment no longer represents a reasonable medical option. Yet, of course, defining that “reasonable chance” is scientifically and ethically complex.

The concept first emerged in clinical ethics in the context of life-sustaining treatments—deciding when continuing therapy no longer benefits the patient.

In fertility care, however, the situation is uniquely different: we are not talking about sustaining life, but about attempting to create one, often after years of emotional investment, physical exhaustion, and financial sacrifice. The moral, mental, and biological dimensions partake here in ways really no other medical field experiences.

From a strictly biological standpoint, the data are clear. Ovarian aging progresses inexorably with time.

Numbers and quality of oocytes decline sharply after age 40, and by the mid-40s, the probability of obtaining a chromosomally normal embryo from one’s own eggs becomes quite low. Even among those rare “good embryos,” implantation and live birth rates are moreover limited.

At CHR, we have developed and refined protocols aimed at maximizing ovarian response in older women, very often achieving pregnancies in cases

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where other centers have denied treatment in the first place because of too far advanced female age.

Yet, despite these advances, we also recognize that sometimes biology ultimately sets a limit that even the best science can currently not yet overcome (though we are working on it!).

Ethical responsibilities: excessive hope vs. realism For physicians and patients, this reality poses a profound ethical challenge with a remarkable emotional toll for the intended parents. On the one hand, assisted attempts to conception thrive on hope and perseverance; on the other hand, they must remain grounded in truth and responsibility.

To recommend continuing treatments that carry no meaningful chance of success risks crossing the line from compassionate care to emotional or even financial exploitation based on “excessive or false hope,” even if unintended. Conversely, to give up too early can feel to patients like a betrayal of their dreams and efforts.

But what’s “too early” or “too late”?

Navigating this delicate space is undoubtedly one of the hardest tasks in fertility care and a constant point of discussion in the CHR’s weekly quality control conference.

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At CHR, we have come to believe that we are not qualified to tell our patients how to live their lives.

But we are very qualified—maybe more so than many of our colleagues at other clinics—to inform our patients as accurately as possible of available treatment options and of their usually quite limited prognosis in establishing pregnancy and achieving birth in comparison to younger women. We have come to understand that our function as physicians is to guide and support, but never to impose on a patient reality that may differ from our own. We see our role as helping patients understand their chances, in the most transparent way possible, so that decisions are made not only with full (legal) informed consent, but with acceptance of cultural, religious, and other personal considerations which are often not addressed in medical risk—and cost-benefit considerations. This includes discussing not only statistical probabilities but also emotional readiness, physical burden, considering possible financial challenges, and reaching a deep understanding of what’s the patient’s personal definition of success.

Yet offering false reassurance, or continuing treatment simply to avoid disappointment, can be equally harmful. True empathy in medicine means being able to sit with a patient’s grief, without rushing to fix it. It means validating frustration, acknowledging loss—not only the loss of potential motherhood, but also the loss of a long-held identity, of plans for the future, and of years and resources devoted to this pursuit.

Some patients, fully informed, may still choose to pursue—sometimes repeatedly—“one last cycle”, not because they expect success, but because they need to reach emotional closure and wish to avoid later regrets. This, understandably, can be especially important for patients who have come a long way in their reproductive journey and invested so much of themselves. For them, “letting go of the dream they have fought so hard for” can feel impossible— particularly when they feel they recently came very close to succeeding. Others may, in contrast, decide to stop sooner, fully ready to open a new chapter in their lives. And truly, both decisions, when made consciously and intentionally, are equally valid and deserve our respect.

Would alternative paths—such as donor eggs, adoption, or child-free living—align better with her life goals now?

The challenge of communication, compassion without paternalism Discussing futility requires exceptional sensitivity.

Clinicians must balance compassion with honesty, avoiding both paternalism and condescension. Telling a patient that “there is no hope” can be emotionally devastating and, at times, scientifically inaccurate because medicine is not always an absolutely predictable science, and rare exceptions do occur.

Shared decision-making and “peace of mind” When approaching the question of whether to continue or stop treatments, it can be helpful to consider all of the following: What are the biological odds of success with another cycle?

What would be the emotional and physical cost?

Has the patient achieved her own sense of “enough”?

For many women and couples, stopping treatments feels like ending a life chapter. At CHR, we have seen again and again how difficult, yet how liberating, that process can be when handled with transparency, emotional support, and respect.

Reaching “peace of mind” rarely happens overnight.

It is often a gradual process, emerging through conversation, reflection, and sometimes through mourning. But for those who reach it, the relief can be profound. They can finally reclaim their time, energy, and emotional space, no longer defined by the next treatment cycle. This sense of closure leads to healing and reframes the story from one of failure to one of courage: having tried, endured, and known when to move forward.

If they reach that point, they will never look back, wondering what might have been if they had only tried a little longer. It is our responsibility to protect our patients from later regrets for not having “tried hard enough.”

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CHR QUICK READS - A LITTLE MORE DETAIL

A bit about Anti-Müllerian Hormone, Intrauterine Inseminations, & Melatonin BRIEFING: The CHRVOICE in this section offers a little more detailed and referenced insights than the preceding Quick Reads section about relevant medical conditions to fertility, fertility treatments, and/ or other medically related subjects. Meant as brief reviews in contrast to the preceding section of summaries, these articles also offer detailed reference lists, so that interested readers can find easy access to further information.

UNDERSTANDING AMH (ANTI-MÜLLERIAN HORMONE) AND ITS ROLE IN FERTILITY

BRIEFING: Anti-Müllerian Hormone (AMH) has become a critical marker in reproductive medicine, offering key insights into ovarian reserve and predicting fertility potential. By measuring AMH levels, clinicians gain important information about the number of eggs remaining in the ovaries of patients, helping guide decisions related to family planning, fertility treatments, and overall reproductive health.

So, what is Anti-Müllerian Hormone (AMH) really all about?

AMH is a glycoprotein hormone secreted by the granulosa cells surrounding the egg in very small follicles. Here is a little more background: Women are born with all of their eggs already in place in very tiny and primitive follicles, called primordial follicles, and sitting in ovaries right below the outer their outer capsule. From birth on, this original pool of follicles constantly shrinks in both of a woman’s ovaries (in reality, the loss of follicles, starts in females already before birth of and, indeed, slows after birth and slows even more after menarche (start of menses), while AMH production in female fetuses starts at ca. 36 weeks of their gestation, ca. 4 weeks before their birth.1 The likely dominant process in this shrinkage of OR— certainly after menarche—is so-called recruitment.

This means that, in a process that is still not fully understood, but to a significant degree involves AMH, some of these very primitive follicles are constantly recruited into what is called folliculogenesis, i.e., a quite length maturation process of follicles and of the oocytes (eggs) that those follicles contain.

This journey takes months (see the Figure to the right) 34

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before maturing follicles become responsive to hormones called gonadotropins, which are the medical drugs infertile women self-inject when getting socalled injectable fertility drugs.

Since the AMH hormone is produced by the granulosa cells of follicles, their production rate (and ultimately the blood levels of AMH) reflects the number of follicles that are undergoing this maturation journey.

The total of all follicles at different stages in this journey after recruitment from their primitive resting stage is, therefore, increasingly called the functional ovarian reserve (FOR), a term, indeed, first proposed by investigators from our CHR. The FOR must, however, be distinguished from the total ovarian reserve (usually just abbreviated as OR), which includes all follicles in a woman’s ovaries, meaning FOR as well as resting OR (all the follicles still at primitive resting state and, therefore, not significantly contributing to a woman’s AMH levels).

Studies have, however, suggested that FOR always correlates to OR. The early stages of folliculogenesis, including the time period between primary and small antral stages, are

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complete number of all follicles remaining in ovaries, including resting follicles which, of course, have only very little to do with AMH levels per se and functional assessments of an infertility patients at any given moment.

The Figure demonstrates schematically the recruitment of primordial follicles out of resting stages into folliculogenesis, a process to a significant degree controlled by AMH. The stage between primary and small antral follicles is called the smallgrowing follicle stage and is the only stage in which medical interventions into follicle development and, therefore, egg quality (with androgen and with human growth hormone) have been so far successful.

also called the small growing stages and, of course, contain still immature eggs in a woman’s ovaries.2 AMH production begins in female fetuses around 36 ­ weeks of gestation and continues throughout reproductive life, gradually declining as egg supply diminishes with age.1 A key feature of AMH is that, unlike other reproductive hormones such as follicle-stimulating hormone (FSH) or estradiol, which fluctuate significantly across the menstrual cycle, its levels remain relatively stable. This consistency allows clinicians to measure AMH at any point during the cycle, making it especially useful in fertility evaluations.³

Why AMH is important for fertility As already noted, AMH levels correlate with the number of actively growing follicles in the ovaries, defining AMH levels as a strong indicator of ovarian reserve.⁴ Higher AMH levels generally indicate a greater ovarian reserve. They are often seen in younger women or those with conditions such as polycystic ovary syndrome (PCOS), a condition marked by an abundance of small follicles that produce elevated AMH levels.⁵ In contrast, lower AMH levels may suggest low FOR (LFOR) by many also called diminished ovarian reserve (DOR), a term we do not like because, as noted before, OR stands for the

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But whether the condition is called LFOR or DOR, this diagnosis indicates that an infertile woman has fewer remaining eggs in her ovaries than most women of her age (ca. 90%, indeed) and that she, therefore, likely suffers from reduced fertility, again given a term increasingly used in the field by investigators from the CHR, premature ovarian aging (POA).

What are the clinical uses of AMH testing?

Assessing ovarian reserve As already noted, AMH is widely used to estimate the FOR in women experiencing infertility or in other indications, like, for example, when considering delaying their childbearing and/or are considering fertility preservation via egg and/or embryo cryopreservation. While neither AMH nor any other laboratory test, alone, can predict whether a woman will conceive naturally, AMH, nevertheless, provides context by allowing for an educated guess as to how many eggs approximately remain in a patient’s ovaries, helping set expectations and guide in this way clinical decision-making.³ Predicting responses to ovarian stimulation In assisted reproductive technologies (ART) like in vitro fertilization (IVF), AMH can help in predicting how a woman’s ovaries will respond to hormonal stimulation with gonadotropins and other fertility drugs. Women with higher AMH tend to produce more eggs in response to stimulation, while those with low AMH may need adjusted medication dosages or alternative treatment plans.⁴ Diagnosing and managing polycystic ovary syndrome (PCOS) Elevated AMH levels are frequently seen in women with PCOS due to the increased number of small follicles. While AMH for the longest time has been excluded from criteria defining a diagnosis of PCOS,5 several recent studies have demonstrated that this has been a mistake because—at least age-specific—MH levels are excellent predictors of PCOS and, even if not 35

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diagnostic on its own, it can support a PCOS diagnosis Summary and be used to monitor the effectiveness of treatments.6 Anti-Müllerian Hormone is a powerful and reliable indicator of ovarian reserve. Produced by follicles, it Limitations and considerations also plays a very important role in determining how many follicles are recruited and released out of their AMH is a useful marker, but it does provide only dormant stage in ovaries into folliculogenesis and, minimal information about egg quality or pregnancy therefore, into the active fertility process. success. Many women with low AMH still conceive naturally, while some with relatively high AMH may face challenges due to other factors, such as egg quality By measuring AMH levels, healthcare providers, therefore, can gain additional insight into a patient’s or uterine health.7 Additionally, AMH levels can be remaining quantity of eggs, which can guide fertility influenced by several variables, including smoking, planning, treatment decisions, and conversations about hormonal contraceptives, vitamin D deficiency, and 3,8 reproductive lifespan. AMH is, however, just one part assay variability between labs. Therefore, AMH results should always be interpreted in the context of a of the fertility puzzle and must be it be interpreted in the context of age, menstrual history, and other comprehensive fertility evaluation. relevant clinical factors. There undoubtedly is more to be learned about the physiological function s of AMH. What do AMH Levels then really mean?

Some, indeed, may go back to the fact that ovaries and adrenal glands share an embryological primordium AMH levels are typically measured (in the US) in and adrenals—like ovaries—contain a very high nanograms per milliliter (ng/mL) or (in, for example, density of AMH receptors. Why? Nobody knows! the UK) in picomoles per liter (pmol/L). Like most hormones, they, should be evaluated based on ageReferences specific normal and abnormal levels; but though 1. Sahmay S, Atakul N, Onur MG. Anti-Müllerian hormone: A appropriate curves can already be obtained from the marker for ovarian reserve and ovarian aging. J Turk Ger Gynecol literature, because diagnostic laboratories still report Assoc. 2018;19(4):252-257. doi:10.4274/jtgga.2018.0120 non-age-specific general values, that, likely, will not 2. La Marca A, Volpe A. Anti-Müllerian hormone (AMH) in female reproduction: is measurement of circulating AMH a useful change in the near future for most reproductively involved hormones, including AMH. Current general tool? Clin Endocrinol (Oxf). 2006;64(6):603-610. doi:10.1111/ j.1365-2265.2006.02591.x guidelines therefore claim—in our opinion, very 3. Nelson SM, Klein BM, Arce JC. Comparison of antimüllerian inappropriately—the following: hormone levels and antral follicle count as predictor of ovarian • • •

High AMH (>4.0 ng/mL) may indicate PCOS or high FOR, for potentially other reasons Normal AMH (1.0–4.0 ng/mL) suggests normal ovarian reserve.

Low AMH (<1.0 ng/mL) suggests LFOR/DOR, impacting female fertility adversely.

The absurdity of this result classification for AMH should be, of course immediately obvious but, curiously, has neither been in the past our is in current practice considered. Here is just one very obvious example in support of our statement: An AMH of < 1.0ng/mL is, of course, a clear sign of LFOR/DOR on a 25-year-old woman; but in a 45-year-old patient this same value will, of course be reflective of an amazingly excellent FOR.

response to controlled ovarian stimulation in good-prognosis patients. Fertil Steril. 2015;103(2):363-370. doi:10.1016/j. fertnstert.2014.10.004 4. Broer SL, Broekmans FJ, Fauser BC. Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications.

Hum Reprod Update. 2014;20(5):688-701. doi:10.1093/humupd/ dmu020 5. Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Müllerian hormone in women. Hum Reprod Update. 2014;20(3):370-385. doi:10.1093/humupd/dmt062 6. Van der Ham, et al., Anti-müllerian hormone as as a diagnostic biomarker for polycystic ovary syndrome and polycystic ovarian morphology: a systematic review and meta-analysis. Fertil Steril 2024; 122(4):727-739 7. Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril. 2022;117(6):1145-1152. doi:10.1016/j.fertnstert.2022.03.022 8. Sowers MF, Eyvazzadeh A, Jannausch M. Anti-Müllerian hormone and inhibin B in the definition of ovarian aging and the menopausal transition. J Clin Endocrinol Metab. 2010;95(4):18171824. doi:10.1210/jc.2009-2287

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INTRAUTERINE INSEMINATIONS (IUIs): What are they, and what are they for?

BRIEFING: Infertility affects roughly 1 in 8 couples overall.1 Fortunately, reproductive medicine offers several tools to help overcome it, including one of the most widely used options—intrauterine insemination (IUI): a relatively low-cost, low-intervention fertility treatment that can significantly improve the odds of conception in the right context.2 This brief article breaks down everything one needs to know about IUIs, how they work, who benefits most from them, when they are most effective, and what experts believe contributes to the highest chances of success for patients.

Let’s begin with what an IUI is Like in vitro fertilization (IVF), IUI is a form of socalled assisted reproductive technology (ART). In contrast to IVF, in which one or more embryos are placed into a woman’s uterus in an attempt to achieve pregnancy, an IUI, however, at approximate the time of ovulation, places washed and concentrated sperm directly into the uterus.3 While in IVF, the hope is that—once in the endometrial cavity—an embryo will implant and develop into a normal pregnancy, in an IUI, the desired goal of achieving a pregnancy is much further removed.

In an IUI, the principal purpose of the procedure is to bring the semen closer to the (in most cases) single egg one of the woman’s ovaries releases at ovulation into one of her two tubes’ so-called fimbriated distal end, where egg and sperm in a natural conception usually meet and where the sperm then fertilizes the egg. The resultant so-called zygote (the embryo at the single cell stage) then starts over five days a journey down the fallopian tube toward the uterus, during which it divides into 2, 4, 8, and ultimately somewhere between 150 and 250 cells when it enters the endometrial cavity usually at the so-called blastocyst stage. Only at that point, therefore, does an IUI meet the starting point of an IVF cycle, the goal of having an embryo in the endometrial cavity in the hope that it will implant and lead to a normal pregnancy.

in some patients the risk of multiple births with IUIs can by far exceed the risks of IVF); (iv) IUIs are more “natural:” and, finally, (vi) IUIs are, on a single cycle basis, also less costly.

But hold on for a moment; shouldn’t cost and outcome be related? Of course, they should and, therefore, one must ask, how do pregnancy and live birth rates compare between IUIs and IVF cycles?

And the answer to this question will likely change your opinion on the cost-effectiveness of IUI vs. IVF because the chance of pregnancy is at least three times better with IVF than IUI (more on that below, but this ratio even applies in IUI cycles augmented by “fertility drugs” and even further improves in favor of IVF with advancing female age). In other words, if one looks at cost with reference to pregnancy chances, IUIs suddenly look much less enticing since the costs

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So why not go in all cases of infertility straight into IVF? The answer is simple and there are several good reasons why IUIs in general are considered a first line of treatment in comparison to IVF: (i) IUIs are technically simpler; (ii) IUIs are less invasive for the patient; (iii) IUIs in most patients, therefore, have less risk (not that IVF is not also a very safe procedure and 37

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of three IUI cycles come very close to the costs for one IVF cycle, and the required patient effort and time to pregnancy will, of course, be greater with three IUIs. Interestingly, most fertility providers nevertheless still recommend (and insurance companies often mandate) up to three IUI cycles before switching to IVF. Especially in older women, the CHR—bluntly speaking—considers this, on clinical as well as economic grounds, foolish!

One more point: In IUIs, the principal practical goal of the procedure is to bypass potential barriers for sperm in reaching the egg in the most distal part of a fallopian tube. Semen is, of course, deposited in the vagina during intercourse. Based on its motility, it then has to find its way through the uterine cervix and its at times thick mucus into the endometrial cavity (where an IUI deposits the sperm). Whether after intercourse or after IUI, sperm then have, however, still find their way into one or both fallopian ostia and “swim” upward all the way toward the fimbriated end of the fallopian tube to meet the egg. It is at that point, in the most distal part of the fallopian tube, where fertilization occurs.3 As already alluded to, treatment success with IUI can be improved if the cycle is combined with the use of “fertility drugs” which convert a woman’s natural single-egg-ovulation into multiple-egg-ovulation. Such treatments, however, of course, also increase the risk of multiple births (if that is considered a risk) and also increase cycle costs because, especially in the U.S, the injectable gonadotropin drugs are quite expensive.

The insemination process is, however, quick and typically painless and, therefore, an office procedure, while an IVF cycle is usually performed in an operating room under IV sedation by an anesthesiologist. The American Society for Reproductive Medicine (ASRM) suggests that IUIs are most beneficial when there is an identifiable and treatable cause of infertility that can be overcome by an IUI or when donor sperm is being used.4 What, however, also must be considered is that before IUI treatments are initiated, evidence must be established that a patient has normally functioning fallopian and patent tubes because IUIs will, of course, not be successful in bringing semen closer to the egg if semen cannot ascend further toward the egg in an obstructed or severely damaged fallopian tube.

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IUIs, therefore, should never be performed without a prior hysterosalpingogram (HSG) to confirm tubal patency and normal tubal architecture, especially the fimbriated charged with catching the egg released by the ovary during ovulation, must be normal.

One more point of caution in that regard: The CHR’s investigators, many years ago, performed a study in which they compared their interpretation of HSG films to those of radiology colleagues. And what they found was quite astonishing: In over half of all cases, the CHR’s interpretation greatly varied from that of our radiology colleagues, and here is why:

The IUI process: Step by step IUI is usually performed in a fertility clinic and involves multiple stages of preparation. Here’s a closer look at what to expect: Ovulation monitoring Precise timing is critical. Ovulation may be tracked naturally or with medications that stimulate egg development, such as clomiphene citrate, letrozole, or gonadotropins.4 Monitoring may involve: • Ultrasound exams to track follicle growth • Bloodwork to measure hormone levels (especially estradiol and LH) • Home ovulation predictor kits (OPKs), which detect the LH surge 24–36 hours before ovulation • Once ovulation is imminent or triggered, the clinic will schedule the IUI for optimal timing.4 Sperm collection and washing A sperm sample—either from a partner or a donor— is collected and specially prepared in the lab. This process, called “washing,” involves removing the fluid around the sperm and separating the healthiest ones.5 It’s a standard procedure that helps improve the chances of fertilization and makes the procedure more comfortable for the uterus.5 Inseminations During the IUI procedure, a thin, flexible catheter is inserted through the cervix to deliver the prepared sperm directly into the uterus. It takes only a few minutes and is generally painless, though some may experience mild cramping.3

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The two-week wait After the procedure, patients can typically resume daily activities. Depending on the type of cycle and medications used,4 a pregnancy test is performed around two weeks later.

Who might benefit from IUI?

IUI is considered a first-line treatment for several types of infertility and is often recommended in the following situations:4,6 Unexplained infertility: For couples who’ve undergone evaluation with no identifiable cause, IUI paired with ovulation-inducing medications can increase pregnancy rates compared to timed intercourse alone.6 Mild male factor infertility: IUI can help in cases of mildly low sperm count or motility, where washed sperm improves the odds of reaching the egg.7 However, for severe male infertility—such as very low sperm count or poor motility—IVF with intracytoplasmic sperm injection (ICSI) is generally recommended.

Cervical factor infertility: If cervical mucus is too dense or prevents sperm from passing through, IUI bypasses the cervix by placing sperm directly into the uterus.4 Ovulatory disorders: Patients with irregular or absent ovulation (e.g., PCOS) may use IUI alongside medications that stimulate or regulate ovulation.4 Use of donor sperm: Single women, same-sex female couples, or couples with severe male factor infertility may choose IUI with anonymous or directed donor sperm.4

When is IUI not recommended?

While IUI is helpful in many cases, it is less effective or not recommended in the following scenarios:3,4 • • • •

Blocked fallopian tubes or severe tubal damage Severe male factor infertility (e.g., very low sperm count or motility) using the male partner’s sperm Advanced maternal age with diminished ovarian reserve Endometriosis, especially moderate to severe

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For all of these conditions, IVF may offer a higher chance of success.4,8

What are the success rates?

IUI success rates vary depending on age, diagnosis, medication use, and the number of cycles attempted.

In general, the following applies: • • • •

Women under 35 have a 10–20% chance of pregnancy per cycle.4,9 Success rates decline with age, especially after 40.4 Combining IUI with ovulation-stimulating medications tends to yield higher success than natural cycles.9 Most fertility specialists recommend trying 3–4 cycles of IUI before considering a different treatment path.4

Risks and considerations IUI is safe, but like any medical procedure, it comes with potential risks, including: • •

•

Mild cramping or spotting after the procedure.3,4 Ovarian hyperstimulation syndrome (OHSS), especially if injectable fertility drugs are used,4 though fortunately these days, in competent hands, a rare event.

Multiple pregnancies (twins or more), especially with oral or injectable ovulation medications.4,9

Monitoring and tailoring treatment protocols can reduce these risks significantly.3

Final thoughts: Is IUI right for you?

IUI can be a valuable step in the fertility journey—less invasive and at times more affordable than IVF, it at times can also be more effective than trying naturally.

It is believed to be particularly helpful for those with mild male factor infertility, cervical issues, or cases where donor sperm is needed.

That said, not everyone is an ideal candidate. A thorough fertility workup, which typically includes a review of medical history, physical examination, and various tests to assess fertility, can help determine whether IUI is an appropriate and strategic next step.

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It’s important to have an open discussion with your fertility specialist about your options and especially about concerns you may have.4,9

References 1. Centers for Disease Control and Prevention. Infertility. US Department of Health and Human Services. Published 2023.

2. Chandra A, Copen CE, Stephen EH. Infertility and impaired fecundity in the United States, 1982–2010: Data from the National Survey of Family Growth. Natl Health Stat Report. 2013;(67):1-18.

3. American Society for Reproductive Medicine. Intrauterine insemination (IUI): patient fact sheet. Published 2023.

4. Practice Committee of the American Society for Reproductive Medicine. Intrauterine insemination: a committee opinion. Fertil Steril. 2022;118(4):683-696.

5. Ombelet W, Dhont N, Thijssen A, Bosmans E, Kruger T. Semen quality and intrauterine insemination. Reprod Biomed Online. 2014;28(3):300-309.

6. Bhattacharya S, Harrild K, Mollison J, et al. Clomiphene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: a randomized controlled trial. BMJ. 2008;337:a716.

7. Zeyneloglu HB, Onalan G. Intrauterine insemination (IUI) for the treatment of unexplained infertility. Reprod Biomed Online.

2009;19(Suppl 4):63-70.

8. Kandavel V, Rajakumar C, Kumaran A. Intrauterine insemination: current evidence. J Hum Reprod Sci. 2017;10(1):3-7.

9. Merviel P, Heraud MH, Grenier N, Lourdel E, Sanguinet P, Copin H. Predictive factors for pregnancy after intrauterine insemination (IUI): an analysis of 1038 cycles and a review of the literature. Fertil Steril. 2010;93(1):79-88.

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An Outside Science Contribution to the CHRVOICE

MELATONIN TO THE RESCUE in female infertility and beyond

By Jan Tesarik, MD, PhD, Medical Director and Chief Scientist, Molecular Assisted Reproduction and Genetics (MARGen) Clinic, Gracia 36, 18002 Granada, Spain. He can be contacted through the CHRVOICE or directly at jantesarik13@gmail.com, and Raquel Mendoza Tesarik, PhD, Laboratory Director, MARGen Clinic, Granada, Spain. She can be contacted through the VOICE directly at mendozatesarik@gmail.com.

CHR

BRIEFING: Despite ongoing progress with assisted reproduction technologies (ARTs), average success rates remain relatively low. To cope with this reality, a variety of adjuvant treatments have been suggested during and/or after the attempts at ART. Melatonin appears to be one of these agents, though it has been widely overlooked.

However, unlike other adjuvants, it is more powerful and acts at various levels of the female reproductive system. Our recent review article, published in Biomedicines1 summarized current knowledge in support of melatonin use in ovarian failure, polycystic ovary syndrome (PCOS), endometriosis and adenomyosis, recurrent implantation failure (RIF), suboptimal in vitro embryo growth, and impaired placental function leading to early spontaneous abortions. The beneficial effects of melatonin on human health, moreover, go beyond female infertility and general aging, also encompassing the defense against respiratory viral diseases and certain forms of cancer. The full-length paper contains a complete list of pertinent references.1 *This article is based on a fulllength article by these two authors that recently appears in Biomedicines1*

Melatonin has been used to boost female fertility and in vitro fertilization (IVF) outcomes since the late 2000s. Equivalent to other antioxidants used for this indication, it was, however, long considered a mere antioxidant, an idea that several recent studies have shattered.1 For two reasons, melatonin is actually more effective than other antioxidants: First, melatonin acts as an indirect antioxidant, through its hormonal action on its specific receptors on the cell surface, and also as a direct reactive oxygen species (ROS) scavenger (Figure 1 to the right). Second, melatonin, unlike many other antioxidants, does not switch between oxidationFigure 1. Demonstrates alternative modes of melatonin action in target cells. Melatonin can act via its specific receptors (MT1 preventing and oxidation-supporting actions. The and MT2) to activate the production of antioxidant enzymes, reason is that, once the antioxidant effect has taken such as superoxide dismutase (SOD), glutathione peroxidase place, melatonin does not return to its original (GPx), or catalase. In addition, as an amphiphilic molecule, it condition in which it was both receptor (antioxidant) easily penetrates the cell membrane to act as a direct scavenger of and a donor (pro-oxidant) of free oxygen radicals.1 reactive oxygen species (ROS).1 In addition, melatonin’s effects exceed those expected from a simple antioxidant. It also acts as a potent immunomodulator and anti-inflammatory agent, through its effects on different types of lymphocytes and macrophages (Figure 2 on following page). This aspect of melatonin action is particularly important for is curative potential against chronic diseases of the female genital tract, further discussed below.

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In addition to slowing down ovarian aging and improving oocyte quality in women with PCOS, melatonin was shown to be effective in mitigating symptoms of endometriosis and adenomyosis, both in animal and human models (Table 1 below).

Both of the latter two pathologies are characterized by a failure of endometrial cells, discarded during menstrual bleeding, to undergo the normal process of programmed cell death (apoptosis) which is normally activated in cells that have been taken away from their natural tissue environment. The consequence is pathological proliferation of these “immortalized” 41

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Finally, it has to be noted that melatonin lacks toxicity, even at much higher doses than those recommended for infertility treatment, and that its effects go far beyond the fertility status and also include protection against respiratory viral diseases and some forms of cancer.1

Figure 2. Several gynecological syndromes, such as endometriosis and adenomyosis, are caused by a dysregulation of the immune system. This is particularly marked by an increased prevalence of T helper (Th) lymphocytes over T regulatory (Treg) lymphocytes, along with an increased ratio of M1/M2 macrophages in the uterine cavity, with consequent prevalence of pro-inflammatory cytokines, harmful for embryo implantation. Melatonin treatment reverts these anomalies and restores the normal uterine receptivity state.1

cells, followed by migration into the myometrium (adenomyosis) or ascending through fallopian tubes toward ovaries and other sites in the abdominal cavity (endometriosis) Ther, they induce an inflammatory response of affected tissues. Both of these processes are, however, apparently inhibited by melatonin which restores the normal apoptotic pathways of these discarded cells and mitigates the inflammatory responses.1 The combination of antioxidant, immunomodulatory and anti-inflammatory effects of melatonin is involved in promoting implantation in women with a history of RIF, while its antioxidant and anti-inflammatory actions are involved in improving placental health. Both, moreover, as a consequence prevent spontaneous miscarriage, fetal growth restriction, preterm births, and other fetal and prenatal sequelae related to oxidative stress and inflammation.1 Moreover, when added to embryo culture medium, melatonin was shown to improve human embryo growth and development.

For reference purposes, a summary of clinical melatonin studies in humans is presented in Table 1 (on previous page).

References 1. Tesarik J, Mendoza Tesarik R. Melatonin in the treatment of female infertility: update on biological and clinical findings.

Biomedicines. 2025;13(10):2434.

2. Tamura H, Takasaki A, Miwa I, et al. Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res. 2008;44(3):280-287.

3. Eryilmaz OG, Devran A, Sarikaya E, Aksakal FN, Mollamahmutoglu L, Cicek N. Melatonin improves the oocyte and the embryo in IVF patients with sleep disturbances, but does not improve the sleeping problems. J Assist Reprod Genet.

2011;28(9):815-820.

4. Batıoğlu AS, Sahin U, Gürlek B, Oztürk N, Unsal E. The efficacy of melatonin administration on oocyte quality. Gynecol Endocrinol. 2012;28(2):91-93.

5. Nishihara T, Hashimoto S, Ito K, et al. Oral melatonin supplementation improves oocyte and embryo quality in women undergoing in vitro fertilization–embryo transfer. Gynecol Endocrinol. 2014;30(5):359-362.

6. Jahromi BN, Sadeghi S, Alipour S, Parsanezhad ME, Alamdarloo SM. Effect of melatonin on the outcome of assisted reproductive technique cycles in women with diminished ovarian reserve: a double-blinded randomized clinical trial. Iran J Med Sci. 2017;42(1):73-78.

7. Espino J, Macedo M, Lozano G, et al. Impact of melatonin supplementation in women with unexplained infertility undergoing fertility treatment. Antioxidants (Basel).

2019;8(9):338.

8. Pacchiarotti A, Carlomagno G, Antonini G, Pacchiarotti A. Effect of myo-inositol and melatonin versus myo-inositol, in a randomized controlled trial, for improving in vitro fertilization of patients with polycystic ovarian syndrome. Gynecol Endocrinol.

2016;32:69-73.

9. Vitale SG, Palumbo M, Conde-López C, et al. Effect of growth hormone administration on ICSI outcomes in patients with polycystic ovary syndrome and recurrent implantation failure: a retrospective cross-over study. Int J Gynaecol Obstet.

2021;153:357-358.

10. Schwertner A, Conceição Dos Santos CC, Costa GD, et al.

Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial. Pain.

2013;154(6):874-881.

11. Qi S, Yan L, Liu Z, et al. Melatonin inhibits 17β-estradiol– induced migration, invasion, and epithelial–mesenchymal transition in normal and endometriotic endometrial epithelial cells. Reprod Biol Endocrinol. 2018;16:62.

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NEWS FROM THE CHR

THE POINT IS NOT TO PRODUCE “DESIGNER BABIES” BUT TO “CORRECT” EMBRYOS WITH SINGLEGENE DISEASES BRIEFING: In a July posting, for the first time, noted that commercial market forces, in addition to preimplantation genetic testing for aneuploidy (PGT-A), had started to aggressively market, in association with in vitro fertilization (IVF), yet another genetic test of preimplantation-stage embryos, so-called polygenic risk scoring (PRS). In reference to PGT-A and preimplantation genetic testing of embryos for single gene (monogenic) diseases (PGT-M), this new test is, therefore, also called PGT-P. More blatantly than PGT-A, which in over 20 years of use has been unable to prove any clinical utility and, indeed, for many infertile patients actually reduces pregnancy and live birth chances, PGT-P, however, creates even more obvious additional ethical, clinical, as well societal concerns. We, therefore, return to the subject for some additional commentary and take the opportunity to inform our readers, without a press release, how the CHR decided to get more directly involved in addressing this issue.

Above-noted July posting was inspired by a shortly before published article in The Washington Post that featured a California company called Orchid and its founder, Noor Siddiqui, a former Thiel fellow (for those who do not know the meaning of being a Thiel fellow, you will be informed below).

Lo behold, and so typical for The Free Press, it published on August 11, 2025, a very informative article by Johanna Berkman which, almost miraculously following The Washington Post article of a few days earlier, appeared to demonstrate the likely unpreventable consequences of PRS/PGT-P. Under the title, “The race to make Designer Babies,” Berkman offered an at times almost comical, but in its relevance very serious story of two prominent individuals strongly determined to take the next step in human embryo manipulation, the genetic editing of an embryo’s genome to correct genetic abnormalities detected in embryos by preimplantation genetic diagnosis for so-called mono-genic diseases (PGT-M), the oldest and most accurate form of testing embryos for a genetic abnormality, in this case caused only by a single gene mutation.

PGT-M is, in the CHR’s opinion, indeed, the only form of preimplantation-stage genetic embryo testing (PGT) that, at the current state of medical art, makes sense, and the reason is simple: It tests for often quickly 44

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terminal diseases and it does so—in contrast to PGT-A and PGT-P—with very high accuracy. In other words, it really accurately predicts whether an embryo should or should not be transferred, a quality standard that PGT-A and PGT-P do not even come close to.

The testing of embryos before embryo transfer arose for the first time as a concept in the late 1990s with the recognition that genetic material from an in vitro produced embryo could be obtained right after fertilization and before embryo transfer, thereby allowing PGT of preimplantation-stage embryos and the deselection of embryos from embryo transfers that were judged to be genetically unworthy of such transfers.

In principle, two indications were pursued: (i) testing for single-gene diseases, PGT-M; and (ii) testing for chromosomal abnormalities (now called PGT-A).

While PGT-M has been a solid success from the earliest days of utilization, PGT-A has become increasingly controversial, with the American Society for Reproductive Medicine (ASRM) and Society of Assisted Reproductive Technology (SART) in late 2024, finally (and in the CHR’s opinion years overdue) issuing a guidance that for the first time clearly noted that PGT-A in over 20 years of clinical use has been unable to demonstrate any beneficial cycle outcome utility.1

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But here is where this story really becomes interesting because, if one does not want to chase after the fantasy of PGT-P for such crazy purposes as choosing eye color or trying to improve the intelligence of one’s offspring, curing an embryo from a monogenic disease would seem like a very reasonable and desirable goal.

Indeed, in a very aged infertile patient population like the CHR’s, where women only rarely produce large egg and embryo numbers, every “cured,” and therefore transferable, embryo is, of course, symbolically speaking, worth gold.

Which brings us back to the original story in The Free Press, involving two very interesting individuals, a Chinese scientist, He Jiankui, PhD, who already in 2018 made headlines all around the world for applying in vivo gene-editing to two female embryos in an attempt to eliminate any future HIV risk for these embryos by manipulating a single gene in their genome. This, at the time, obviously prematurely executed experiment (it did not follow standard ethical and medical-legal practice for experimental medical treatments) did not earn him the scientific applause he had expected and, instead, rewarded him with a prison sentence in China. In the international press, it also awarded him with the nickname, “Chinese Frankenstein” (a name also given by some prominent media outlets to early IVF researchers out of fear that IVF would produce Frankensteinian monsters). The second player in this evolving tragicomedy was at the time only a 28-year-old additional Thiel fellow by the name of Cathy Tie, who, at that young age, already was a serial entrepreneur who had founded several companies and—on the side—was trained as a concert pianist.

So, who are all of these Thiel fellows? Peter Thiel is a many-times-over billionaire, co-investor, and friend of Elon Musk. He, in addition, is also a founding partner in many highly successful companies in Silicon Valley unrelated to Musk. In 2011, he established the so-called Thiel Fellowship. This announcement made headlines around the world (originally named “20 under 20”) because, already 15 years ago, Thiel recognized what nowadays represents the much more prevalent opinion that, for carefully selected individuals, college represents a waste of time. They—as well as society in general—might be better off if so-talented candidates started “something new” instead of attending college.

Creation of the Thiel Fellowship was then the next

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logical step. And to quote the website: “The Thiel Fellowship gives $200,000 to young people who want to build new things instead of sitting in a classroom.”2 And—interestingly—two female Thiel fellows, Noor Siddiqui and Cathy Tie, are now central players in the story we are telling here.

The following are other worthwhile quotes from the website of the Thiel Fellowship: “to understand who the candidates are who, like Noor Siddiqui and Cathy Tie, became Thiel Fellows, with many among them by now already prominent actors in the business world of Silicon Valley and beyond.

“Knowledge that is acquired under compulsion obtains no hold on the mind.” -Plato “My grandmother wanted me to have an education, so she kept me out of school” -Margaret Mead “That major that she majored in don’t make no money / But she won’t drop out, Her parents’ll look at her funny” -Kanye West

A little bit more relevant history Tie travelled to Beijing to meet He, who, by then, had resurfaced in public in China after having spent three years in jail for practicing medicine without a license (when performing the HIV-prevention experiments in 2018). And the two were now openly planning such in vivo human embryo editing experiments to cure by PGT-M diagnosed embryos suffering from monogenic diseases through a new start-up company in Austin, Texas.

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It appears that the Chinese government was not very happy about He’s resurfacing in the public eye because he was travel restricted and not permitted to leave China, while Tie was access restricted to China.

As a consequence, Tie split from He and decided to do all of this with a new scientific partner-founder, Eriona Hysolli, PhD, a former postdoc in the George Church, PhD, laboratory at Harvard University, who, before partnering with Tie, was the Scientific Lead of the famous/infamous Woolly Mammoth Deextinction Project at the Colossal® company.3 The duo’s new project, interestingly, was called the Manhattan Project (if the name sounds familiar, it probably is not coincidental!). Tie earlier in the years already had launched a Los Angeles Project with famous/infamous biohacker Josie Zayner, PhD.

Eriona Hysolli, PhD (left) and Cathy Tie (right)

Human genetic embryo editing, of course, represents the logical next step following a genetic diagnosis of a single (i.e., monogenic) pathological human trait in an embryo. But this apparently is not what Noor Siddiqui’s Orchid (and other new start-up companies in the field) appear to consider their future main business to be. Practically all of these companies are instead pursuing the concept of genetic germline editing with the goal of “improving” PRS/PGT-P results (i.e., changing the alleged risk for one or more polygenic diseases). They, indeed, are planning to go even a step further by moving from using germline editing from “correction” to “enhancement” of human embryos, for example, claiming to be able to improve the intelligence of offspring through whole genome screening. Siddiqui’s Orchid, indeed, claimed to be able to perform the required whole genome screening for PRS/PGT-P from the DNA of as few as five to six 46

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trophectoderm cells of a blastocyst-stage embryo, a by several experts we spoke to not considered a very credible claim.

The claim, indeed, reminds us of Elizabeth Holmes and, if this name doesn’t sound familiar, it, indeed, should: because this young society lady with excellent family connections founded Theranos. This health technology company claimed to have developed a revolutionary blood testing technology that needed only a drop of blood to do multiple tests at once. In what has been estimated as a ca. 700-million-dollar fraud, she fooled even sophisticated investors and— unless pardoned—will, likely, still be spending a good number of years in prison.

In contrast to Holmes’ never-realized new technology, the CRISPR technology used in potentially editing the germline of human embryos is not only already well established but has been rewarded with a Nobel prize.

It has also been the foundation for the establishment of private and public companies by now worth in excess of $20 billion. Proof of principle for the technology has been, moreover, already repeatedly established, and it concomitantly has been relatively “derisked” many times over, including in above above-noted experiments of the Colossal company and in the recent treatment of a neonate.

In somewhat of an analogy, the above-noted Washington Post article pointed out that several leading genomic experts they had queried about Siddiqui’s testing claims of being able to assess the complete genome from only, on average, the DNA of ca. five to six trophectoderm cells, had expressed significant doubts about the accuracy of extensive genomic amplifications from only so few embryonic cells.

And if we, indeed, want to explore this claim a little further, one also must consider where Siddiqui and coworkers published their formal report about Orchid’s allegedly quite revolutionary amplification method: The paper appeared in one of the only recently established extension journals of Fertility and Sterility, named F&S Reports—not really where one would expect a first report to appear about such an important new technology. Hard to believe that a credible new technology of such importance—if technically indeed solid—would not have been published in a Nature or Science journal with a much higher impact factor. One

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wonders which journals had rejected the paper before F&S Reports accepted it, and why?

An additional claim made by Orchid, according to The Washington Post article, was that these microtrophectoderm biopsies of DNA through the above-noted whole genome amplification can accurately predict polygenic risks of preimplantationstage embryos for basically every polygenic disease, from diabetes to hypertension, cardio-vascular disease, cancer, etc. And this claim is, of course, even more incredulous because even adult medicine is still struggling with the concept of risk prediction through polygenic risk scoring, and, in adult medicine, validation studies have already been going on for years. We, in contrast, are unaware of any published validation studies of significance in human embryos.

And then there is, of course, one additional major problem when it comes to PRS/PGT-P: In polygenic inheritance, it is correct that multiple genes on multiple chromosomes establish risk for the occurrence of polygenic diseases. This genomic risk represents, however, only a very small fraction of the total risk of developing a polygenic disease. A large majority of this risk has nothing to do with an individual’s genome, but derives from environmental factors affecting an individual’s genomic risk. One, therefore, really must wonder how Siddiqui’s corporate laboratory plans to account for future environmental risks of embryos, starting during 40 weeks of pregnancy (the time period most important for the establishment of epigenetic effects on the genome) and then after birth over an undetermined lifespan.

Consider, for example (rightly or wrongly), that a patient’s embryo has a 2.7% chance of developing type 2 diabetes, a 3.1% chance of becoming hypertensive, and a 4.5% chance of having a heart attack The patient’s second embryo may have a 1.6% chance of having a heart attack later in life, but a 3.2% chance of diabetes, and a 5.8% chance of developing hypertension. Which of the two embryos should—or would—a patient then choose?

All of this, of course, assumes these embryos even implant, are not miscarried, and end up delivered, which, of course, is an incorrect assumption because only a small minority of embryos ever implant and, depending on age, between at least a third to over half

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of all pregnancies end up as miscarriages. Moreover, assuming the multifactorial often barely different risk percentages for various diseases based on the germline alone, does a choice between two embryos, so-defined, in most cases really make sense? We don’t think so!

How Silicon Valley has gotten interested According to media reports, the evolving commercial concept surrounding the popularity of PRS/PGT-P in Silicon Valley appears no longer to be only the mass production of “designer babies.” The new goals are “super babies,” uniformly conceived through IVF (goodbye to sexual intercourse for conception!). Under this business model, all embryos will undergo genetic testing before transfer into a uterus (i.e., except for unwanted “accidents” reproduction will, therefore, primarily occur through IVF). And, based on the test results obtained, the embryo will then, through genomic manipulations, be made “more super,” whatever that may mean for the future parents.

Some very prominent names in Silicon Valley have been mentioned in media reports, who, allegedly, have already had children who, as embryos, have undergone all of this absolutely nonsensical testing and enhancement. We’d better get ready not only for PRS/PGT-P, but also for the genetic editing of embryos through various techniques and with different technologies. The editing of embryos at very early stages of development (where an embryo at the cleavage stage has only 6-8 cells and at the blastocyst stage roughly 250-300 cells) can also not be equated with using CRISPR therapy in already born babies. A first case of at least so far, of temporary clinical cure of a single-gene disease was recently reported in a newborn.4 That there are distinct ethical as well as clinical distinctions between modifying the germline in a preimplantation stage embryo and in a newborn is, of course obvious: With all the special considerations given by society (including the research community) to human embryos, preimplantation-stage embryos— whether in nature or in an IVF cycle—much more likely will never implant in a uterus than achieve successful implantation. But at the same time, while there is almost no chance for either ethical or clinical abuse in trying to cure an embryo or a newborn from a deadly disease, the opportunity for abuses is wide open 47

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in modifying the genome of a preimplantation-stage embryo in an IVF laboratory for a distinctively defined genetic modification of embryo enhancement rather than embryo cure from a terminal disease.

And then something interesting happened at the CHR As fate, at times, plays an unpredictable role in life, at exactly the time when the CHR started addressing above-noted articles in The Washington Post and The Free Press in the CHRVOICE and The Reproductive Times, the CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, suddenly found one morning an e-mail in his in-box from none other than Cathy Tie and Eriona Hysolli, PhD, expressing interest in having a chat. As it turned out, a very prominent reproductive biologist at a university on the West Coast had referred them to Dr. Gleicher because they were interested in establishing a relationship with a knowledgeable clinician-scientist in the IVF field.

References 1. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology.

The use of preimplantation genetic testing for aneuploidy: a committee opinion. Fertil Steril 2024;122(3):421-434 2. Thiel Fellowship.™ 3. Colossal.

4. Children’s Hospital of Philadelphia. May 15, 2025.

5. Gleicher N, Tang YX. Fertil Steril 2004;81(4):977-981

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Tie and Hysolli had, in the meantime, decided to establish their new company in New York City, naming it the Manhattan Laboratory and the project they wanted to pursue in their company—to “fix” genetically abnormal embryos prior to implantation— the Manhattan Project. Tie as well as Hysolli moved to NYC and, as of October, the company also has offices and a brand-new research laboratory in the city. After several meetings, Gleicher accepted an invitation from Tie and Hysolli to join the company’s scientific advisory board.

For Gleicher, this development closed a very personal research circle because he, already in 2003, published a study that proposed already then the concept of “curing” embryos from single gene diseases prior to embryo transfer at preimplantation stages.5 He and the CHR are now looking forward to helping in making this over 20-year-old dream come true, utilizing all the amazing new technologies now available to scientists to edit the germline by following the highest ethical study principles and, of course, obtaining first all appropriate regulatory approvals for the development of such treatments.

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THE CHR IN THE NEWS

CHR’S RESEARCH AND EXPERTISE SPOTLIGHTED IN WIRED AND THE WALL STREET JOURNAL WIRED: “A New Startup Wants to Edit Human Embryos”

Relatedly, Emily Mullin, a science writer at WIRED, on October 30, 2025, penned an article about Tie’s and Hysolli’s new startup, Manhattan Genomics,1 in which she, among other members of the advisory board of the company and several outside experts, also quoted The CHR’s Norbert Gleicher, MD. In his statement noted that what attracted him to join the company’s advisory board was the company’s principal therapeutic goal of correcting in human embryos single gene diseases because the ability to do so would be especially helpful for infertile women who can no longer produce good eggs and embryos. And since such patients represent a large majority of the CHR’s patient population, the concept of “correcting” embryos affected by a single gene disease appears compelling. Every additional embryo available for embryo transfer in such patients, of course, significantly improves their pregnancy and live birth chances.

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THE WALL STREET JOURNAL: “A Couple Wagers Time, Hope and $300,000 on a Quest for Children”

In a very interesting and precinct front-page article on IVF, Amy Dockser Marcus in the November 15 & 16, 2025 issue of The Wall Street Journal quoted the CHR’s Norbert Gleicher, MD, in an article that addressed an important issue we never before saw discussed in the lay media, namely that in the quest to achieve pregnancy in infertile patients, costs pile up as chances diminish.2 Data suggest that, while for approximately the first three cycles chances remain the same in most IVF clinics, with additional cycles, chances of pregnancy and live births, indeed decline, leaving the patient with an oftendifficult decision-making process.

And since chances decline with increasing speed as women age, this is, of course, a very common issue to arise in the CHR’s patient population, which—as the article noted—in 2024 for the first time hit a median age of 45 years.

As Gleicher is also quoted in the article, whether to continue treatments with their own eggs is then a decision patients themselves must make, though, hopefully, with fully transparent advice about

chances and alternative treatments from their medical providers.

References 1. Mullin E. A New Startup Wants to Edit Human Embryos. WIRED. October 30, 2025.

2. Dockser Marcus A. A Couple Wagers Time, Hope and $300,000 on a Quest for Children. The Wall Street Journal.

November 15–16, 2025: A1, A9.

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We are so proud of Min Yang, PhD, and congratulate her, our past postdoc, for winning the 2025 Ira and Ester Rosenwaks New Investigator Award of the ASRM.

chromosomal abnormalities in the embryonic cell lineage and was published in Nature Cell Biology1 (the paper also reported on a new group of women at the CHR who had so-called allegedly chromosomal “abnormal” embryos transferred, yet had chromosomal “normal” babies.) And, yes, while in NYC, she also found the time for a first baby!

Min Yang, PhD (Photo Courtesy of the University of Washington Department of Obstetrics & Gynecology)

And as children leave their homes to make their parents proud, so do postdocs leave to make their former lab directors proud. Yang, in 2023, went on to head her own research laboratory at the University of Washington, where she is now an Assistant Professor in the Department of Obstetrics and Gynecology, the Institute for Stem Cell and Regenerative Medicine (ISCRM), and the Department of Genome Science. And continues to use stem cell and animal models to study early human development and the molecular mechanisms underlying pregnancy failure and disorders affecting reproductive and maternal-fetal health.

Former CHR and Rockefeller postdoc won 2025 ASRM New Investigator Award

Min was for several years a joint CHR and Rockefeller University postdoc and during that time period got interested in the subject of chromosomal abnormalities in human preimplantation-stage embryos, most of our readers, of course, know is a longstanding interest at the CHR. She, in that time period, also became the first author of a joined study between the CHR and the Brivanlou Laboratory at Rockefeller University which, among other important new findings, for the first time demonstrated the ability of human embryos to self-correct

Her lab, indeed, just this year published another groundbreaking paper in Nature Communications on chromosomal instability (leading to aneuploidy) in human trophoblast cells and placentas,2 which attracted considerable attention in the research community. And we cannot wait to hear about her lab’s even more recent research at this year’s FRM Conference here in NYC (see the program on pages 3-11), where she, of course, will be an invited speaker.

Alan DeCherney, MD (Photo Courtesy of Longdom Publishing)

And since we are already talking about the 2025 recipients of the ASRM Society Awards, we, of course, also want to congratulate an old colleague and friend of the CHR, who won the Kavoussi Family Outstanding Teacher Award, Alan DeCherney, MD. He—totally coincidentally, shortly after receiving this award—once again (for the third or the fourth time over several decades) presented very interesting GrandRounds on November 11 of this year at the CHR, building on his many years of experience as a medical journal editor, first at The New England Journal of Medicine and later as Editor-in-Chief at Fertility and Sterility.

REFERENCES 1. Yang M., et al., Nat Cell Biol 2921;23:314-321 2. Wang et al., Nat Commun 2025;16:3918

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Recent publications from the CHR team

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Gayete-Lafuente S, Mian U, Choong E, Barad DH, Gleicher N. Discordant phenotypic outcomes in monozygotic twins conceived via IVF: A case report involving Hirschsprung’s disease, tricuspid and pulmonary atresia, and orofacial clefts without detectable genetic mutation. Case Reports in Women’s Health 2025;48:e00752 In this short paper, the CHR’s investigators reported the incidental finding of discordant congenital anomalies in monozygotic twins, dichorionic twins conceived through IVF. One of the twins presented with several severe congenital anomalies, as described in the title of the paper, while the second twin was completely normal. Subsequent genetic testing, including wholeexome sequencing, revealed no associated mutations. The case reemphasizes the potential impact of postzygotic mosaicism, epigenetic dysregulation, and/ or environmental disruption of neural crest-derived development, demonstrating once more the complexities of embryologic development.

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DR. ALBERTINI’S PHOTO GALLERY

This month, our image gallery calls attention to human embryos in the context of more than just genetic testing. Imagine - as the CHR’s motto goes - that “fighting for every egg!” is but the very beginning of what may seem like a journey encompassing the days between when the egg was fertilized and when a given embryo was chosen for transfer to a suitably prepared uterus. Perhaps 3 days after fertilization or longer in cases where a trophectoderm biopsy was indicated for purposes of PGT-A, PGT-M, or even the newest “kid-on-the-block” PGT-P (polygenic risk scoring-vide infra). Making inferences about a genetic future, dictating long-term health risks or physical features like eye color, for any embryo over these early days of development is a reach of disturbing proportions when, and only when, we in the medical community face the realities of the genetic and genomic chaos that ensues upon fertilization of any human egg. Captured below are a series of images that illustrate how the seemingly “normal” appearance of human embryos can be deceiving to even the most well-trained observer, unaware of what lies beneath!

FIGURE I: Where it all starts within hours after fertilization: In this case, after intracytoplasmic sperm injection( ICSI), maternal egg-derived) and paternal (sperm-derived) genomes migrate to the center of the newly formed zygote as the two pronuclei (red spheres ) approach and consider mingling with each other to make a new genetic individual. Repairing DNA damage carried along with either of these genomes is but the first of a long series of complex molecular reorganizations the embryo is challenged with as it initiates its journey to becoming a blastocyst. If you are wondering about all the tiny white spots, think mitochondria, all of course inherited from the egg.

Figure I Figure II FIGURE II: A first big mistake a cell can make! When the one-cell zygote gets ready to divide into 2 cells, correctly aligning and segregating the mix of mom’s and dad’s chromosomes turns out to be a huge problem for many human embryos made by IVF. Here in a human tissue-cultured cell is an example of an abnormal tripolar mitotic spindle, with the chromosomes in red, the spindle microtubules in white, and the cell boundaries demarcated in blue. Note: in contrast, the normal bipolar spindle in the lower left of the image, representing the configuration one would expect cells of an early normal and euploid embryo to form.

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FIGURE III: This field illustrates a number of actively developing mouse embryos at the transition from two to three cells. Nuclei are visible in each blastomere, and current wisdom suggests that each cell division demands energy resources to advance development, the question being whether these embryos are generating their own fuel from the activity of the mitochondria inherited from the oocyte,or was the gas tank (fuel for development) already filled by granulosa cells during the oocytes’ long journey in the ovary? What is your guess?

Figure III FIGURE IV: Cleaning house of cells that have failed to follow a normal pattern of cell division over the first 5 days of development is something of great interest in human embryology these days.

To restate what that means, if human embryos are prone to making mistakes in mingling the mother’s and father’s chromosomes correctly as the embryo constantly divides its cells from one to a hundred plus cells, as shown in this image of a 5-day human blastocyst, can the embryo correct mistakes? Are there mechanisms available to some but not other embryos to eliminate cells carrying an over- or underdose of chromosomes due to faulty cell divisions? Though some argue that the jury is still out, CHR investigators, in collaboration with investigators from the Brivanlou Laboratory at Rockefeller University, in 2021 reported that (like British investigators had previously reported in the mouse) human embryos, indeed, can self-correct.1 This image is consistent with the notion of such “self-correction.” This embryo apparently has taken what looks like a triploid cell (chromosome bundle in white at ca. 11 o’clock) that appears to be in the process of, so to speak, being “ cast-aside.” The red label denotes cell junctions that hold the cells of the embryo together. Because of the density of these cell junctions, you can probably discern the difference between cells of the inner cell mass and trophectoderm (where embryo biopsies are taken from).

Figure IV

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General Medical News General Medical News General Medical News BRIEFING: In this section, the CHRVOICE offers opinions about medical news, not necessarily connected to reproductive medicine, but with potential relevance to the field. News more directly about reproductive medicine are reported in a later section of this CHRVOICE. Since, like outside opinions, the CHR’s positions on issues can be biased, it is important to reemphasize that we are fully cognizant that “expert” opinions in medicine are considered the lowest level of evidence and should be viewed as such by our readers. Unable to offer, therefore, consistent “truth” (assuming that something like that really exists in science), the CHRVOICE strives to come in its selection of topics and in its content as close as possible to the most likely “truth of the moment.” We, therefore, welcome from our readers especially opposing opinions.

THE BUSINESS OF MEDICINE & THE EFFECTS OF POLITICS How serious is the Trump administration about improving access to IVF? This is, indeed, a serious question one must ask these days after all the promises that were made before the 2024 election. And, yes, Trump recently—along with other international pharma companies—“convinced” Merck/ Serono, through its US subsidiary, EDM Serono, to sell its fertility drugs as of 2026 at a whopping 84% discount when bundled and directly sold to consumers via what is now called the TrumpRx platform. And cheaper infertility drugs, especially considering the percentage decline in costs, are an excellent first step to improving access to IVF in the US. In return, the company received an easing of tariffs on the company’s drugs when imported into the U.S. and—what likely was the strongest motivation—a promise from the

government to speed up the FDA’s approval process for Pergoveris, the company’s product containing follitropin alfa (FSH) and lutropin alpha (LH) in a 2:1 ratio,1 which in the European Union has been already approved a while ago and has become a bestseller.

This, of course, raises the question of what the other companies with gonadotropin products will do to stay competitive. So far, though, not a word from them!

But then there is also another side to the original question, and it is reflected in how Congress has been dealing with the issue of IVF coverage for members of the military. As The New York Times reported on October 19, 2025, and then reprinted by the Springfield News Sun on October 24, 2025, like on so many other matters, Congress is split on the subject. Though there is bipartisan support for coverage, there also appears to be substantial opposition from President Trump’s own party, including, apparently, the Speaker of the House, Mike Johnson, R-LA.2 In contrast to such medical

insurance-related issues as Obamacare, where the political disagreements between the two big parties potentially affect billions of dollars in the already heavy on deficit national budget, the cost of IVF coverage for the military would only be a pittance. The issues to be resolved here, therefore, are not so much fiscal in nature, but ideological and, at least in part, religious. And those, at times, are the most difficult to resolve!

The New York Times—not necessarily the most favorably inclined news outlet toward President Trump and his administration—probably characterized the current perception about how the administration has overall been addressing IVF practice in the country best in a front-page article under the heading, “They’re Against Trump, but Not His I,V.F. Policy,” primarily referring to the remarkable reduction in medication costs for infertility patients.3 References 1. European Medicines Agency.

Pergoverist

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2. Mineiro M, Kitchner C. Springfield News Sun. October 24, 2025.

3. Kitchener C. The New York Times, November 15, 2025. ppA1&A13. https:// www.nytimes.com/2025/11/07/us/politics/ trump-ivf-women-pregnancy.html

Very few fertility-related M&A deals so far in 2025 In one of his almost always interesting articles in Inside Reproductive Health, Ron Shinkman noted on October 2 that the year 2025 so far produced hardly any M&A deals in the fertility field, though some experts believe that deal-making will heat up.1 But not much time is left in the year. Moreover, the two biggest deals were overseas, with IVI RMA Global apparently still being flush because the company spent another $400 to $450 million on the socalled ARTS Clinics Chain, based in the UAE, and with significant clinic presence in the Middle East in general as well as India.

According to the article, only three M&A deals closed in the US, and one deal was unwound only six months after its announcement.

But what everybody appears to be waiting for is the quite openly discussed attempt to sell US Fertility, which operates Shady Grove Fertility and several other fertility clinics, and also purchased a while back Ovation Fertility, a network of IVF labs. Amulet Financial Partners back the company and, already in August, was allegedly in the second round of an advanced sales process.2 That by early November, when these words are being put to paper, no further news has been announced, appears to confirm rumors that several major equity investors in

IVF clinic networks had to delay their exits for a lack of buyers.

References 1. Shinkman R. Inside Reproductive Health. October 2, 2025, 2. Martinez C. ION Analytics. August 13, 2025. https://ionanalytics.com/insights/ mergermarket/us-fertility-in-secondround-of-sale-process/

Private equity is reported to tighten its grip on fertility clinics Rachel Robertson from MedPage Today reported from ASRM 2025 that Private Equity does not appear to care very much about state laws that aim to protect the healthcare industry from corporate influences.

This is at least what one study, presented by a second-year medical student from the University of Michigan in Ann Arbor, reported.1 As Robertson’s article noted, 33 states plus Washington, D.C., have corporate practice of medicine laws, which bar nonphysician or nonhospital entities from owning or controlling medical practices. Six of those states— Washington, Oregon, Nevada, New York, Massachusetts, and Connecticut—also have attorney general notice laws, which require formal notification to and/or approval from state attorneys general for healthcare transactions surpassing a set monetary value.

The likelihood that fertility clinics would be affiliated with private equity was not associated with state corporate practice of medicine laws (HR 5.9, 95% CI 0.45-78.0, P=0.18) nor attorney general notice laws (HR 0.82, 95% CI 0.18-3.7, P=0.79).

Nobody can be surprised. As we have repeatedly noted in these pages, private equity is buying IVF clinics in order to make money, and make money quickly in 5-7 years because that’s how long the average buy-sell cycle for an investment runs. As also noted in the preceding commentary, rumors in the investment community suggest that Private Equity investments in fertility clinic networks have difficulties finding buyers (or getting the desired price) for their exits.

This should not surprise because profit margins in fertility clinics are small and require careful management. With ownership of clinics out of physicians’ hands, they have fewer incentives to work profitably than they probably had as owners, even if Private Equity offers financial incentives.

Another reason why Private Equity investments may turn out to be disappointing may not necessarily be fertility-practice related but may be applicable to all Private Equity investments in medicine and even related areas: And that is the image Private equity has acquired pretty much in all

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medical specialties and not only in practice management but also in hospital and even geriatric home ownership, uniformly characterized by higher prices and poorer service quality. Yet money is still coming into medicine. One wonders for how much longer investors will experience profitable exits, and we suspect for not much longer, unless AI can improve profitability appropriately, and we doubt that as well, even though AI was everywhere in the exhibition hall at ASRM 2025 in San Antonio, TX. Reference 1. Robertson R. MedPage Today.

November 3, 2025. https://www. medpagetoday.com/meetingcoverage/ asrm/118282

Other signs of instability in IVF clinic networks Ron Shinkman in Inside Reproductive Health on September 11, 2025, reported that three Boston IVF physicians “broke off ” to form a new IVF clinic in Dedham, a Boston Suburb, called Terra Fertility. The clinic operates in a space that Fertility Solutions previously occupied. The availability of this space allowed for a rapid start for the new venture, which is also planning a second, smaller location in downtown Boston. Fertility Solutions, an exclusively female team of REIs, recently announced a merger with Fertility Centers of New England, which has evolved into the main competitor of Boston IVF in the New England region.1 The motivations given by one of the physicians were: (i) That that Boston had no longer any physician-owned IVF clinics—only

three private equity backed clinic networks and one universityowned clinic, thereby offering an opportunity for a physician-owned group “that offered a better patient experience.” (ii) Worries about the future of private equity-dominated IVF clinics. On an interesting side note, the physician also noted that it costs these days ca. $6 to $8 million to build a clinic, which, to us, appears somewhat of an exaggeration.

Unsurprisingly, Boston IVF representatives, of course, did not agree with the argument that clinic network under Private Equite provided inferior medical service quality, with former Boston IVF and current Kindbody CEO, David Stern, suggesting that certain service quality issues, like for example quick appointments, may be difficult to obtain in Boston due to the large demand for fertility services in the state which was the first to mandate infertility coverage (including IVF) by insurance companies. He, as an additional reason for patient complaints, also pointed out that getting an insurance company approval for fertility services usually takes weeks, further slowing down treatment dynamics.

Stern also made an additional important point by noting that being in a mandated insurance state has economic benefits as well as risks for provider organizations: While in such states, the number of individuals with infertility benefits is usually greatly increased, the reimbursements for services clinics receive are much lower than in selfpay states, of course, establishing very specific management needs.

Another article by Inside Reproductive Health on the same day reports on several independent (still physician-owned) fertility clinics that have been rejecting buyouts amid ongoing acquisition offers.2 The principal reasons the involved physician owners cited were the desire for continuous control over medical care, culture, and long-term stability. The last point, of course, refers to repeated ownership changes that come automatically with control by private equity. Boston IVF, for example, in five years underwent two ownership changes: In 2015 was acquired by the NMC Eugin group, owned by German NM Health at the time, and in 2024 was taken over by IVI RMA, when this company acquired the Eugin Group.

References 1. Shinkman R. Inside Reproductive Health. September 11, 2025.

2. Inside Reproductive Health. September 11, 2025.

States are tightening the rules to curb the influence of private equity in healthcare So far, Indiana, Maine, New Mexico, Oregon, and most recently California—all, of course, blue states—have passed laws affecting private equity investments in health care-related businesses in their states. The most recent California law that was enacted bars investors from interfering in health care decisions.1 Good luck, California! Your Private Equity investors were either staying away from further investments or would cheat by hiring figureheads, as medical insurance companies

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have learned to do to avoid being accused of practicing medicine (see also the next commentary).

And just 5 days later, Governor Gavin Newsom signed another bill that required health care entities to submit a written notice of any transaction that results in a material change in ownership or control of the entity, and extends the requirement to private equity, hedge funds, and management services organizations.2 Several other states—allegedly some red states included—are considering similar legislation, which could be a worrisome trend for some investors.

References 1. Cummings C. The Wall Street Journal.

October 7, 2025. https://www.wsj.com/ articles/californias-newsom-signs-bill-tocurb-private-equitys-role-in-healthcare2. Appelbaum E. Center for Economic and Policy Research. October 14, 2025. https:// cepr.net/publications/private-equitygreed-in-healthcare/

More on the corporatization of US health care In these pages have been following the recent series of articles in The New England Journal of Medicine, which addressed the various aspects of corporatization of US health care in all of its aspects.

And that brings us today to an article that asks the question, what motivates hospitals and delivery systems.

The author held leadership positions at several prominent academic health systems and is now retired. Remarkably, he, however, noted in the introduction of his article that—until he was asked

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to write the article—he had never heard the term “corporatization.”

Readers who have been following us in these pages, following this series of articles in The Journal, may recall that we made the same comment when first using this word.

Interestingly, this author starts his article with the rather provocative statement that, “corporatization seems to have become the culprit for everything wrong with US health care.” Though maybe to a minor degree true, the statement appears to be more emotional than factual because nobody can deny that—what encompasses this new term of “corporatization” is, indeed, what has radically changed health care (and not only in the US) and has led to exactly what federal as well as state legislatures have claimed for decades they wish to avoid—the corporate practice of medicine.

This is not the place to go into too much detail regarding this article, but the lack of selfawareness as a representative of the corporatization of medicine demonstrated by the author throughout the article is quite telling. Nobody, of course, accuses corporations of—on purpose— harming (though one on occasion may wonder) and—at a very basic level—we do believe that the overwhelming number of people working in health-related corporate entities do wish “to do good.” We, therefore, agree when he notes that, “nobody benefits if we ascribe poor health outcomes to corporatization and ignore true determinant.”

But lots of people are harmed when corporations ascribe bad outcomes to innocent determinants, just to cover up their own responsibility.

And this brings us back to the subject of who is entitled to practice medicine. Corporations very obviously have concluded that, not only are they entitled to practice medicine, but in the best interest of their patients, they are obliged to do so, when the real reason, of course, is that a manager’s principal obligation—by which her career will be measured—will be to exceed expectations with maximal savings for the corporate budget.

Corporations, of course, strongly deny that they are practicing medicine, but let’s look at a few examples for a moment: For example, medical insurance companies started to practice medicine when preapprovals for medical treatments became routine. What else is it, if an insurance company mandates that an infertility patient have three IUI cycles before being advanced into IVF? A simple issue, but clearly a practice of medicine because many REIs will, for a variety of reasons, in many patients, for very good reasons, prefer to go straight to IVF. Insurance companies, then, in cases of disagreement, offer a peer-topeer conversation, as if the REI representing the company really has the freedom to decide (that is, if she wants to keep her corporate job). The physician the company pays to represent the company in the peer-to-peer conversation does not practice medicine. She/he, indeed, cannot practice medicine because she/he has never met the patient and doesn’t really 57

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know the patient. The corporate physician just enforces a policy, usually once again not established by independent physicians, but by a committee of hired “specialists” who, of course, first and foremost, represent their employer, the corporation.

And even when the employer is an academic institution, all of this applies because the days when the chairperson of a medical department established practice policy are long gone. Like the physician employed by the medical insurance company, the department chair is nowadays nothing more than a mid-level hospital and/or university employee who is not judged by how good a clinician or researcher she/he is, but by how well she/he execute the orders of the mostly non-medical management structure.

So far, clearly the most disappointing article in an otherwise mostly quite interesting and overdue series of invited articles in The Journal. It, to a telling degree, indeed, well demonstrates the difference in intellectual depth between the management structure of the contemporary health care system and many physicians, scientists, and other employees they manage.

This fact was better demonstrated than we can ever put into words by the most recent article in this series,2 published barely one month after the previous one by a member of the Department of Health Services, Policy, and Practice at Brown University. Three paragraphs best summarize it:

regional health systems, and private equity firms control a growing share of US hospitals, nursing homes, and physician practices. This trend of corporatization is characterized by consolidation and the use of sophisticated financial strategies that prioritize the interests of shareholders over those of patients, health care workers, and local communities.”

“Although nonbinding, the updated merger guidelines highlight concerns about serial acquisitions and emphasize the competitive risks posed by vertical integration and cross-market mergers as well as risks to workers resulting from labor-market concentration.”

And finally, “The healthcare system of the 2020s is being remade by financial intermediaries and corporate entities whose aim is to maximize financial returns.

Antitrust enforcement, revitalized by new merger guidelines and state action, represent a critical tool for limiting the harms of corporatization that result specifically from reduced market competition. But it cannot fully address the deeper problem (and here it comes): A health system increasingly driven by financial returns rather than patient outcomes.”

Reference Lipstein. S. N Engl J Med. 2025;393(13):1249-1251 Singh Y. N Engl J Med 2025;393(18:17611764

Surrogacy business is growing and, according to The WSJ, ripe for financial abuse It seems that every few years, the surrogacy business makes the front pages again because all the deposits paid by patients for their carefully selected surrogates have disappeared at a surrogacy agency.

In other words, the surrogacy business always carried a certain smell of decay with it. And here we go again: Money went missing and The Wall Street Journal was telling the story on the front-page (of course, continued in the back on page A9, this time involving a company called Surrogacy Escrow Account Management (SEAM) where the owner—instead of paying ca. $16 million deposited with the company in escrow to pay patients’ surrogacy services (medically more correctly called “gestational-carrier” services), used the money instead to fund her recording studio. The Justice Department is investigating, and the FBI is seeking information from victims.1 With rapid growth, according to the article, turning surrogacy in the U.S. into a multibillion-dollar annual business, nobody should, of course, be surprised. Demand is up, prices are very significantly up, and now fraud also appears to be peaking again. As we have noted on previous occasions in these pages, the only thing that is down is the medical quality of available gestational carriers. Likely also a consequence of rapidly increasing demand, we have especially noted this decline since the end of the COVID pandemic.

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It is the CHR’s practice to recommend to our patients in search of gestational carriers to let us interview their choice candidate before making any down payments.

Before COVID, we only rarely recommended against a carrier patients had selected; by now, we don’t like almost half of them. All we can say to our patients is that they should be careful with whom they are willing to enter into a long-standing business relationship because that is what a surrogacy (i.e., gestational carrier) contract is all about. Patients enter into a significant dependency not only on their gestational carrier, but also on the agency that arranged and legally documented all the arrangements.

Reference 1. Foldly B. The Wall Street Journal.

October 21, 2025; https://www.wsj.com/ us-news/surrogacy-escrow-moneymissing-08f943a7?gaa_at=eafs&gaa_

Even the United Nations (UN) now has an opinion about surrogacy As if the UN does not have other and more important problems to solve, the British Medical Journal (BMJ) just informed us that a special UN rapporteur (i.e., in simple language, a person appointed to investigate and report on an issue of importance) just issued a report on surrogacy, “encouraging the world to ask difficult questions.”1 Her name is Reem Alsalem, and she is a much “bigger” rapporteur for the UN than just regarding surrogacy (correctly called use of gestational carriers); she is the Special UN Rapporteur on violence against women and girls.

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Reem Alsalem, born in Cairo, Egypt, and a Jordanian citizen, is an anti-transgender activist and Special UN Rapporteur (Photo Courtesy of UN Photo/Rick Bajornas)

The report was even presented in October during the UN General Assembly (one wonders whether before or after President Trump’s speech?). It yielded not unexpected conclusions in noting that “the practice of surrogacy is characterized by exploitation and violence against women and children, including girls,” and concluded, in the usual objectivity of the UN, that “all forms of surrogacy around the world should be eradicated.”

Even the super-liberal BMJ, therefore, could not restrain itself from concluding that “the report took a particular viewpoint” and “is not intended as an objective survey on the global surrogacy landscape.”

In other words, just another excellent example of how almost everything the UN touches turns out to be a complete waste of effort and UN budget, of which, according to the Pew Research Center, the U.S. contributes 26.158% (see below).2 Yet, there is reason for some

concern regarding gestational surrogacy (i.e., gestational carriers), as several recent studies reported much higher maternal as well as fetal morbidities than had been appreciated up to now. The general belief has been that gestational carriers are “carefully selected,” usually relatively young women, and, therefore, maternal as well as neonatal outcomes should be excellent. Reports suggesting clearly bigger risks, therefore, came as something of a surprise.3,4 These findings, therefore, clearly warrant some reconsiderations when it comes to gestational carriers. Even more importantly, these findings are asking for an explanation.

We can think of potentially only two possible explanations: The first is based on anecdotal observations previously noted in the CHRVOICE of gestational carriers over recent years at the CHR, which gave us the distinct impression of declining candidate “quality” especially since end of the COVID pandemic, when—for unclear reasons—the demand for gestational carriers (and, therefore, costs) significantly increased.

Like almost all IVF clinics, the CHR does not maintain its own pool of potential gestational carriers. Patients, therefore, are depending on agencies for selection, though we recommend that our patients let us interview their planned carrier before they put money down at the agency.

Before COVID, we only very rarely recommended against carrier candidates. Since COVID, we have been doing so for almost half of all candidates.

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The second possible explanation is biological in nature: In all pregnancies, unless an egg donor is involved, the fetus is a so-called semi-allograft. This means half of its genetics comes from the father and, therefore, is “foreign” to the pregnant woman’s immune system.

In a gestational carrier pregnancy, however, 100% of the embryo is “foreign” to the carrier’s immune system. To overcome the innate desire of a pregnant woman’s immune system to attack any “foreign” invader, a process called induction of immune tolerance, is, of course, more complex in a 100%. than in a 50%, allograft. Increased difficulties in inducing tolerance pathways with a 100% allograft may, therefore, very well contribute to the increased pregnancy complications seen in gestational carriers.

Using the UN report as a pretext, Ferrukh Faruqui, MD, an Ottawa, Canada-based family physician and essayist who focuses on medical ethics, therefore, in a recent opinion article concluded that, “even with regulations, the risk of surrogacy seems too great. We need to hit pause, to listen what the evidence is saying.”5 A complete pause appears to us like too extreme a remedy; but closer attention to the issue, especially in selecting gestational carriers, informing them about risks, and taking care of them during pregnancy as “high-risk patients,” certainly appears indicated.

References 1. BMJ 2025;391:r2182 2. Leppert R. Pew Research Center. July 31, 2025.

3. Velez et al., Ann Intern Med

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2024;177(11):1482-14-88 4. Velez et al., JAMA Network Open 2025;8(7):e2523428 5. Faruqui F. Undark. October 20, 2025. https://undark.org/2025/10/20/opinionsurrogacy-health-risks/

Misleading pharmaceutical advertisement In a recent article in JAMA, the current head of the Food and Drug Administration (FDA), Martin A. Makary, MD, MPH, one of our heroes during the COVID pandemic, made the point that “direct-to-consumer pharmaceutical advertising (DTCA) has evolved into a public health crisis.”1 And we couldn’t agree more!

These advertisements, moreover, have in many cases become a nuisance. Being forced to watch many commercials in commercial breaks on TV, one comes to understand why so many developed countries do not allow DTCA for prescription medications. Indeed, as the article informs, the U.S. is one of only two countries in the world allowing DTCAs. They very obviously are often directed toward the lowest common denominators in society and, as Makary noted in this Viewpoint article, they flood U.S. consumers with promotional content that frequently is outright misleading.

Here is further evidence for the absurdity that, unfortunately, only too often rules so many of our government agencies: In the late 1990s, the FDA sent hundreds of enforcement letters annually to companies alleged to violate advertisement regulations. How many of such letters might have

gone out by 2023 and 2024? The answer boggles your mind: One and none!

Yes, hard to believe; but just one more of so many simply unbelievable realities recently discovered in how our government works (or, should we say, doesn’t work?)

Makary then noted that a 2023 study suggested that direct-toconsumer advertisement drove approximately 31% of the increase in drug spending since 1997, when the FDA relaxed restrictions for such advertisements under legal threats from the pharma industry, and what, at least in present days, is considered the most powerful lobby in Washington. It, therefore, of course, does not surprise that drugs with low effects get more (+14%) DTCA than drugs with high efficacy.

Makary also noted in the article that this issue has relevance significantly beyond just the economic damages the current policy causes because it affects the core of medical practice by having moved prescription patterns from being driven by best medical evidence to being taken over by marketing-induced patient demand.

Also unsurprising is, therefore, the fact that large pharma companies consistently allocate more resources to advertising and marketing than to research and development of new drugs. Especially advertising on social media has exploded in recent years, often presented as “entertainment.” Indeed, 88% of advertisements for top-selling medications came from actors

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ignoring basic fair balance rules.

It will be interesting to see how the renewed enforcement of such fair balance rules by the FDA will change the advertisement environment for pharma products.

It can only get better!

Reference 1. Makary MA. JAMA. Published online on September 12, 2025. Doi: 10.1001/ jama.2025.18197

The steady increase in denials of medical insurance claims, and some thoughts about patient rights to the best health care Everybody hates medical insurance companies, and there are many good reasons for that since basically every one of their business models contradicts everything patients want, health care providers want, and hospitals want. All three providers of health care—let’s for a moment incorrectly assume that they have no financial interests in driving up charges—of course want to, respectively, provide and receive the best medical care, and better medical care is always automatically associated with higher costs.

Medical insurance companies, in contrast, and let us for a moment (also incorrectly) assume that obtaining best care for their insured clientele is at the top of their demand list, will in principle agree with the three provider arms only on, that better medical care is always automatically associated with higher cost, and that any form of cost control, therefore, must be based on control of utilization.

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Insurance companies, therefore, at significant cost, routinely engage huge utilization review teams, in principle made up of nurses, but also including much higher-paid physicians. And, unsurprisingly, their job is to restrain the utilization of “everything” by much as possible. Nobody, therefore, can be surprised that squeezing utilization on a steady downward trend is a core activity in every medical insurance company.

A recent article in The New York Times reports that health insurers are denying more drug claims,1 therefore should not surprise.

It is, after all, one of their basic functions.

According to the article, denials by private insurers of prescription drug requests in the US between 2016 and 2023 increased by 25%.

According to a Becker’s Hospital Review report of 4 billion (billion !!!) claims studied by Komodo Health, a healthcare analytical company, denials increased at Cigna 25%, 24% at Aetna, 23% at UnitedHealthcare, 22% at Anthem, and 20% at Humana, all exceeding increases at public insurers and employer-funded insurance plans.

With the expense of health insurance now after the last election cycle in November and the shutdown of the federal government mostly over rising expenses for Obamacare at the political center stage, we can expect in Washington, DC, considerable political activity regarding health insurance in the coming months.

In these discussions, it will be important to remember that, while there is, of course, a correlation between the quality of health care

and the cost of providing these services, health care in many ways functions like the restaurant industry. Here is why: Like in health care, the quality of medicine practiced at a service provider must be considered the, ultimately, most important goal.

In a restaurant, it is the taste of the food. But as with food tastes and sensitivity to tastes can differ (even though almost everybody, of course, can differentiate between good and bad), so may there be differences in perception between what is good or bad health care (but—once again—most patients can clearly differentiate between good and bad). Yet, in both of these important spheres of life, we will be influenced in our ultimate judgments about the service by factors of clearly secondary importance.

Obviously, we all would like everything to be perfect, but we can live a very good and enjoyable social life using a variety of good restaurants without ever setting foot into a three-Michelin-starred restaurant. This analogy must be considered when thinking about the cost-effectiveness of health care.

An extreme example is, at least in some ways, the Chinese health system, where the government’s responsibility is to provide the health care framework, including expertise and staff. Still, the rest is up to the patients and family, including, for example, the bedsheets, cleaning up services, and the food.

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to the best hotel care. As long as the medical care provided is topnotch, everything else should not only be of secondary importance to patients as well as society, but should be where insurance companies watch their expenses.

Another way of saying this is that private rooms and other luxuries should not be part of society’s health care responsibility but should be ours. And in practical terms, this means that insurance companies—when looking at cost savings—should be mandated to concentrate on secondary costs and should not be allowed to try to cut costs by adversely affecting treatment outcomes.

This, of course, also would mean that health insurance companies should be prohibited from “practicing medicine,” which, under the law, they are forbidden, but, as discussed elsewhere in this issue of the CHRVOICE, they currently increasingly do.

That all of this also, of course, greatly affects infertility care was not too long ago also raised in an article in Insider Reproductive Health, noting that broken insurance processes and rising costs have resulted in a fight for financial survival in fertility care in the industry.3 We quote from the article, which, in turn, quotes a well-known former embryologist: “Revenue cycle management (RCM) in fertility care generally follows three key stages: benefits verification, pre-authorization, and claims management. Each step introduces potential delays, errors, and administrative costs. Benefits verification requires staff to confirm 62

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coverage details, often navigating insurer-specific portals or calling directly to clarify plan terms.

Pre-authorization then mandates the submission of detailed clinical documentation to justify proposed treatments, with no guarantee of approval. The final stage, claims management, presents its own set of challenges. “Submitting the bills with all the diagnostic and procedure codes doesn’t mean they’re automatically going to get paid. Denials can stem from reasons as nuanced as incorrect diagnosis codes or missing documentation. Then it falls back on the clinic to figure out why a claim was denied, gather more records if needed, and resubmit.”

And she continues: “For some clinics, the burden proves too great. You will find some fertility clinics that do not accept any insurance. Clinics may choose to operate as cash-only practices to avoid the operational drag of insurance processing, despite the potential for lost patient volume.

Others selectively contract with insurers that offer more predictable reimbursement processes. These operational hurdles directly affect patient access to care. Patients with insurance may find their coverage unusable at certain clinics, while others face opaque cost estimates due to insurers’ variable reimbursement structures.”

References 1. Kliff S. The New York Times. July 18, 2025.

2. Becker’s Hospital Review. July 18, 2025.

3. Krause D. RCM pressure mounting: billing chaos drains clinics and patients.

Inside Reproductive Health. April 10, 2025. https://www.fertilitybridge.com/newsarticles/fertility-clinics-revenue-cyclemanagement-crisis.

Two Israeli companies are driving the development of home ultrasound monitoring The Israeli company Pulsenmore ES system (located in Haifa) just received FDA approval for its ultrasound home monitoring device during pregnancy.1 This is potentially interesting news for obstetrical practice but, much more interesting for the infertility field is that another Israeli company, IMMA Health, won Israel Innovation Authority funding ($1.6M) and European Union recognition for AI-powered transvaginal ultrasound technology (the prestigious Seal of Excellence) from the European Innovation Council), believed to be the world’s first self-operated transvaginal ultrasound solution. It involves a platform that combines robotics with AI. It is meant to enable women to perform 3D vaginal ultrasound scans from home.2 Such self-monitoring at home would, of course, revolutionize how infertility services are currently provided, often requiring daily visits by patients to the infertility clinic.

At the same time, some caution is indicated: While AI technology to measure follicle sizes is already available in the marketplace from several ultrasound equipment manufacturers, several crucially important issues in regard to home monitoring of follicles remain unresolved: (i) Whether a vaginal probe is manipulated by a qualified sonographer or the patient herself, of course, makes quite a

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difference. How well this issue has been resolved via robotics has so far not been reported. (ii) Sequential follicle monitoring is currently also not only dependent on follicle size measurements but also on hormone evaluations (estradiol, progesterone, LH).

How this issue would be resolved has also remained unexplained because blood draw and analysis still cannot be performed at home.

And, finally, (iii) one, of course, cannot judge any home monitoring without information about costs.

How expensive will the use of these home-testing set-ups be?

References 1. Rosen S. Israeli at-home ultrasound device earns FDA approval. United with Israel. Nov 5, 2025. https:// unitedwithisrael.org/israeli-at-homeultrasound-device-earns-fda-approval/ 2. Ynetnews. September 8, 2025. https:// www.ynetnews.com/business/article/ s1zkyb3qeg

ADVANCED EDUCATION REMAINS IN THE NEWS Is higher education in need of receivership or reform?

John Ellis, PhD, a professor emeritus of German literature at the University of California, Santa Cruz, and the author of the book “The Breakdown of Higher Education,” according to an Op-Ed he wrote in The Wall Street Journal,1 thinks it is too late for reform. Only full receivership of institutions of higher learning can still safe our higher education. We are quoting: “The radicals who hollowed out America’s universities can’t be trusted to restore their proper purpose.”

“Observers have long shrugged off the danger with the complacent idea that students will see through their professor’s foolishness—if not right away—then when they enter the “real world.”

“The election of a veritable communist as mayor of New York (and of a female communist in Seattle) shows how shortsighted that is. After a radicalized college education has been fed to an entire generation, we face the prospect of the remaining well-educated people in their middle and late years being replaced by a second radicalized generation. Reform is urgent.”

And he concluded: “The only viable solution is to place schools in “receivership,” a well-stablished procedure to reform ailing college departments.

A new chairman is imposed on a department with a free hand to make whatever appointments he thinks necessary to restore the departments to health. By action of lawmakers or trustees, a new president can be imposed on a campus with a mandate to return the school to its proper mission by appointing subordinate administrators, especially deans, committed to reform.”

Do university trustees have their heads in the sand?

This is at least what Ben Sasse, a former Republican US Senator and University president, suggested in a recent Op-Ed in The Wall Street Journal.1 One sentence in the article summarized his opinion best and probably also explains his short tenure as President of the University of Florida best: “Radicals run wild at US universities and colleges because those in authority (i.e., the board of trustees) came for status and consensus, not seeking a fight.”

A more detailed explanation comes from the following paragraph: “The Trump administration has moved aggressively against grotesque antisemitism tolerated by elite schools. Universities have fought back, accusing the administration of extortion in pursuit of political sound bites. But the locus of the

“Radical political zealots are ruling higher education like petty tyrants. The proper response isn’t to nudgethem toward good behavior. Reformers have to dethrone Them.”

References 1. Ellis JM. Higher ed needs receivership, not reform. The Wall Street Journal.

Published November 10, 2025.

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Benjamin Eric Sasse, former US Senator (R-Nebraska) and 13th President of the University of Florida (Photo Courtesy of the University of Florida)

problem—and of eventual reform— is neither the faculty lounge nor the Oval Office. It’s the boardroom... but for too long, when confronted with anti-intellectual activism, politicized inquiry and attacks on campus free speech, trustees have buried their heads.”

The motivation for his Op-Ed was the kind of opinion paper leading medical and science journals have been publishing in recent years, rather routinely and usually, as we have in these pages repeatedly pointed out, without ever publishing opposing opinions.

In this case, it was a paper published by, likely, the most prestigious science journal in the world, Nature (like several other prominent British medial and science journals well known for its super-liberal political stance and quite radical editor-in chief), in which eight prominent scientists noted the following: “Decolonizing scientific institutions don’t just diversify them” and, “Western science is rooted in colonization, racism, and white supremacy.”

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are basically arguing that the task of scientists is no longer the dispassionate pursuit of (as good as possible) objective truth (by the authors dismissed as a myth), but the anti-racist effort of decolonization of university disciplines and promotion of indigenous research methodologies by pursuing “citation justice.” And if you don’t know what kind of justice that is, he explained: for example, “sorting footnotes by race, sex, and sexuality.”

He further notes that these eight hyper-progressive authors are no longer outliers at universities, and who can argue with this conclusion after October 7, 2023, and especially after the recent mayoral election in New York City!

We also cannot argue with his conclusion that it is up to the boards of institutions of higher learning to control this insanity.

He concluded his article by noting that, “board members can’t possibly claim to be doing their jobs if they can’t explain in simple terms what they fund and subsidize and (likely most importantly) what antiintellectual can’t they tolerate.” He has a point!

politics on campus, and students’ professional options and success after graduation. And, lo and behold, the ranking looked very different from what we are used to: University of Florida The University of Texas at Austin University of North Carolina Chapel Hill Texas A&M University University of Notre Dame Georgia Institute of Technology Florida State University Purdue University – main campus University of Georgia Clemson University In place of Harvard and Yale, the University of Florida and the University of Texas, Austin, and in place of the Massachusetts Institute of Technology, the Georgia Institute of Technology.1 Sounds good to us!

Reference 1. Editorial. The Wall Street Journal, October 23, 2025, P16

Betting $100 million on the University of Austin

Reference 1. Sasse B. University trustees have their heads in the sand. The Wall Street Journal.

Published September 11, 2025.

Is this the new elite among US universities?

This is at least what the Manhattan Institute’s City Journal suggested, according to an editorial in The WSJ under more good oldfashioned criteria, which have again gained in favor, such as free speech,

Billionaire, writer at The Free Press, and co-founder of The University of Austin, Jeff Yass enjoying some downtime.

(Photo Courtesy of Philadelphia Magazine)

And only in its third year of selecting and welcoming a class of

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students, the University of Austin is already totally oversubscribed and, likely, even harder to get accepted into than Harvard University.

And now, Jeff Yass (a billionaire businessman with according to Forbes net worth of $59 billion) and, together with Bari Weiss (of The Free Press and now also CBS News boss) in 2021 co-founders with serval other brilliant minds of the university, made in what he called a “seismic” announcement in a November 5, 2025, article in The Free Press which will make the university even more popular than it already is.2

President and Provost of the University of Austin, Carlos Carvalho, PhD, giving a speech to students during convocation on August 31, 2025 (Photo Courtesy of The Free Press).

And the reasons are obvious: The university committed to never charging tuition and—at the same time—never to take government money. And Yass made this commitment possible through a $100 million gift, the largest donation the university had ever received.

And why he did it is well explained in his article, which we recommend reading in its entirety.1 Here are only a few teasers: I am giving the money “because the feedback mechanisms of higher education are broken.” And he goes on: “Most systems and institutions that don’t work have broken feedback

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mechanisms” (he could be talking about biology or medicine).

“Think corrupt politicians, or crony capitalists, or ideological echo chambers. Unfortunately, higher education belongs into this category.”

Not mincing words, he goes on: “… the school is paid regardless of students’ outcomes, while the student shoulders the risk and carries the debt after graduation, whether or not the education delivers results, … while massive endowments insulate many of these institutions from healthy financial pressure to deliver results to their students.” We, of course, couldn’t agree more, and the following story offers a very good example!

References 1. Priest J, The Texas Tribune, November 5, 2025. https://www.texastribune. org/2025/11/05/university-austin-jeff-yassdonation-free-tuition/ 2. Yass J. The Free Press. November 5, 2025. https://www.thefp.com/p/imbetting-100-million-on-a-new-university

Instead of fighting antisemitism, US university professors fight antisemitism prevention policies implemented at the University of Pennsylvania Considering all the media outlets we are trying to follow, interestingly, we found the issue we are addressing here only reported by The Allgemeiner, an obviously Jewish (should we say Zionist publication?). Everybody in academia, of course, knows the American Association of University Professors (AAUP), allegedly the oldest and largest US organization founded for the purpose of

defending faculty rights (can we call it a union for professors?).

And if anybody thinks that the AAUP might be concerned about the tsunami of antisemitism that flooded university and college campuses nation and worldwide after October 7, 2023, you are very much mistaken. AAUP’s concern went exactly the other way.

By way of background, an October 2024, 325-page-long report by the US House Committee on Education and the Workforce, after a yearlong investigation of the University of Pennsylvania’s response to very obvious campus antisemitism over the preceding year, of course, revealed serious shortcomings.

In the university’s administration’s response. Penn President Liz Magill, J.D., indeed, had to resign.

Under pressure from the Trump administration, like many other leading universities and colleges, the University of Pennsylvania, therefore, implemented new policies targeting antisemitism prevention on campus.

In a letter to the university’s administration regarding antidiscrimination investigations opened by Penn’s Office of Religious and Ethnic Interests (OREI), AAUP now charges— according to the article in The Allgemeiner—that efforts to investigate alleged antisemitism on campus and punish those found to have perpetrated antisemitic acts can constitute discrimination.

But what makes this letter particularly interesting, and as also noted in the article, its main argument basically repeats

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statements of the Council on American-Islamic Relations (CAIR), which, of course, is notorious for its antisemitism, defense of Sharia law, and alleged ties to jihadist groups such as Hamas.

This is not the first—and probably also not the last—time that the AAUP has defended antisemitic speech and activities. At the University of Pennsylvania, a good number of the university’s prominent faculty members, indeed, immediately come to mind when the subject of antisemitism comes up. For example, In 2023, Associate Professor of Arabic poetry, Huda Fakhreddine, helped organize the infamous “Palestine Writes Festival,” just days after October 7, a gathering of antiZionists (more appropriately, really called antisemites) at the university.

One guest was Gaza-based professor, writer, and poet, Refaat Alareer, who is said in 2018 have answered publicly his own “lyrical” question, “Are most Jews evil? Of course they are,” was his answer. Another honored guest was Palestinian alleged historian, Salman Abu Sitta, who once said in an interview that Jews were hated in Europe because they played a role in the destruction of the economy in some of the countries. And, so they would hate them.

A few final words regarding the AAUP letter: It described the university’s efforts to protect Jewish students from antisemitism as government interference in university procedures. It also claimed that merely reporting antisemitism subjects any accused 66

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to harassment, thereby, of course, automatically converting the Jewish victim into the perpetrator. Along the same lines, the letter also argued that minority groups, such as Arabs and African Americans, are disproportionately investigated for antisemitism. Seriously?!

Reference 1. Pierre D. The Allgemeiner. October 24, 2025. https://www.algemeiner. com/2025/10/23/major-body-universityprofessors-targets-antisemitismprevention-policies-universitypennsylvania/

If we are already talking about antisemitism, the UK failed to protect Jews from “racist doctors” This is at least what Britain’s health minister, Wes Streeting, on October 6, 2025 (the day before the October 7 second anniversary), in an interview with The Times acknowledged. To be specific, here is what he said in the interview: “The National Health Service (NHS) is a universal health service, which means that everyone, regardless of race, religion or creed, should feel safe seeking its care. I deplore the fact that this is frankly not the current reality for many Jewish patients and staff, and I am determined to change this for once and for all.”

Like in other countries in Europe and in Australia, the NHS has, since October 7, 2023, faced multiple high-profile cases of blatant antisemitism within the NHS involving medical staff as well as patients. The Jewish News reported in July that roughly 500 formal complaints about antisemitism linked to not fewer than 123 NHS

physicians had been submitted by that date to the General Medical Council. But 84% of investigations were closed without any further investigation at the triage stage.

And here is the most recent news item: A UK physician by the name of Dr. Martin Whyte, who works for the NHS and who had referred to the Jewish people as “banker goblins,” insinuated that the Holocaust was an elaborate hoax, and advocated “to gas the Jews” (and, yes he also served in the past as an executive member of the British Medical Association)—in a decision of The General Medical Council which regulates physicians in the UK—was allowed to keep his license to practice medicine after accepting his excuse that his antisemitic postings were merely distasteful jokes.2 His X account tells otherwise because it repeatedly expressed hatred for Jews and celebrated the murder of Jewish people. After the 2018 mass shooting of Jews at the Tree of Life synagogue in Pittsburgh, his posting was “ha-ha,” with the Nazi salute “Sieg Heil” (misspelled) and the additional comment, “Gas the Jews.” Who would want this guy as their doctor? Certainly not a Jewish patient!

References 1. World Israel News. October 8, 2025. https://worldisraelnews.com/britainis-failing-to-protect-jews-from-racistdoctors-minister-warns/ 2. World Israel News Staff. November 9, 2025. https://www.yahoo.com/news/ articles/doctor-joked-gassing-jewslet-110000602.html?guccounter=1&guce_

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Considering the professor’s Cornell University remains Jewish background, the reason in the news, but, this time, for an understandable reason may be somewhat surprising:

Cornell University campus in Ithaca, New York

The headline that “Cornell suspended a Jewish professor,”1 only several months ago, would probably have been interpreted as further evidence for a substantial level of antisemitism at the university.

But the recent headline had a very different meaning when the university suspended Eric Cheyfitz, the Ernest I. White Professor of American Studies and Human Letters at Cornell University and faculty of the American Indian and Indigenous Studies Program, of which he served as the director of the Mellon Post-doctoral Diversity Seminar. In other words, Cheyfitz very definitely cannot be accused of being on the political right.

And why was he suspended and, therefore, since then negotiated his retirement?2

A Cornell University encampment (Photo Courtesy of Nina Davis/The Cornell Daily Sun)

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He apparently didn’t like to be challenged by an Israeli graduate student in an undergraduate course about the Gaza war and, therefore, asked him to drop the course (AIIS 3500: Gaza, Indigeneity, Resistance), in which he accused Israel of being a “terrorist state” and compared Gaza to a Nazi extermination camp, while describing Hamas as a legitimate resistance movement.

Cornell President Michael Kotlikoff considered this a “biased view of the conflict,” and a Cornell spokesperson stated that the faculty member acknowledged conduct that violated federal civil rights laws and did not meet the university’s standards for student engagement.

Especially after many prior transgressions since October 7, 2023, we saw ourselves forced to point out in these pages before, good for the new academic leadership at Cornell, which, apparently, does not exhibit the hesitancy of the prior President, who basically always had her hands full. The new President appears to—simply—have more common sense!

This was also demonstrated by Cornell reaching a settlement ($60 million) with the Trump administration regarding the allegation that the university’s administration, post-October 7 events, did not protect the university’s Jewish students according to the law. In doing so, it followed the examples of Brown University ($50 million settlement) and Columbia University ($220

million settlement), while some other major universities, including Harvard University, have so far failed in reaching such an agreement. That such an agreement was reached restored more than $250 million in research funding from the government to the university. Obviously, not a bad deal for the university!

References Rosen S. United with Israel. October 5, 2025. https://unitedwithisrael.org/cornellsuspends-professor-for-blocking-israelistudent-from-gaza-course/ Leynse B. The Cornell Daily Sun. October 13, 2025. https://www.cornellsun.com/ article/2025/10/gaza-course-professor-toretire-amid-discrimination-incident-withisraeli-student Calfas J. Cornell University reaches $60 million deal with Trump administration to restore research funding. The Wall Street Journal. November 8-9, 2025: A3. https:// www.wsj.com/us-news/education/cornelltrump-deal-funding-investigationscfc44088

Harvard faces $113 million budget shortfall from Trump cuts Despite months-long rumors about a $500 million settlement, contrary to Cornell and Columbia, Harvard University has, at the time of this writing, not yet settled with the Trump administration. And at least according to The Allgemeiner, this—for at least now—means a $113 million budget deficit,1 which—considering the school’s sizable endowment—really is an almost irrelevant sum and likely explains why Harvard hasn’t settled yet.

According to the article, Harvard had a total income in 2025 so far of $6.7 billion; what is $113 million within such a context, when, 67

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thanks to Wall Street, Harvard’s endowment in 2025 grew by 11.9% to $56.9 billion. And yet the school is charging a fortune in tuition.

How absurd has our academic education system become!

Reference 1. Pierre D. The Algemeiner. October 21, 2025. https://www.algemeiner. com/2025/10/20/harvard-faces-113million-budget-shortfall-after-trump-cuts/

At academic institutions, transgender activism is alive and well Out of all media players, only The New York Sun appears, still, to be following what is going on in academia regarding transgender activism. In October, The Sun reported that Gordon Guyatt, MD, Professor McMaster University in Hamilton, Ontario, and worldfamous evidence-based medicine maven, has either caved in or even assumed a level of command in suppressing what Benjamin Ryan in The Sun described as “inconvenient” information on practices within the increasingly controversial field of pediatric gender medicine from appearing in the medical literature.1 After putting his name on a paper, he and some members of his junior faculty then, however, decided to withdraw their names from the publication they had submitted to the BMJ, leaving it in complete publication limbo.

And then something interesting happened: Anna Miroshnychenko, PhD, the health research methodologist who managed the academic project as a PhD student, advised The Sun that she was only now able to speak up because she had just defended her doctorate and, therefore, was no longer dependent on the good will of Guyatt and other senior researcher who oversaw her work on the research project. She, moreover, noted that “the paper in question was executed with a very high level of integrity and rigor and, therefore, would be beneficial if published.”

Anna Mirishnychenko, PhD

Hired by contract, Guyatt and his team had earlier published three systematic reviews of different gender-transition treatments for minors, resulting in a hate campaign by trans activists demanding a retraction of all three papers, a four-year effort, according to The Sun, with their principal argument being that they did not like the funding, in the US-based NGO, which was “focused on scrutinizing only evidence behind gender transition treatments in minors.”

And here is where the story starts smelling fishy: In August, the McMaster crew, excluding Miroshnychenko, published a denouncement of the NGO, the Society for Evidence Based Gender Medicine (SEGM), accusing it of poor evidence based medicine by breaching (unidentified) rules and, in addition, complained about the NGO’s use of their three already published papers in support of pushing the argument that minors should not receive any gender transition treatments. Guyatt et al., however, did not accuse the NGO of misinterpreting or misrepresenting the results of their three papers and, thereby, basically

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discredited their own work in these three papers (which, of course, makes absolutely no sense).

Those three papers were the first three out of five studies/papers the SEGM had contracted for with Guyatt. At least one of the two other papers, covering different aspects of gender transforming care in minors, is basically the subject of the current submission to the BMJ. Moreover, even though study results very much allegedly matched outcomes of the first three publications, Guyatt et al. have very obviously been trying to distance themselves not only from those publications, but from the SEGM in general, and that may mean that Guyatt may be in breach of contract with the SEGM. Guyatt allegedly told the BMJ in July that he and his Canadian crew were withdrawing their names from the remaining two papers. And, according to a coauthor from outside Guyatt’s group who maintained participation in the paper, they still refuse to return their names to the paper.

Interestingly, Guyatt has remained silent and one, of course, remains wondering why he is not publicly announcing what drove his and his team’s resignation.

But this is not yet the end of the story: The next victim of very obvious transgender hyperactivism appears to be Washington State University’s medical school, which was forced to suspend access to several accredited CME courses that were critical of the field of pediatric gender medicine and were developed by the SEGM.2 The trouble was initiated by two trans journalists

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who somehow succeeded in getting the Accreditation Council for Continuing Medical Education (ACCME) to intervene, which then ordered the university to suspend the complete list of courses developed by SEGM even before a formal investigation was concluded.

The campaign against SEGM was further intensified by the by now rather infamous Southern Poverty Law Center (SPLC) when it added SEGM to its famous list of alleged “hate groups.” Suffice to say, many in the political center and likely even more on the right of the center would, in turn, describe the SPLC as a quintessential hate group of the left. And that this opinion may not be that far-fetched as it may sound is not only demonstrated by this designation of the SEGM and by the fact that the SPLC’s “hate-list” also includes Turning Point USA. In short, in contrast to most of Europe, US academia appears to be much more ideologically driven when it comes to transgender care of minors than our European colleagues (the only alternative motivation would be the significant economic benefits to providers of care and hospitals, but that would, of course, be even more reprehensible, wouldn’t it?). There are simply no other explanations for the continuous support of aggressive transgender treatments of juveniles in the US and, considering what published data show, including in the papers from Guyatt’s group, that is really shameful and must be called out.

References 1. Ryan B. Pressured by transgender activists, star academic backs out of his own research. The New York Sun. 2025 Oct 8. https://www.nysun.com/

article/pressured-by-transgenderactivists-star-academic-backs-outof-his-own-research?member_ gift=CUZ5qwd3crq4pmz-xrd 2. Ryan B. Pressure by transgender activists forces Washington State University to suspend courses critical of medical gender treatments for minors. The New York Sun. 2025 Nov 3. https://www.nysun.com/article/ pressure-by-transgender-activistsforces-washington-state-university-tosuspend-courses-critical-of-medicalgender-treatments-for-minors?member_ gift=CUZ5qwd3crq4pmz-xrd.

Restorative Reproductive Medicine (RRM) is suddenly a hot topic, but what is the news?

When we first heard the term Restorative Reproductive Medicine (RRM), we had to look up what it meant because—at least to us— it seemed like it, suddenly, had appeared out of thin air. And then we found out that what apparently propelled RRM to such sudden prominence in the infertility field was its “moral opposition” to in vitro fertilization (IVF).1 But what made RRM the subject of a whole series of papers in the infertility literature and policy statements from professional societies remained unclear to us because there haven’t been—often religiously motivated—groups which morally opposed IVF (the Catholic church, just being one among them) since the beginning days of IVF? Three colleagues recently offered in an Inkling commentary in Fertility and Sterility further information, starting with a definition of RRM: “RRM purports to be a scientifically grounded model that treats the root causes of infertility rather 69

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than bypassing or suppressing natural reproductive processes.

It uses hormone analyses, cycle tracking, and targeted medical or surgical interventions, including ovulation induction and laparoscopy. Although some of these individual practices may be scientifically valid, none are distinct from what is already foundational within the field of reproductive endocrinology and infertility.”

On first impression, this definition does not appear too far removed from what, indeed, represents common practice in the infertility field, which, at least in our longstanding opinion expressed already in the year 2002, paradoxically, especially in younger women, still, basically to this day, uses IVF inefficiently as an infertility treatment of only last resort.

Then, Newsweek published an article on RRM, giving voice and visibility to some members of the RRM community, making an appeal to President Trump (who, in his reelection campaign, had promised to expand access to IVF), describing IVF—as above-noted Inklings article—as “a flawed and grossly unethical approach to addressing infertility.” And why had they reached this rather extreme— though, of course, in several religions widely held believe, despite births of over 13 million human beings who, but for IVF, in a large majority would not share this world with us?

Because (i) of its costs—an interesting argument in an economic and political sense, but certainly not a valid ethical argument.

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(ii) Low success—of course, a rather uneducated statement considering that IVF clinical pregnancy and live birth rates are close to spontaneous age-specific conception rates; and (iii) because IVF “destroys countless human lives,” which is, obviously, at least biologically, a rather ignorant statement because human embryos do not represent life, as most embryos created in IVF—just like in nature—never are given a chance of implantation in the uterus. And without a chance of implantation, there can never be a pregnancy; and without pregnancy, there can never be even minimal consciousness and, therefore, even potential human life.

at young ages and in the absence of infertility, couples produce one embryo pretty much every month. Yet, even at peak fertility, only 30%-38% of these couples conceive. From these data alone, one can with absolute certainty conclude that only approximately 1/3 human embryo—seven at peak fertility—have the potential of leading to pregnancy. Both nature and IVF, therefore, have basically no use for roughly two-thirds of human embryos because something is wrong with these embryos that does not allow them to implant. In other words, neither nature (nor if you are a believer, God) nor IVF practice don’t uses them and/or dispose of them for good reasons.

It is important to note that we here, respective of various believe systems, are not attempting to address the age-old question when human life starts. We are basically only making one indisputable argument: Nature (and if you are a believer, therefore, God) and IVF treat embryos in identical ways: Both produce them in large quantities in a very error-prone process called fertilization, which, therefore, produces a large number of “unfit” embryos for implantation.

The argument of RRM that IVF destroys countless lives is, therefore, shallow. Trying to avoid the politically sensitive question of when human life begins (we, of course, have an opinion), we are presenting here a logistical argument against the accusation that IVF destroys countless human lives. It is obviously a biologically incorrect statement, but at the same time also an ethically false statement because—assuming good standard-of-care medical practice— IVF in principle just mimics nature.

Consequently, a large majority of embryos are never even given a chance of implantation and pregnancy. Neither nature nor embryology laboratories don’t use or dispose of a large majority of embryos produced whenever a couple tries to conceive, whether in their bedroom or through IVF. Couples trying to conceive on their own cannot actually even know whether they produced an embryo in a given cycle or not, but at least

In an Editorial, its Editor-in-Chief noted that “there is nothing new about the maligning of IVF.”3 He also—and we are very grateful for the information—let us know that The Heritage Foundation actually coined the name RRM in a document entitled, “Treating Infertility. The New Frontier of Reproductive Medicine,”4 which revealed that The Heritage Foundation really appears to “have lost it.”

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Everybody, of course, by now knows about the Foundation’s President, Kevin Roberts, sweettalking antisemitism when defending Tucker Carlson’s interview with the card-carrying true Nazi, Nick Fuentes, and, in doing so, blew up several of the foundation’s boards, and lost some important donors. His survival at the head of the foundation appears questionable. Moreover, the Antisemitism Task Force of The Heritage Foundation decided to split off from the foundation.

And then there is Emma Waters, a political analyst at the Center for Technology and the Human Person (whatever that may mean). Still, she must have switched professions— and maybe picked up an MD degree on the subway—because she has started writing commentaries on infertility like crazy. Topics have been “Treating the Root Causes of Infertility,” “ Beyond IVF: Why America Needs Fertility Care That Treats the Whole Person,” “The Rise of Consumer Eugenics,” etc.4 And this lady, as President Trump is apparently trying to make progress in making IVF more accessible (he already succeeded in reducing drug costs of IVF significantly), as The New York Times reported, leads the charge at The Heritage Foundation toward a “more natural” approach toward infertility, i.e., RRM. And, trying to be polite, that is crazy in infertility, where especially female age is a factor of such profound importance.

So, frankly speaking, we have somewhat of a hard time understanding all the uproar about

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RMM. It is nothing new and will likely be there for as long as we practice infertility. There is an amazing honor in being the only medical field that produces life, but there is also quite a lot of suffering involved when one reads some of the nonsense the RRM movements spread around.

References 1. Peipert et al., Fertil Steril 2025;124(4)”630-632 2. Gleicher et al., N Engl J Med 2000;343:27 3. Paulson RJ. F&S Reports 2025;6(3):235236 4. Waters E, Dodson N. Special Report.

Marriage and family. March 24, 2025. https://www.heritage.org/marriage-andfamily/report/treating-infertility-the-newfrontier-reproductive-medicine

Cesareans are not only in principle unnecessary surgeries but can have rare—but devastating— consequences. One is a, fortunately rare, increase in prevalence of so-called placenta accreta in subsequent pregnancies;2 a second one, much less acknowledged, is a significant incidence (between 24% and 70% of women with at least one Cesarean section delivery)3 of so-called Cesarean section scar windows (also called an isthmocele or uterine niche), which have been strongly associated with several medical consequences, including, indeed, placenta accreta, placenta previa (the placenta covers the uterine outlet into the cervix) and—only relatively recently recognized—secondary infertility of so-affected women, often requiring a second surgery to fix the window.4

How come only the OB/ GYN field—or should we say—women’s health care— continues medical treatments A placenta accreta exists when the that, over decades, have been placenta grows into the muscle established as useless? of the uterus, and after birth, The New York Times, in a front-page article by Sarah Kliff on November 7, 2025, pointed out that obstetrical practice has been continuing with continuous fetal heart rate monitoring during labor now for decades, even though several wellexecuted studies over the years have clearly demonstrated no outcome benefits. Moreover, because of false-positive interpretation of monitoring strips, the US has witnessed an unnecessary increase in cesarean section rates, now applied in roughly one-third of all deliveries.1 Cliff in the article summarizes the situation as, “the ‘worst test in medicine’ is driving America’s high CS-rate.” And unnecessary

therefore, does not easily separate.

Forced separation then often leads to major hemorrhages in the mother and can result in the need for an emergency hysterectomy and even maternal death. Windows in Cesarean section scars—as already noted—can lead to subsequent female infertility and, if suspected to be the reason for a woman’s infertility, require corrective surgery before pregnancy.

And, if continuing a treatment over decades even though it over and over has proven not to fulfill any of its promised outcome improvements, sounds familiar,you, of course, are correct and just have to return to the opening article in this issue of the CHRVOICE on the use of preimplantation genetic 71

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testing for aneuploidy (PGT-A) in embryos during IVF cycles. One, indeed, could argue that Kliff was incorrect in describing continuous fetal monitoring during labor as “the worst test in medicine.” It, indeed, may only be the secondworst test in medicine, after PGT-A! References 1. Kliff A. The New York Times. November 7, 2025.p1.

2. ACOG. Placenta Accreta Spectrum.

Reaffirmed 2025. https://www.acog.org/ clinical/clinical-guidance/obstetric-careconsensus/articles/2018/12/placentaaccreta-spectrum 3. Cleveland Clinic. Last review June 22, 2022. https://my.clevelandclinic.org/ health/diseases/23351-cesarean-scar-defect 4. Visser et al., Hum Reprod 2020;35(7):1484-1494

A DETERIORATING WORLDWIDE CRISIS IN THE SCIENTIFIC PUBLISHING INDUSTRY & THE UNAVOIDABLE CONSEQUENCES FOR DEVELOPING NEW EVIDENCE Has academic publishing become a racket?

This is at least how Prachee Avasthi, PhD, Chief Science Officer at Arcadia Science, academic publishing, recently described in an Op-Ed in The Wall Street Journal.

She also noted what we all, of course, have known for some time, namely that academic publishing is likely the only industry where the industry customers provide the product (for free), perform quality control (for free), and then pay to buy back what they created.

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“Scientists aren’t merely victims, they are accomplices. They desperately feed the machine, trading replication for reputation, discovery for job security. The credential “peer reviewed” matters more than the reviews themselves.

Editorial benediction has replaced the scientific method. Papers become “truth” by masthead, not by surviving scrutiny.”

Prachee Avashti, PhD

What an amazing business model!

Publishers like Springer/Nature and Elsevier, unsurprisingly, therefore reported profit margins of 28% and 38%, respectively. NIH grants alone contribute between $240 and $280 million, and, as the author notes, those publishing houses charge physicians and scientists thousands to publish a paper about work funded by taxpayers and then charge taxpayers for access to these publications. And they are not alone. Many leading journals are owned by usually not-for-profit professional science and/or medical societies, which, according to the authors, “have become addicted to the scheme, defending paywalls and denying millions of people access.”

And we let her Op-Ed do the talking for the rest of this commentary: “Careers live and die by Nature and Science. These prestige journals manufacture scarcity like luxury brands—limiting slots, not predicting impact. Science become a lottery where tenure is the prize, truth an afterthought.”

“The system is so broken that science often advances faster without it. In 2023, when reserachers claimed they had achieved room-temperature superconductivity—a potential revolution in computing and energy—they posted findings on public servers. Within hours, physicists worldwide were testing.

Labs from Berkley to Beijing shared data in real time. What would have taken years under traditional publishing, unforlded with radical transparency. The claims were debunked in three weeks, not three years.”

“Half-measures won’t break this cartel. The NIH should end the shake-down. Science depends on it.”

Avasthi sounds like a CHR staffer.

We, of course, fully agree with her.

Reference 1. Avasthi P. Academic publishing has become a racket. The Wall Street Journal.

September 14, 2025.https://www.wsj. com/opinion/academic-publishing-hasbecome-a-racket-6af215df

A sequence of opinions in the BMJ An international group of investigators published a very

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interesting paper in the BMJ in which they investigated what seemed to have a so obviously predictable answer: what is the impact of retracted clinical trials in the ecosystem of evidence? And, while everybody would, of course, expect some impact, the magnitude of the impact—or should we say the magnitude of the damage on the evidence ecosystem—was quite astonishing.1 Retracted trials demonstrated a significant effect on evidence synthesis, clinical practice guidelines, and—of course—evidence-based clinical practice, and the authors, of course, correctly concluded that such contaminations must be quickly identified and corrections must be initiated.

Nobody, of course, would argue with these conclusions, but it also must be pointed out that clinical trials—though at the top of the evidence pyramid—are, of course, only a very small part of what in medicine is considered evidence.

And, while they—as the authors correctly point out—are a main source for high-quality evidence synthesis, as their study documents, even later retracted studies not infrequently slip through the study selection process for meta-analyses.

What does that say about the value of meta-analyses?

The CHR has in these pages repeatedly pointed out that few examples fit the old IBM dictum, “garbage in—garbage out,” as well as meta-analyses, and we have also over and over made the point how many, if not most, metaanalyses are extremely biased exactly because of selection biases of studies that are included and,

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respectively, excluded. In other words, we have always represented the opinion that the value of metaanalyses in the medical literature is greatly exaggerated, and we feel that this paper validates this opinion.

Moreover, the flood of metaanalyses performed has further reduced the value of meta-analyses, many coming from paper mills in China, India, and the Middle East, and others from investigators who discovered that they can relatively quickly accumulate a reasonable publication list by simply sitting on their desk and writing metaanalyses on sometimes the most bizarre subjects.

We, therefore, saw with great pleasure a letter-to-the-editors regarding this paper from several international authors, with lead author Zeev Shoham, MD, Professor Emeritus at the Hebrew University in Jerusalem, Israel, and an old friend, colleague, and collaborator of the CHR team, who, independently, have come to a similar conclusion.2 References 1. Xu et al., BMJ 2025;389:e082068 2. Shoham et al., BMJ 2025;390:r2014

Fake scientists “infiltrating” journals It is hard to believe the extremes to which publication fraud has come!

A recent article by Miryam Naddaf, in no less than Nature magazine, reported that identity checks helped to expose fictitious authors. The article reported on a network of 26 fictitious authors and reviewers that had infiltrated four mathematics journals, all created by a paper mill, in the article described as

Fake scientist1 (Illustration by Adam Wójcicki/Nature)

“a company that manipulates peer review and sells fake research papers to researchers (can they really still be described as such?) looking to booster their profiles.

Having a stable of fake scientists, those paper mills can create a steady supply of publications.

And by inserting these fictitious scientists, then, based on their publications, as “experts” into the peer-review process, they can also manipulate the peer review of their own submission. Those paper mills at times also don’t hesitate to impersonate real legitimate scientists, and medical as well as science journals; therefore, we now have to start verifying the identities of authors.

Some interesting detail: A paper mill, between 2013 and 2020, published 55 papers utilizing 13 fictitious reviewers and 13 fake authors. Fake authors mostly appeared on a paper only once, but then were suggested to journals (which ask for reviewers’ names) 68 times. It took Springer Nature two years to figure out the ring of conspiracy, presumed to be from a China-based paper mill, and get all affected papers retracted.

In an article a month earlier, Nadaff reported on what was likely Europe’s largest paper mill. It 73

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produced 1500 research articles.2 In this case, a group of companies has apparently flooded 2027 380 journals with hundreds of papers.

Amazing!

Likely at least partially motivated by these and other similar recent disclosures, Nature recently announced that all new submissions published by Nature will be accompanied by reports from the peer reviewers and the authors’ responses.3 References 1. Naddaf M. Nature. 2025;646:792-794.

2. Naddaf M. Nature. Published 2025. https://www.nature.com/articles/d41586025-02809-y 3. Editorial. Nature. 2025;642:542.

Industrial-scale publishing fraud is expanding And to stay with the subject: An article in Science, Cathleen O’Grady noted the ”sheer size and sophistication of the industry that churns out fake publications” and points to a recent paper by Northwestern University metascientist Reese Richardson, PhD, et al., in PNAS who identified networks of editors and authors colluding to publish shoddy and/outright fraudulent paper (including likely some in the previous commentary noted excesses).2 The below quotes are from this paper.

“Scientific and journalistic investigations demonstrate that systematic scientific fraud is a growing threat to the scientific enterprise. In large measure, this has been attributed to organizations known as research paper mills.

We uncover footprints of activities connected to scientific fraud that extend beyond the production of fake papers to brokerage roles in a widespread network of editors and authors who cooperate to achieve the publication of scientific papers that escape traditional peerreview standards. Our analysis reveals insights into how such organizations are structured and how they operate.”

Addressing the issue in an earlier article in Nature, Christine Ro and Jack Leeming correctly concluded that this kind of fraudulent behavior thrives in a scientific culture that equates success with a strong publication record.3 Noting that some paper mills even “actively promote their services by handing out business card,” they also present a case study involving such a paper mill in Kazakhstan.

Several authors contacted, admitted using “intermediaries with the goal of achieving publication in a journal indexed by Scopus of Web of Science,” with one of the authors even noting that he took out a loan to pay the intermediary a fee of $1,500.

References 1. O’Grady C. Science. August 7, 389(6760):558-558 2. Richardson et al., PNAS 2025122(32):e2420092122 3. Ro C, Leemin J. Nature 2025;642:823825

More troubles with the peer review process—reviewers will more likely approve your submission if you cite them When it comes to peer review of submissions to medical and science journals—even the good ones—nothing should surprise anymore because the process appears to become more chaotic by the day. Journals’ editorial offices are simply overwhelmed with too many submissions and too few good reviewers, with—as noted above—increasing numbers of fake submissions from paper mills in China, India, Egypt, Kazakhstan, and God-knows where else, publishers who pay editors still believing that actually they should be paid for the honor of letting somebody be the editor of a journal and don’t ever suggest to them that, maybe it was time to start paying reviewers for their work.

Who then can be surprised that, as Rachel Fieldhouse reported in Nature, a recent preprint reported that reviewers who found themselves cited in a manuscript they reviewed were more likely to approve an article at the first review than referees who were not cited. And the data got even more interesting when the investigator looked at reviewers who, in their comments after the first review, suggested that their own work should be cited. They were only about half as likely to approve an article as to reject it or express reservations. If a reviewer was not cited in a first review round but—in response to a request in the review—was then, indeed, cited in the second review round, 92% of reviewers recommended

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acceptance of the paper, while those who again were not cited approved papers in only 76% of cases.

We leave it to you to decide whether this is conscious or subconscious corruption, but corruption it is!

Reference Fieldhouse R. Nature 2025;645:14-15

where he recently retired to move back home to Philadelphia. But, as we recently found out, when he at our invitation once more visited the CHR (after many prior occasions— first in Chicago and later in NYC) to present GrandRounds, a subject we will return to in a moment. He let us in on a secret: he’s really not completely retired; he still teaches students and residents at Sidney Kimmel School of Medicine, at Jefferson University.

What a surprise!

Alan DeCherney, MD (Photo Courtesy of Longdom Publishing)

Nine lessons from Alan H. DeCherney, MD, one of the past Editors-in-Chief of Fertility and Sterility Alan H. DeCherney, MD, has done it all: he was a leading microsurgeon (even if he may not admit it, probably still his most favorite activity), a REI pioneer in general, an IVF pioneer, starting as head of the REI division at Yale one of the first IVF clinics in the US ( and when the CHR and he for the first time “collided.”).

He then became Chair of OB/ GYN at Tufts, followed by UCLA, and, finally, he moved into various leadership positions at NIH, from

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And those were just his full-time jobs. On the side, he was also the first OB/GYN member of the editorial executive board of the prestigious New England Journal of Medicine, likely at least one reason why the ASRM offered him the editor-in-chief position at F&S (we, indeed, from his recent visit, learned that accepting this appointment required his resignation from The Journal’s board.

The CHR invited DeCherney to give the CHR’s GrandRounds after the current editors of F&S had asked him for an article about his experiences as an editor for the 75th Anniversary issue of F&S. And once we read a preprint of his comments, we felt we wanted to hear a little more.

We don’t have the space here for too much detail about this—in many ways personal—and, because of who he is in the history of US REI, a historical article in its own right.

But we strongly recommend the reference below to read it in its full length.1 But here are Alan DeCherney’s “Nine Lessons From The Editor’s Chair” in shortened format: •

•

•

•

• • •

•

•

Clarity is king: “There is nothing stronger in communication than a good story well told.

Sometimes money wins over integrity: Integrity is essential, but sometimes pragmatism pays the bill.

Even (or maybe especially) schmucks need attention: Not everyone arrives at the table calm or respectful, but they usually come around if they know you’re listening, even schmucks.

Give the young a chance: Some of the most exciting science I’ve read came not from established authorities, but from those still finding their voice.

Use the editorial platform to speak: Editors must speak, not just edit.

Build a brain trust: The lesson is simple—don’t go it alone.

Make people feel good: Making people feel good about themselves is not fluff—it’s a foundational concept of leadership.

Deal with issues immediately: You are, by necessity, an autocrat, and political pressure, even from friends, must never compromise the mission.

Embrace new technology: Editors—and doctors—must not fear innovation. We must lead it.

Reference 1. DeCherney A. Fertil Steril 2025;124(4):582-583

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EDITORIAL

WHAT HAS BEEN HAPPENING TO OUR MEDICAL JOURNALS? FERTILITY AND STERILITY, AS AN EXAMPLE

BRIEFING: Shortcomings in the medical and general scientific publication enterprise are becoming increasingly more obvious, with voices suggesting a need for radical reorganization increasing in numbers as well as volume. The same sense also permeates medical publishing in the infertility field. By being the mother journal among F&S Journals, owned by the ASRM, Fertility and Sterility (F&S) is the leading US medical journal in Reproductive Endocrinology and Infertility (REI) and reflects US REI. The journal, therefore, presented itself for several reasons as a powerful example for changes that have taken hold in medical publishing, which deserve not only criticism but also mandate change. Here presented article, therefore, clearly centers on F&S, though it does so not in a personal way, but as an example for all of medical publishing. We hope that this Editorial will be understood as such.

So let us be clear, what is happening to journals in reproductive medicine is not unique. What we will be describing here, with reference to mostly infertility, applies not only to fertility-related medical journals. All the points we will be making, very likely also apply to many—if not most— medical journals in other medical specialties. But since REI is our specialty area, we, of course, feel a special obligation to REI journals and other medical journals with relevance to our specialty.

So, let’s get going: (i) Our journals have forgotten what they are here for. Their principal purpose was from the beginning—and in our opinion still is—to inform practice as objectively as possible in a timely fashion about new and important findings and developments in our specialty. What, at least in our opinion, they are not here for is to feed us with what selected “experts” believe are important new findings in our specialty, how they should be interpreted, and how they should be clinically applied.

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F&S… and its offspring medical journals

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In practical terms, this means that our journals should, of course, publish scientific papers, one after the other, after they, by careful peer review, were found worthy of publication. Every accepted (and well-edited) manuscript should, therefore, have an interesting story to tell that does not require further augmentation or explanation by a commentary, as has become fashion in Fertility and Sterility and its offspring F&S journals.

form of commentaries and, of course, review articles with attached meta-analyses (the latter—as noted above—not infrequently the product of commercial paper mills) and in our opinion—contrary to widely held believes—in a large majority of cases not even wort the paper they are written on because no other paper category in medical and scientific journals fits better the old IBM dictum, “garbage in— garbage out.”

We already here—at the very beginning of this Editorial—want to apologize for the obviously disproportional attention given in this communication to F&S (for example, in comparison to Human Reproduction) and its offspring journals, but F&S is the most important journal in our field in this country. We find it especially painful when we see it deviating from what we consider to be its principal purpose.

So, what were then the consequences: less and less original science, and more and more “expert opinion,” the lowest evidence level on the evidence pyramid and further augmented by a steadily increasing flood of completely worthless, often AI-generated review articles with meta-analyses.

(ii) The broken peer review process.

At the end of this section of the VOICE and following the earlier CHR reports in this section, there, likely, is not much need to explain why we consider the peer review process broken, but a few issues, once again best reflected in F&S, deserve further discussion: Let us start with what every publisher, editor, and author wants from a medical journal—a good and everimproving citation index.

And it didn’t take a genius to discover that scientific papers are usually much more sparsely cited than opinion papers and review articles. So, what did many medical journals end up doing, they published ever increasing numbers of “expert” opinions in

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But even that is not the end of the story, and, once again, F&S is a good example. What we are talking about now is what we have come to call the self-perpetuating circular reinforcement of opinions, characterized by reviewers, based on their subjective judgments, having recommended to the editor acceptance of a paper and then having been given the opportunity to reemphasize their judgment by writing a commentary to the paper they recommended for acceptance.

We believe that this kind of policy is harmful because published papers already reflect the opinion of the reviewers and the editorial board (otherwise, the paper would not have been published).

What is needed at this point is a commentary that is critical of the publication and not only a reinforcement of the paper’s message.

This circular reinforcement of opinions is further aggravated by how editors at practically all journals choose referees: Reviewers are usually chosen by editors based on their expertise in the subject the paper addresses, and that means that they usually have distinct opinions on the subject they are asked to review, a polite way of saying that they, by definition, must be biased.

To offer an example for the unpreventable consequences of this circular reinforcement of biased opinions in the peer review process, investigators at the CHR—literally for decades—have had difficulties getting papers that criticized PGT-A accepted because reviewers were usually strong proponents of PGT-A who opposed the publication of manuscripts that criticized the test/procedure.

As a consequence, it took over 20 years for ASRM/SART to reach the opinion that PGT-A was useless in producing IVF cycle outcome benefits, as aggressively advocated by its proponents without proper evidence for over 20 years.1 As we noted elsewhere in this issue of the CHRVOICE, this, for example, also has been going on for an even longer time period in obstetrical practice in regard to continuous fetal heart rate monitoring2 and— with absolute certainty—is also happening routinely in other medical specialty areas.

The psychological effect on the reader is, of course, also substantial if a prominent journal like F&S not only publishes a paper with a distinct opinion but then also offers an “expert” commentary— invited by the editor—that further augments this (often biased) 77

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opinion, rather than invites a critical opinion about the published article. (iii) What editorial offices can and must do. To continue with F&S as an example, current practice must end, and the responsibility for this change lies with publishers (including professional societies that own many leading journals) and editorial offices at those journals. How absurd current practice is was again perfectly demonstrated by F&S with the publication of its recent “special issue” on embryo testing.3 Fourteen months after publishing the previously noted policy statement of ASRM/SART that PGT-A in over 20 years of clinical utilization in IVF has failed to establish even one clinical outcome utility,1 the editors of the journal made the very unusual—and to a degree unprecedented—decision to publish a special issue of F&S outside of the usual monthly publication schedule, entitled “HUMAN EMBRYO TESTING Phased Validation: from Innovation to Practice.”

Considering the rather staggering policy statement by ASRM/SART in September of 2024 that PGT-A in over 20 years was unable to proof any clinical benefits in IVF (which—apropos—was published in F&S), this would seem like a very logical, even courageous decision, considering how much damage the rapidly growing practice of PGT-A has caused over these more than 20 years for thousands, probably even hundreds-of-thousands of patients and couples. One would furthermore assume that this special issue of F&S would 78

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address the reasons why and how it was possible that such a highly consequential misdirection in clinical IVF practice could have occurred, and what changes should be implemented to prevent similar misdirections in practice in the future.

But that did not happen!

Indeed, the opposite happened, as well demonstrated by the first few sentences of the brief introductory article of the four editors of this special issue of F&S, and we quote: “The field of embryo diagnostics has undergone remarkable transformation over the past few decades, evolving from rudimentary assessments of morphology to sophisticated genomic, morphokinetic, and molecular analyses.

Preimplantation testing of human embryos—once a specialized adjunct to in vitro fertilization—is now a rapidly expanding domain with profound implications for reproductive decision-making, clinical outcomes, and ethical discourse. Yet, with these advances comes a challenge: how do we ensure that innovation translates into meaningful evidence-based improvement in patient care?”

Not a word about the September 2024 ASRM/SART policy statement, yet, paradoxically, a loud and clear acknowledgment that this alleged “progress” has so far produced no meaningful evidencebased improvement in patient care.

And, of course, also not a word about the damage this alleged “progress” has caused to patients and the IVF field overall in over 20 years of PGT-A utilization in

more detail by the CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, in the introductory article to this issue of the CHRVOICE. In 104 pages and 15 articles, only one article alone by Sarah Lensen, PhD, Marcella I Cedars, MD, and Sebastiaan Mastenbroek, PhD (8 pages, 7.7% of page volume), concluded that, “the current evidence does not justify the widespread use of PGT-A.” This stands in contrast to the following comparatively completely unimportant statements in other articles (the text in bold letter represents verbatim key quotes in those articles) in the following points.

•

•

•

•

… a test should be demonstrated to have good characteristics in each stage of development before moving to the next one, but not a word about the ASRM/SART document about PGT-A. Currently, no embryo diagnostic method has been proven to increase the cumulative live birth rate for a given cohort of embryos,7 but not a word about the ASRM/ SART document about PGT-A, and why then use PGT-A? Standardized, transparent analytical validation grounded in precision, accuracy, and feasibility will strengthen the PGT-assay development and deliver more reliable, clinically meaningful results.8 Basically, an acknowledgment that the current PGT-A does not deliver reliable, clinically meaningful results, without saying it.

Prognostic and diagnostic studies should immediately

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•

•

•

follow analytical validation and before clinical application of a test.9 And how about PGT-A? Recommendations for randomized trials with no comments regarding current PGT-A practice.10 According to the authors, it only briefly discusses the legal and ethical obligations of genetics testing protocols.11 PGT-A does not appear to increase obstetric or neonatal risks, but study variability and confounding factors limit certainty.12

The following 11 pages presented 6 “Editorials,” with 2 written by authors of above above-listed articles: •

•

•

•

The clinical advantage of these tests (i.e., PGT-A) is attained by correctly identifying those embryos with little or no reproductive potential and ranking embryos accordingly.13 PGT-A, of course, has never demonstrated the ability to “correctly differentiate with certainty euploid vs. aneuploid embryos.

It is imperative to recognize the moments when the need for precision outweighs the value of brevity.14 The substance of this statement is truly amazing!

Only a commentary about “the future” of reproductive medicine, with no obvious connection to the subject of the supplement.15 A commentary on the ethics of heritable human genome editing, also with no direct connection to the subject discussed here.16

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So, what was then the purpose of this special issue of F&S? We wish we knew, but we can say with certainty that this special issue of F&S did not benefit US and worldwide IVF practice. We can also say with certainty that avoiding a fair and open discussion of PGT-A was at least 10 and likely 15 years overdue when ASRM/ SART finally published their joint committee document. Nobody is served well if patients continue to be misled, and their pregnancy and live birth chances continue to be adversely affected.

By practically completely avoiding this “never too late” document in their special issue of F&S, its four editors—in themselves an interesting combination of “experts”—however, ended up drawing attention to themselves: Probably most surprising and to a degree reflective of how F&S has been handling the PGT-A controversy since his ascension to the position, the editor-in-chief of F&S, himself, apparently took the lead in producing the special supplement (also being an author on 3/15 articles, 20%). Some editorial offices maintain a policy of no original articles from editors or their departmental colleagues except for clearly marked editorials.

The number two on the team of editors for the special issue was one of the most prominent and long-term proponents of PGT-A, with considerable responsibility for the misdirection of the field when it came to PGT-A. There, of course, was no balancing opponent of PGT-A among the

editors because—somewhat paradoxically—the two other editors of the supplement issue are not known for any association or special expertise with the subject of PGT-A. One, of course, does not have to be a hands-on “expert” to develop valid judgment, but both of these editors are from France, where PGT-A is forbidden because it is not considered a medical necessity. (iv) Ethical and professional responsibilities. We, that is, we physicians, we scientists, we reviewers, we editors, and, yes, we members of medical societies like the ASRM and SART, have professional responsibilities, and our first and foremost responsibility is “primum non nocere,” do no harm! And nobody can any longer claim that the utilization of PGT-A does not do harm every single day to large numbers of women and couples undergoing fertility treatments.

In other words, it is no longer good enough—as ASRM has finally done—to agree that PGT-A does not improve IVF outcomes, but it is essential to point out the damage that PGT-A has done to so many patients over so many years by reducing their pregnancy and live birth chances because of misdiagnoses of embryos with pregnancy potential that were not transferred or were even discarded.

And, indeed, thousands of such embryos are still cryopreserved, with most colleagues refusing their transfers. But that is not all: How about all of the women who were prematurely driven into thirdparty egg donation because PGT-A didn’t give them “transferable” embryos, and how about all of the 79

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women and couples who, simply, abandoned parenthood for the same reasons.

We can no longer simply accept that PGT-A does not improve IVF outcomes and have to, finally, face the truth that for many patients, PGT-A, indeed, harms pregnancy chances in IVF. Why is this of importance?

Because “primum non nocere,” therefore, ethically no longer allows us to simply do nothing and continue in our ways with PGT-A practice as usual. And this is why the CHR perceives the recent special issue of F&S3 as so offensive. Reading this supplement, one gets the overall impression that “everything is fine as is.”

There, indeed, is no reason why we should not just continue in our PGT-A utilization as usual. There is nothing to worry about; sometimes in the future, we will figure out how to do everything right, and then and only then will a beneficial utility for PGT-A become obvious.

This is, however, not how medicine is ethically practiced. Time for our medical journals and medical societies to speak up!

And a final positive word about F&S That medical journals including F&S, can do better was recently demonstrated in a Reflections article in F&S (i.e., a commentary) by two scientists from Ireland and the UK, respectively,17 who commented on an article in the same issue which attempted to present recommendations to improve the quality of 80

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nonrandomized studies of interventions (NRSIs) in fertility treatment research, addressing their roles as complements to randomized controlled trials (RCTs) in evaluating treatment outcomes, with the subject being patients undergoing IVF treatments.18 In doing so, the authors reported what they called a “multidisciplinary expert consensus,” by worldwide consensus, the lowest level of medical evidence.

We are pointing these two articles out because they demonstrate exactly the point we earlier in this commentary attempted to make: Recognizing that even the best team of journal editors cannot and will not be perfect in deciding which manuscript to accept for publications and will overlook major errors in published papers, it behooves the journal—if a commentary is published—to choose “experts” as authors who are respectfully critical of the published manuscript. These two manuscripts demonstrate this point perfectly, as the following closing paragraph of the Reflections article demonstrates.

“The recommendations of Schwarze et al. (name misspelled in article) help draw our attention to the importance of rigorous methods in assisted reproductive technologies (ART), where critical errors in the design and analysis of NRSIs are common. In an evaluation of PGT-A investigators may include any participant with no embryos in a control group, on the grounds that they did not undergo PGT-A, introducing a form of immortal time bias. In an evaluation of an embryo culture

medium, investigators might adjust for the number of embryos transferred, introducing bias because of overadjustment. The recommendations, if followed, will prevent instances such as these. Nonetheless, we believe it is important to hold the line.

The NRSIs should be used when necessary, but the impracticalities and apparent ethical limitations of conducting RCTs should not be overstated."

Cudos to F&S in this case; we only wish this would happen more often!

References 1. Practice Committees of ASRM & SART. Fertil Steril. 2024;122(3):421-434 2. Kliff A. The New York Times. November 7, 2025.p1.

3. Fertil Steril 2025;124:5P1 4. Barnhart et al. Idem: 801 5. Lensen et al., Idem: 870-877 6. Barnhart et al., Idem: 802-811 7. De Ziegler et al., Idem: 812-821 8. Popovic et al., Idem: 822-838 9. Pirtea et al., Idem: 839-848 10. Wilkinson et al., Idem: 849-859 11. Capalbo et al., Idem: 860-869 12. Wang et al., Idem: 878-892 13. Franasiak J, Pirtea P. Idem: 893-894 14. Lee et al., Idem: 896-897 15. Penzias AS, Adashi EY. Idem: 898-899 16. Joffe S. Idem: 900-901 17. Dahly DL, Wilkinson J. Fertil Steril 18.

2025;124(4):657-658 18. Schwarze et al., Fertil Steril 2025; 124(4):749-758

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FERTILITY WITHOUT SEX? NOT OFTEN TALKED ABOUT

TURNING UP THE HEAT—AND THE SCIENCE OF DESIRE: Women's testosterone levels and their libido

By Lara Guijarro-Baude, MD, Research Intern at the FRM and the CHR, and Sonia Gayete-Lafuente, MD, PhD, Clinical Research Fellow at the FRM and the CHR. Both can be reached through the editorial office of the CHRVOICE.

BRIEFING: A recent New York Times feature brought testosterone therapy for women back into the public spotlight, and did so for good reason. The piece reignited conversion about women’s libido, hormones, and aging—topics frequently untreated and misunderstood. Yet, in doing so, it also blurred the line between evidence-based medicine and social commentary. Across the US, more middle-aged women are turning to testosterone to help revive their energy, mood, and sex drive. The renewed attention is welcome, as female sexual health deserves far more discussion. But as enthusiasm grows, so does confusion: how much is too much, what’s truly safe, and what options do women really have?

CONFLICT STATEMENT: Please note that the CHR owns shares in a company called Fertility Nutraceuticals, LLC, which does business under the name Ovaterra. Ovaterra produces a DHEA product under the name VIVO®, which could be viewed as a potential economic conflict for any CHR employee.

The cover of the November 3, 2025, Sunday New York Times Magazine

A powerful hormone

roles in maintaining energy, mood, muscle tone, and sexual drive and function. Physiologically, levels

Women naturally produce testosterone, though in much lower amounts than men. Beyond its reputation as the “male hormone”, testosterone in women plays vital 82

gradually decline with age, particularly after the late 30s, and this decrease can contribute to a reduced sense of vitality and sexual

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desire. Clinical research has shown that restoring testosterone to the range typical of a woman’s younger reproductive years can meaningfully improve libido and sexual satisfaction. However, maintaining physiologic levels is crucial, and

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it is important to remember that “more” is not always necessarily “better.”

that low-dose transdermal testosterone, administered to restore physiologic premenopausal levels, can significantly improve Because it is a relatively taboo sexual desire, arousal, and subject, a recent lead article satisfaction. These benefits appear also conquering the cover of the without major safety concerns when magazine in the Sunday New used under medical supervision York Times Magazine by Susan and with regular monitoring of Dominus (with cover picture by serum hormone levels, although Fromm Studio, see above) came as long-term safety data are still somewhat of a surprise. The article missing. reported that many women are now Recognizing this, several experimenting with much higher countries—including Australia, doses of testosterone, in some the UK, New Zealand, and cases, even reaching the levels of South Africa—have approved teenage boys. While some notice standardized testosterone creams or impressive results (including raging patches for women. In the UK, for sexual desire awakening stories example, demand for female-dose all over social media—as The New testosterone increased nearly 400% York Times article remarkably between 2019 and 2022, reflecting caricatures), others experience both growing awareness and unmet unwanted side effects like acne, hair need. In the United States, however, thinning, or voice changes. women who seek treatment must navigate a regulatory gray zone.

The narrative, though provocative, Because of the lack of FDAmissed the clinical nuances: approved products, many testosterone therapy for women physicians hesitate to prescribe should not be about mimicking testosterone, while others may male physiology, but about lack experience in proper dosing restoring balance. and monitoring. Clinicians often prescribe off-label low-dose testosterone using compounded The evidence and the gap formulations or adapted male products. Moreover, insurance For men, testosterone replacement coverage is rare, and some women is nothing new. Those men resort to med-spas or wellness experiencing the effects of low clinics offering testosterone testosterone—low libido, low “boosts” with little oversight. energy, loss of muscle mass—the The result is a landscape where FDA has approved more than 30 products since the 1950s; and yet, to medical prudence and marketing enthusiasm coexist uneasily. this day, there is no FDA-approved testosterone cream, patch, pill or For these reasons, medical societies shot for women, even though their recommend caution. Until longtestosterone levels fall far more precipitously than men’s as they age, term safety data become available and standardized formulations and despite robust data supporting are approved, testosterone therapy its efficacy in specific contexts. for women should be approached High-quality randomized conservatively and under expert controlled trials have shown

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supervision. Still, androgen deficiency in women is real, and its impact on well-being and libido should not be dismissed. This is where other, milder androgenic compounds—such as DHEA—may play a valuable role.

DHEA: the FDA-approved androgen for women While testosterone continues to attract public attention and regulatory debate, another member of the androgen family, dehydroepiandrosterone (DHEA), has long been recognized for its therapeutic potential in women.

Unlike testosterone, DHEA is FDA-approved for specific medical uses, including in women, and plays a pivotal role in reproductive endocrinology.

DHEA is a naturally occurring prohormone, serving as a precursor to both testosterone and estrogen.

Its production peaks in early adulthood and then declines steadily with age, contributing to a gradual reduction in overall androgenic activity. Because DHEA is converted into active hormones only as needed, its effects tend to be milder and more physiologic than direct testosterone therapy, offering a subtler way to support hormonal balance without the risks of supratherapeutic exposure.

At the Center for Human Reproduction (CHR), DHEA has been a centerpiece of research and innovation for more than two decades. Our clinical investigations and numerous pioneer publications have shown that DHEA supplementation can enhance the ovarian environment, improve follicular function, and 83

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increase oocyte quality, particularly in women with diminished ovarian reserve or advanced reproductive age. These findings have shaped global fertility practice and have been validated across multiple independent studies.

Beyond fertility, DHEA’s mild androgenic properties have also been associated with improvements in sexual well-being, mood, and energy levels in women experiencing hormonal decline.

Our own research concludes that supplementation with DHEA can remarkably improve sexual function in older premenopausal women with low baseline Female Sexual Function Index (FSFI) scores, mainly enhancing desire, arousal, and lubrication. While not a substitute for testosterone in cases of severe androgen deficiency, DHEA offers a gentle, physiologic pathway to support libido and vitality; one that aligns with the principle of restoring balance rather than imposing excess. As such, DHEA represents a bridge between endocrinology and quality of life: a safe, evidence-based approach that reflects CHR’s philosophy of precision and personalization in women’s health.

can stem from hormonal decline, but also from stress, relationship issues, mood disorders, medication effects, or chronic fatigue. Effective care means addressing these layers holistically.

Reading List Dominus S. Testosterone is giving women back their sex drive—or then some. The New York Times Magazine.

October 22, 2025. https://www.nytimes. com/2025/10/22/magazine/testosteronewomen-health-sex-libido-menopause.html Gleicher N, Barad DH. Dehydroepiandrosterone supplementation in diminished ovarian reserve. Reprod Biol Endocrinol. 2011;9:67.

Shohat-Tal A, Sen A, Barad DH, Kushnir VA, Gleicher N. Conversion of DHEA to testosterone. Nat Rev Endocrinol.

2015;11(9):521.

Kushnir VA, Darmon SK, Barad DH, Weghofer A, Gleicher N. Effects of DHEA on sexual function in premenopausal infertile women. Endocrine.

2019;63(3):632-638.

SEX AS EXERCISE? This is at least what a recent article in World Health.Net suggested, and it, therefore, and we are not kidding, appears also associated with certain health benefits. Like “usual” exercise, it produces an increase in heart rate as well as blood pressure and, of course, results in the release of endorphins.

And who knew, it can also be a fun and enjoyable physical activity, according to the article.1 And if you want to know even more detail, the article describes in detail the physical, mental, and emotional benefits of sex and - not kidding the sex positions that burn the most calories, Reference 1. Webber TJ. Sexercise: Beyond the Sheets, Sex as a Calorie-Burning Activity.

WorldHealth.net. Published August 20, 2025. Accessed November 25, 2025. https://worldhealth.net/news/sexercisesex-as-a-calorie-burning-activity/

The CHR perspective At the CHR, we’ve long recognized that androgens play a vital role in women’s reproductive and sexual health, far beyond what estrogen alone can do. Yet, we’ve also warned that medical indications, not social trends, must guide androgen therapy. The key lies in personalized dosing, careful monitoring, and understanding that libido is a multifactorial phenomenon. Low sexual desire 84

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This graphic shows how DHEA levels rise sharply during puberty, peak between ages 20– 25, and then steadily decline across the lifespan in both men and women. Men maintain higher overall levels than women, but both sexes experience the same downward trajectory, with DHEA production dropping to a small fraction of its peak by older age.

(Graph Courtesy of Anna Cabeca, MD)

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FOOD IS MEDICINE All about nutrition, obesity drugs, & food in general BRIEFING: That “food is medicine” is an increasingly frequently heard phrase in medicine that also applies to fertility. This section of the CHRVOICE caters to this concept in a variety of ways. A prominent current subject is, for example, weight loss with GLP-1 receptor agonist drugs since obesity is becoming an increasingly frequent co-diagnosis in infertility practice.

A mother’s pregnancy diet apparently affects the offspring’s neurodevelopment A quite significant study in Nature Metabolism made a somewhat surprising connection between maternal pregnancy diet and subsequent neurodevelopmental disorders in offspring.1 The study found significant associations with attention-deficit hyperactivity disorder (ADHD) and autism diagnoses (the ADHD association was validated in three large, independent mother–child cohorts (n = 59,725, n = 656, and n = 348) through self-reported dietary modelling, maternal blood metabolomics, and fetal blood metabolomics. Metabolome analyses identify 15 mediating metabolites in pregnancy that improve ADHD prediction.

Associations between western dietary pattern metabolite scores and neurodevelopmental outcomes were consistently significant in early–mid-pregnancy. The authors suggested that these reported findings open the possibility of targeted prenatal dietary interventions to prevent neurodevelopmental disorders.

The report, therefore, also emphasized the importance of early 86

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intervention. Especially considering the apparently rapidly increasing prevalence of ADHD and autism in Western countries, this study received too little attention in the media. One point of caution, however, must be made: The study depended on self-reported diets, and self-reporting has its problems,2 as we have discussed in these pages before.

published mega-study in PNAS, which, like the study discussed in the previous commentary, also did not receive enough media exposure; however, has now radically changed his mind.2 “Just getting our children moving,” as he had believed for the longest time, would dramatically reduce childhood obesity (and, therefore, lifelong obesity), was fully dispelled by this study.

References 1. Horner et al., Nat Metab 2025;7:586-601 2. Stubbs RJ, Hopkins M. Nat Food.

2025;6:8-9

Somewhat surprisingly, the study demonstrated that daily energy expenditures are greater in developed populations and active energy expenditures are not reduced in more industrialized populations. Instead, it was the dietary intake that played a much larger role in increasing the prevalence of obesity that has been observed to occur with economic development.

It is the diet, stupid; why our diet determines our destiny!

William G. Wilkoff, MD, has been a primary care pediatrician for almost 40 years and is well known for authoring several books. In a recent Medscape Commentary under the masthead, “Our Diet Is Our Destiny,” he acknowledged having completely changed his mind about what was the most critical factor leading to obesity.1 He now recognized his longstanding bias in believing that physical inactivity and Western society’s gravitation toward a primarily sedentary lifestyle were ’at the heart of the problem,’ leading to increasing obesity. A recently

Wilkoff concluded with the following paragraph: “I will continue to preach the gospel of activity and sleep, but I will remove any reference to obesity. To be honest, even before I encountered this study, I was beginning to have my doubts about their effectiveness in weight management. From my own personal experience and observations, the primary reason to promote activity and sleep is their obvious positive effects on mental health.”

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References 1. Wilkoff WG. Medscape. September 10, 2025. https://www.medscape.com/ viewarticle/our-diet-our-destiny2025a1000ngw 2. McGrosky et al., PNAS 2025;122(29):e2420902122

A surprising impact of the keto diet on mental health That a ketogenic diet (KD) may positively affect neurological and neuropsychiatric disorders has been previously reported. But now a small study in Translational Psychiatry suggested that this effect may be significantly larger than had previously been assumed.1 BACKGROUND: People with excess adiposity are more likely to meet the criteria for and report symptoms of depression.

The correlation between obesity, insulin resistance, and depression may be partially mediated by alterations in inflammatory pathways that manifest in higher levels of various immune/inflammatory mediators, such as TNF-alpha, IL1beta, and IL-6.

THE KETOGENIC DIET is a very low-carbohydrate diet in which carbohydrates are restricted to <50 g/day, protein is consumed in moderation (~1.5 g/kg/day), and fat ad libitum to satiety.

The study examined the tolerance for a KD in 24 young adult students diagnosed with major depressive disorder and assessed their symptoms of depression and metabolic health. They received standard of care counseling and/or medication treatment at

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baseline. They were enrolled in a 10–12-week KD intervention that included partial provision of ketogenic-appropriate food items, frequent dietary counseling, and daily morning tracking of capillary R-betahydroxybutyrate (R-BHB). Only 16 students (10 women, 6 men, mean age 24 ) completed the intervention. Nutritional ketosis (R-BHB > 0.5 mM) was achieved 73% of the time. Depressive symptoms decreased postintervention by 69% and 71%, respectively, by two standard assessment methods (p < 0.001), with improvement occurring within 2–6 weeks. Global wellbeing increased nearly 3-fold (p < 0.001). Participants lost body mass (−6.2%; p = 0.002) and fat mass (−13.0%; p < 0.001). Serum leptin decreased (−52%; p = 0.009), and brain-derived neurotrophic factor increased (+32%; p = 0.029).

Performance improved on several cognitive tasks.

The authors concluded that in students with mild to moderate depression, implementation of a WFKD for 10–12 weeks is a feasible adjunctive therapy and may be associated with improvements in depression symptoms, well-being, body composition, and cognition.

Though in this study reported effects of KD are remarkable, this study, too, must be considered with caution, considering the very small number of study participants. The study, however, also deserves some additional comments regarding its relevance to reproductive medicine: First, there exists some evidence to suggest that the KD, especially in obese individuals, is anti-inflammatory.2 A recent article

in CookUnity, in an attempt to compare the KD with a Paleo diet, concluded that both had some antiinflammatory effects.3 A relatively recent review article suggested a beneficial effect of the KD on women with PCOS.4 In summary, there exists weak evidence that a KD may positively affect at least some infertility patients.

For us here at the CHR, the most interesting aspects of this discussion are, however, the potential anti-inflammatory of the KD (or for that matter whatever other diets) because—if factual— such an association would provide further support for the argument that depression—at least in some forms (for, example in peripartum depression)—must be an autoimmune disease, an argument the CHR’s investigators have been making for many years.5,6 References 1. Decker et al., Translational Psychiatry 2025;15:322 2. Rondanelli et al., Nutrients 2024;16)23);4002 3. CookUnity 2025; https://www. cookunity.com/blog/paleo-vs-keto-forinflammation 4. Tsushima et al., Front Nut. 2024;11:1395977 5. Gleicher N. Autoimmune Rev 2007;6:572-576 6. Gleicher N, Weghofer A. Hum Reprod 2009;24(3):760-761

We could never stop writing about GlucagonLike Peptide-1 (GLP-1) drugs We, indeed, could fill almost limitless pages with GLP-1 news.

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drastically lowering their costs to the public, in economics sections because the economic effects of rapidly increasing use of these drugs in the population will only further speed up because of lower costs.

All of this, of course, has major consequences for manufacturers of GLP-1 drugs (and, yes, oral GLPs can be expected very soon; see also below). And then there is, of course, the FDA, which stopped some companies from selling GLP1s after the announced “shortage” in availability had been overcome.

But where is the FDA now, with liquid GLP-1 being openly advertised with the bizarre claim that the liquid form of this medication can be added to any fluid and allows for dosing, depending on how much weight one wishes to lose. One, of course, should ask where the data are in support of these claims, even if made by prominent “TV doctors.”

And, yes, the public should be very careful where and from whom those medications are purchased.

The CHR, indeed, strongly recommends staying away from flyby-night outfits.

GLP-1s, after all, are serious medications with serious consequences, but in some patients, also with potentially serious side effects. Moreover, like all medications, they have contraindications and, therefore, should always be taken supervised of a physician. A very solid review paper on the effects of GLP-1 agonists on reproduction was recently published in the JCEM, which we strongly recommend.

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The CHR has advocated for their use in selected infertile couples with significant obesity (female as well as male) since their rise to stardom started. We are also very pleased to report that increasing real-world data (mostly from women who conceived unexpected while on a GLP-1) suggest that these medications do not appear to have any adverse effects on pregnancy and/or newborns, but at least, for the short-term future, they are still considered contraindicated in pregnancy, and we recommend a ca. one month wash-out period after taking them prior to pregnancy before attempting pregnancy.

Above above-noted review article noted two principal concerns about their use in pregnancy: (i) Weight loss of women during pregnancy has—basically universally—always been associated with adverse fetal outcomes. Moreover, preclinical studies of GLP-1s suggested some fetal toxicity.1 Interestingly, the use of GLP-1s within 24 months pre-conception was, in a recent paper in the American Journal of Obstetrics & Gynecology, reported to be associated with decreased risk of adverse obstetrical outcomes, including gestational diabetes, hypertensive disorders of pregnancy, preterm delivery, and Cesarean section delivery.2 What this observation, however, basically likely means is that losing weight in the two years prior to conception reduces pregnancy risks, and that, of course, is no surprise.

And since we, of course, cannot cover all of the above-noted areas GLP-1s have relevance to, we

will here offer only a very short summary of highly selected recent publications, only addressing clinical or basic physiologic subjects, important for the understanding of how GLPs work.

REAL-WORLD GLP-1 WEIGHT LOSS RESULTS DIFFER FROM THOSE AT CLINICAL TRIALS It, of course, should never surprise that real-world data fail to meet expectations created by clinical trials, which usually select patients carefully and follow them with much more detailed interest than patients receive from medical providers in the real world.

As colleagues from Cleveland reported in Obesity (Silver Spring) in—importantly—a retrospective study (with all of the shortcomings of such a study model), the average weight reduction in this cohort was lower than that observed in the main phase 3 trials of semaglutide (Wegovy®) and tirzepatide (Zepbound® and Munjaro®). The authors concluded that the likely causes were higher rates of discontinuation and lower maintenance dosages. In short, we really can’t be sure of the data!

CAN GLP-1s REDUCE U.S. MORTALITY BY UP TO 6.4%?

This is at least what reinsurance company Swiss Re claimed, according to Reuters, should be the case by 2045.3 Under the most pessimistic assumptions, the decline would be only 2.3%

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ORAL GLP-1s ARE COMING In an article in Medscape on the future of GLP-1s, Jennifer Larson noted that over 42% of the adult population in the U.S. is considered obese, and almost 31% are considered overweight. This, of course, predicts huge future market growth for GLP-1s and potentially other weight loss medications currently under development.4 As she furthermore noted, “a daily oral GLP-1 could be a good fit for certain people according to some obesity experts.” It could be a particularly good option for people who want to lose only relatively little weight or want to maintain the weight loss achieved with injectable medications.

It may come down to cost!

HOW DO GLP-1s WORK IN THE BRAIN? A recent interesting review article in Endocrinology reviews how GLP-1s act on hypothalamic feeding circuits and proposes a conceptual framework highlighting opportunities for the therapeutic potential from targeting central GLP-1 pathways in obesity treatments.5 We recommend the article.

FEMALE HORMONE LEVELS CAN INFLUENCE HOW GLP1s WORK In this case, using Tirzepatide (Zepbound® and Mounjaro®), researchers from Mayo Clinic— according to Conexiant—reported at the 2025 Annual Meeting of

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the Menopause Society that the reproductive stage of a woman and hormonal treatments can influence weight-loss outcomes treated with GLP1s. Postmenopausal women, indeed, experienced the greatest weight loss.6

GLP-1s WILL END UP AFFECTING ALMOST ALL OF MEDICINE Originally developed as diabetes drugs, then—much more recently— discovered as very successful weight loss drugs, GLPs are now investigated for beneficial treatment effects in almost every medical specialty. JAMA in a Perspective review article recently offered some very worthwhile insights into what new molecules for GLP-1 medications are under development (Retatrutide, Survodutide, MariTide—who is inventing these names?!—Insulin degludec-liraglitide and Insulin glargine-lixisenatide, Amycretin, Semaglutide, and cagrilintide) and for what maladies.7

pharmaceuticals/swiss-re-says-glp-1drugs-could-reduce-us-mortality-byup-64-2025-09-17/ 4. Larson J. Medscape. September 10, 2025. https://www.medscape.com/viewarticle/ pill-vs-pen-can-oral-glp-1s-transformobesity-treatment-2025a1000nwy 5. Hwang et al., Endocrinology 2025;166(10):bqaf125 6. Conexiant. October 27, 2025. https:// conexiant.com/obgyn/articles/howhormones -may-influence-tirzepatideoutcomes/ 7. Gonzales-Rellan MJ, Drucker D. JAMA 2025;334(14):1231-12 34 8. Srinivasan et al., J Endocrine Society 2025;9:bvaf141

The Journal of the Endocrine Society offered a Review article on the emerging role of GLP-1s in alcohol and substance abuse disorders by elucidating their interactions with various neurobiological pathways involved in addiction.8 It is really amazing how multifaceted the therapeutic effects of this family of drugs apparently are.

References 1. Couldwell et al., J Clin Endocrinol Metab 2025110:3009-3024 2. Imbroane et al., Am J Obstet Gynecol 2025;233:116.e1-7 3. Burger L. Swiss Re says GLP-1 drugs could reduce US mortality by up to 6.4%.

Reuters. September 17, 2025. https:// www.reuters.com/business/healthcare-

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NEWS FROM NYC’S RESTAURANT SCENE

REVIEWS OF RESTAURANTS WE RECENTLY VISITED, PLUS AN UPDATE Our readers probably have noticed that, on occasions, restaurants are added or removed from our most favorite and, therefore, recommended restaurant list.

This reflects continuous visits by our reviewers, but also the fact that restaurants change. To maintain quality is, likely, the most difficult task a restaurant faces among the many difficult tasks that have made the management of a restaurant one of the most, if not the most, difficult management jobs in business.

Melissa McCart in Eater, it was planning to reopen further downtown in NoHo in the spring. But no further details have been announced since, and we are anxiously awaiting the restaurant’s rebirth under its very talented chef-owner, Markus Glockner.

The good news is that we also added two restaurants to our recommended list above, with both also joining our most favorable restaurants list, Soothr, LIC— our first Thai place—and Maison Nur, a beautiful restaurant-lounge with a nightclub in the basement that only opens at 10:00 pm. More on both in our restaurant review section below.

Moreover, since we have found the food at 425 (Park Avenue) during several recent visits greatly improved, we added a third star (***) to the restaurant’s description. Chef Jonathan Benno is doing an amazing job in an amazingly beautiful setting.

Restaurants we are following There is also a third list of restaurants we follow, and those are the ones we can’t make up our minds about or are just not certain enough yet whether to recommend them. Here are the names of a few of them, which you may see again in the future.

Markus Glockner, the very talented chef of the just-shuttered Koloman (Photo Courtesy of Eater)

Restaurants removed from our recommended list above are more frequently among the more (or most) expensive restaurants on the list. On occasion, we may bring back such a restaurant to our list, but that is an exception. Sometimes, even very good restaurants close and have to be taken off the list. That recently happened with one of our favorite restaurants in the city, Koloman, a one-star Michelin restaurant on West 29th Street, which very successfully blended Austrian and French cuisines. It was announced on very short notice at the end of the summer announced a split from Nomad’s Ace Hotel, but, according to 92

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There is, for example, Genesis House Restaurant, an absolutely gorgeous Korean restaurant above the Genesis car show room at 40A 10th Avenue in the Meatpacking District. It is now managed by one of our all-time favorite restaurant managers, Ahra Ko, who used to be the manager at one of our favorite Korean restaurants, Oiji MI. We have visited the restaurant several times and have been impressed by the improvements in food quality as well as service, but we are not yet fully ready to add this restaurant to our recommendation list.

And then there is the Crane Club by the Tao Group Hospitality in West Chelsea, like the Genesis House

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Genesis House Restaurant, so named after the car company, Genesis, which has its showroom on the ground floor

on 10th Avenue, just a few blocks higher on the other side of the Meatpacking District. This restaurant/ club has now been around since 2024 and has become quite popular with a usually younger crowd. But the food—while, of course, not bad—is really also not great. And, frankly, it is not good enough for our recommendation list and has over almost two years also unfortunately not gotten any better.

This is too bad because the place is attractive, has a vibe, and offers excellent staff service and has Michelin-starred Melissa Rodriguez as chef, who in the same space years earlier had run the kitchen at Mario Batali’s Del Posto.

And then there is, of course, Babbo, another former Mario Batali restaurant at 110 Waverly Place, which recently reopened under new ownership but with the same chef, Mark Ladner. We have been there only twice so far, and the barroom has not changed much despite reports of a major renovation. We, unfortunately, really didn’t like the food, but considering the same chef is again overseeing the kitchen, it frankly does not surprise us because —even in those days—Babbo was not one of our favorite Italian restaurants. But to be fair, running in a restaurant can take time. Hopefully, it's just the early days after reopening, and the restaurant will find its footing over the next few months.

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SOOTHR LIC (NEW)+/***/$$v – Amazing Thai Food 25-20 43RD Street, LIC, Queens; T: (929) 554 9955

We have known the two Soothr restaurants on Eastand Westsides of lower Manhattan for some time and liked the food (East- better than Westside); but their new restaurant in Long Island City is a different story: not only do we love the food, but we are really ecstatic about everything at this new restaurant, just across the Ed Koch Queensboro Bridge—the food, the staff service, the design of the place and, ultimately, about its success because—as large as the place is seating ca.

350—it is always packed and probably turning over tables up to three-times every evening.

An arch separating between two of the three main dining rooms...

According to the restaurant’s website, Soothr LIC draws inspiration from the bustling heart of Bangkok’s Yaowarat Chinatown, and this is exactly how it feels every evening (it is also open for lunch). With a very young and mostly Asian clientele, the place radiates the energy of a busy city in any one of many Asian cities and countries with substantial Chinese heritage.

It is a feast just to step into the environment.

If you like Thai food, this is now the place to be. The menu offers a wide choice of dishes, and after too many visits to count, we really have not had a bad dish. Suppose there is one shortcoming—especially for Thai soup lovers—the menu offers, unfortunately, only one soup, an absolutely delicious Tom Yum Seafood Hotpot. Our favorites among appetizers are fried dumplings filled with pork, shrimp, and crab meat, scallion, water chestnut, sesame oil wrapped in soy sheets with plum sauce nuts (Hoi Johr), and jeeb dumplings stuffed with ground pork, shrimp, water chestnut, cilantro, scallion, and sesame oil, served with a spicy vinaigrette, as appetizers, delicious!

And the main courses, of course also don’t disappoint, from Yaowaral Roasted Duck—a true masterpiece of flavors, including ginger and garlic, a steamed branzino in a ginger-soy sauce, and whole Dungeness Crab Karee swimming in the restaurant’s widelyused curry-rich and very velvety sauce, the crispy pork belly (Moo Krob), the best Pad Thai we have ever tasted with shrimp, and innumerable additional dishes, many we have still to try out in future visits, including what the restaurant calls. Soothr Green—t's a vegetarian and vegan menu.

A wonderful addition to New York City’s dining scene!

...and the room behind the arch (Both Photos Courtesy of Soothr LIC)

Dungeness Crab Karee (left) & Yaowarad Roasted Duck (right)

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if the menu item has a very familiar name like steak au poivre—the kitchen’s execution varies greatly from the standard, making the dish stand out.

Hoi Johr (Left) & Tom Yum Seafood Hotpot

MAISON NUR (NEW) +/***/$$$v - A place to see and be seen 217 Bowery, Lower East Side. T: (646) 668 7738

The menu is still quite small, and choices are, therefore, limited, but they include a range of meats and seafood dishes cooked to perfection and even improving over the short time of this restaurant’s existence, suggesting that further improvements can be expected. And, yes, even the espresso machine is working by now, and making a delicious espresso!

And the place is gorgeous and comfortable, especially in the lounge area facing a long bar, where the full menu is served, giving singles of both sexes, similar to the Crane Club, an opportunity to mingle, though with a less noisy background, even if every barstool is occupied.

Unsurprisingly, the establishment is attracting a rather young and attractive crowd, which, to balance the vibe, is served by a very attentive and, what can only be described as, the most attractive staff we have seen in years in a New York restaurant. Give it a try!

The lounge part of the restaurant across from the bar in the front and the table service on the podium in the background.

(Photo Courtesy of Maison Nur)

This restaurant was a surprise! When first recommended by a friend, we were skeptical because the guy behind this newly opened “Downtown inplace” was not known for good food but for fun nightclubs, like Sway and the Tao Downtown, Maison Nur, however, is different (and we here review only the upstairs restaurant; the nightclub in the basement only opens at 10 pm, a time when we usually are already beyond dessert and on the way home).

As Justin Goldman reported in Eater on August 26, 2025, Nur Khan recruited Paris chef Richard Farnabe as executive chef, who’s prior jobs included time at leading New York establishments like Daniel and Jean-Georges (and others) creating a restaurant with a very special vibe as well as excellent—and more importantly a “distinctive” menu—that did not include the standard dishes which one these days can find in almost all new upscale restaurants and—even

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An entrance at Maison Nur by artist Venezuelan street artist Harif Guzman (Photo Courtesy of Maison Nur)

A notable dish: the spaghetti wrapped around parmesan (Photo Courtesy of Maison Nur)

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Reproductive Medicine Reproductive Medicine Reproductive Medicine BRIEFING: In this section, the CHRVOICE offers opinions about recent articles in the medical literature directly refe rring to reproductive medicine and infertility practice. Like in the earlier general medicine section, the commentaries on papers in the recent literature are, again, to a degree subjective opinions of the CHR. And —while hopefully mostly unbiased, they are usual referenced. We are starting today with a section on legal issues, but want to point out that in this issue of the CHRVOICE discussed two very important legal issues for reproductive medicine already in the two opening full-length articles.

THE CLINICAL PRACTICE OF ART ASSISTED REPRODUCTIVE TECHNOLOGY (ART), INCLUDING IN VITRO FERTILIZATION (IVF) CHR OPINION: Ethics Committee Opinions of ASRM & SART: The mysterious disappearance of an important Ethics Committee opinion BRIEFING: The CHR here comments on periodic mailings ASRM members receive from the society announcing the pending publications of Opinions

by Ethics or Clinical Practice Committees of the ASRM and its daughter organization, SART, and requesting final comments from the membership before publication. The impetus for this CHR Opinion came from two related recent events: (i) The disappearance without explanation of an Opinion of the Ethics Committees that strongly opposed the clinical utilization of PGT-P (preimplantation genetic testing for polygenic conditions); and (ii) publication—possibly by 96

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invitation—of a strongly supportive Opinion article for the utilization of PGT-P in Fertility and Sterility (F&S), the flagship journal of ASRM, by three obviously economically conflicted individuals, one of which having been a longstanding and very influential proponent of PGT-A (preimplantation genetic testing for aneuploidy). These two obviously contrasting events, of course, speak for themselves. They also urgently ask for an explanation from the ASRM and F&S.

Members of the ASRM, under the signature of their respective Ethics or Practice Committees, periodically receive from the society drafts of combined Opinions of ASRM and SART (why these two societies of ASRM have separate committees is unclear).

The apparent purpose is solicitation of comments on the proposed Opinions from the membership before formal publication (in F&S).

The subjects of such Opinion documents can at times be rather banal, like the most recently circulated document on “Compassionate (embryos) transfer,” a process where patients, most often for religious purposes, request at non-fertile times in their

menstrual cycle clinically useless transfers for non-reproductive purposes. But fortunately, more often than not, these Opinions address really important ethical and/or clinical issues, where comments from membership would seem of significant importance.

But as has been our impression (and we have to point out that we have not conducted a formal study), the mailed drafts only rarely change in a significant fashion before formal publication. But in some rare cases, something funny can apparently happen—a proposed draft can disappear!

Such a disappearance act was, indeed, what happened several months ago, when the membership received a usual prepublication request for comments on a suggested policy recommendations from the combined Ethics Committees of ASRM and SART under the heading, “Use of preimplantation genetic testing for polygenic disorders (PGT-P), very obviously really important potential document in these days—when lay media—as elsewhere discussed in this issue of the CHRVOICE—have suddenly discovered the subject of polygenic disease risk screening

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and several laboratories are already commercially offering such screening for human embryos. As we have noted before in these pages on repeated occasions, several genetic societies have, indeed, issued opinions on the commercial utilization of PGT-P, universally condemning it a premature and, at times, even unethical.1-3 A professional opinion from the leading fertility society in the US, ASRM (and, on a side note, in Europe from ESHRE), would, indeed, seem especially urgent not only because infertility practice controls the IVF process, but also because PGT-P is not only (falsely) advertised as a tool to prevent polygenic diseases, but also as an enhancing tool to, for example, produce offspring with blue eyes, higher intelligence, etc. In other words, PGT-P is presented as the eugenics tool of our times and is already finding a significant following among investors in Silicon Valley and, as at least one public opinion poll has suggested, in the general public.4 It is important to note that the preliminary ASRM/SART document on the subject reached all the correct conclusions and— without disclosing any secrets— condemned the use of PGT-P for trait selection, described PGT-P as a nascent and unproven technology, not recommended for clinical use which, therefore, should not be offered as a clinical service as of this point, and stressed that research on PGT-P should only be conducted under IRB supervision and clinical use should occur only after safety, efficacy, ethical and societal concerns have been addressed.

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This vanished document, indeed, reached practically the identical conclusions several professional genetics societies had reached already quite some time earlier.

It is not only high time for ASRM/SART to publicly explain what happened to the proposed Ethics Committee draft, but the infertility field is in urgent need of a document that defines the field’s position on the clinical and commercial use of PGT-P. We are fairly certain that the Committee’s document was not pulled because one or more ASRM members opposed some wording in the draft. The lobbying had to come from much more powerful sources in industry (i.e., genetic testing labs, investor-controlled IVF clinic networks, etc.), now the major contributors to the ASRM budget after big pharma in the fertility field has shrunk to very small and mostly uninvolved pharma.

Also telling is in this context— rather paradoxically—a very recent, apparently invited pure Opinion article by three individuals—in ASRM’s main flagship journal, F&S, the senior author among them likely the most prominent and most consequential proponent of PGT-A since its inception. All three identified themselves in their conflict statement as employees and stockholders in a new startup company, which specializes in polygenic predictions, and which describes itself on its website as “a team of scientists building the highest quality genetic tests for families.”

And we are quoting here from the introductory paragraph of their article: “Over the past few decades,

insights from genetics have given IVF couples new options for deciding which embryo to transfer.

The purpose of this brief essay is to defend PGT-P—the newest form of genetic testing of embryos—as a clinically useful and morally defensible option for women who use IVF.” In other words, ASRM shut down its own Ethics Committees’ negative opinions about PGT-P, but offered its flagship medical journal, F&S, up for obviously economically conflicted authors voicing their biased opinions, favoring the clinical utilization of PGT-P. And not to be forgotten, the senior author—based on a good number of publications in the fertility literature - is, likely, the single most responsible individual for the widespread current U.S. use of PGT-A in IVF. References 1. Behavior Genetics Association.

BGA Statement on Polygenic Embryo Selection. June 2025. https://www.bga. org/content.aspx?page_id=22&club_ id=971921&module_id=734874 2. International Society of Psychiatric Genetics (ISPG). Advisory on the use of polygenic risk scores to screen embryos for adult mental health conditions. May 2021; https://ispg.net/ethics-statement/ 3. Forzano et al., on behalf of the Executive Committee of the European Society of Human Genetics & The Public and Professional Policy Committee of the European Society for Human Genetics.

European Journal of Human Genetics.

2022;30:493-495 4. Furrer et al., JAMA Network Open 2024;7(5):e:2410832 5. Anomaly et al., Fertil Steril 2025; September 10, 2025. https://www.fertstert. org/news-do/polygenic-revolution-andfuture-embryo-testing; DOI: 10.1016/ e375f228-4e6a-4fc1-b742-ab70649d3ac1 Ahead of print.

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Preimplantation genetic testing (PGT) in IVF and related subjects NOT ALL F&S JOURNALS SUPPORT PGT-P To be fully transparent, not all F&S journal articles support the current use of PGT-P. A consortium of investigators from the US and Israel, indeed, in a Narrative Review article in F&S Reviews, concluded that, “current evidence lacks long-term outcome data and generalizability. Before offering PGT-P to patients, additional clinical validation studies are needed. Also, ethical and social considerations raised by PGT-P should be carefully delineated.”1 HEALTHY TWINS AFTER TRANSFER OF 2 BY PGT-A FULLY ANEUPLOID EMBRYOS It took almost a decade for at least some colleagues to accept that, selectively, so-called “mosaic” embryos under the (physiologically false) PGT-A definition of “mosaicism” can be transferred.2 The CHR’s investigators had started transfers of chromosomalabnormal embryos already in 2014 and reported the first healthy pregnancies in the world following such transfers in 2015.3 A good number of IVF clinics nowadays do transfer “mosaic” embryos, though most restrict such transfers to only so-called “low-mosaic” embryos. The cutoffs of “low-” vs. “high-mosaic,” however, vary between laboratories, and this distinction, therefore, according to the CHR, really makes absolutely no sense (since we have 98

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covered this subject in these pages repeatedly before, we will here not again explain why that is CHR opinion).

Practically nobody, besides the CHR, however, to this day transfers

by PGT-A as fully “aneuploid” signed out embryos, even though, considering how error-prone PGT-A is in reporting PGT-A results, mostly because of falsepositive diagnoses, the distinction between a “high-aneuploid” and truly aneuploid embryo can never be made with an acceptable degree of accuracy. The CHR, therefore, has been arguing forever that such distinctions, still, commit embryos with pregnancy and live birth chances to non-use or even disposal and, therefore, reduce at least cumulative—if not, immediate— pregnancy chances.

And while pregnancy chances of an embryo, of course, can be expected to decline with increasing aneuploidy percentages of cells in a given embryo biopsy, at least some so-called “fully aneuploid” embryos will still reflect in reality only mosaic embryos that can be safely transferred and may result in a pregnancy. The chances of that happening will just be lower, as a PGT-A 100% “aneuploid” embryo will, of course, have a bigger chance/risk of being truly fully aneuploid than, for example, a “low-mosaic” embryo.

Consequently, the CHR to this day does selectively transfer by PGT-A “fully-aneuploid” embryos, even though several prominent colleagues in the PGT-A field have (falsely) repeatedly and categorically claimed that every PGT-A “aneuploid” embryo is truly aneuploid and, therefore, must not

be transferred.

The CHR—until very recently—has been the only IVF center in the world that reported a small number of healthy live births even from embryos by PGT-A reported out as “fully aneuploid.” This solitude is, however, now over, as colleagues from Stanford University in CA (who are performing a clinical trial of transfers of chromosomal abnormal embryos) recently reported in F&S healthy euploid dizygotic twin births after transfer of non-mosaic “abnormal” (i.e., allegedly “fully-aneuploid) embryos.4 And we want to give our colleagues from Stanford full credit for their effort, and also want to thank them for having given the CHR full credit in their paper for being the first fertility center in the world to have reported healthy births following transfers of chromosomalabnormal embryos, and also having reported healthy births after allegedly “fully-aneuploid” embryo transfers.

COUNSELING INFERTILITY PATIENTS ABOUT/BEFORE PGT-A So—and this is not a joke— colleagues from the University of Iowa seriously conducted a prospective trial of patients going through IVF plus PGT-A and randomized them into three groups in order to determine prospectively best methods of education and counseling for PGT-A: (i) By only REI MD; (ii) REI MD + handout; and (iii) REI plus handout and brief genetic counseling intervention.5

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The primary outcome was a post-visit (%) knowledge score.

Secondary outcomes were knowledge scores 2 weeks post-visit (%) as well as decisional conflict and/or decisional regret.

acceptance of this “important” manuscript. was then asked to provide a Reflection article, i.e., to offer further commentary. And, hardly surprising, the commentary considered the findings sobering.6

105 patients and 97 partners enrolled. Respective mean ages were 32.2 (4.2) and 33.9 (5.2).

In comparison to REI only.

Knowledge scores after the handout and with brief genetic counseling were better. At 2 weeks post-visit, patient knowledge scores were again higher with the handout and brief genetic counseling for female patients, while for partners, there was only a benefit with brief genetic counseling. There were no differences in decisional conflict or decisional regret, but the authors rightly felt that they were underpowered regarding those issues.

But did the authors’ conclusions from this study seriously warrant publication of a manuscript in F&S? We, frankly, don’t think so because who these days still seriously believes that IVF patients would still utilize PGT-A in the numbers they currently do if they had received only a decent degree of pre-PGT-A counseling? We don’t think so!

This is the kind of study we at CHR call a self-fulfilling prophecy study.

What is meant by that is that not every question in medicine requires a prospectively randomized study.

Would anybody in his/her right mind have expected a different outcome than the authors reached, that patient and partner knowledge improved with educational handouts and brief genetic counseling?

Seriously?!

But it was not enough to accept a really basically useless paper for publication (think how much really important work could have been done with the same effort and expense on a really important issue; and they even registered the study!) but, likely one of the reviewers who recommended

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example, as blastocysts) steadily produce de novo mitotic errors in cells.

Existing methods for imaging chromosome segregation errors are not suitable for studying human embryos at advanced preimplantation stages. As chromosomal errors are a leading cause of miscarriage and infertility, it remains unclear whether missegregation arises postfertilization.

The reproductive biology team at Cambridge University in the UK, now with Kathy K. Niakan, PhD, at the helm, of course, does not need any introduction. They are among the best in the field and have had an interest in embryo aneuploidy for many years. Indeed, in those days in the laboratory of Magdalena Zernicka-Goetz, PhD, our Cambridge colleagues were, indeed, the first to demonstrate in a mouse model that embryos could self-correct certain chromosomal abnormalities,7 a few years later also confirmed in human embryos by the CHR in collaboration with the Brivanlou lab at Rockefeller University.7

Optimizing nuclear DNA labeling via messenger RNA electroporation and applying light-sheet live imaging to reveal chromosome segregation errors immediately before implantation of blastocysts, the investigators demonstrated that embryos, even at these advanced preimplantation stages, still display missegregation, including multipolar spindle formation, lagging chromosomes, misalignment, and mitotic slippage.

Most lagging chromosomes were passively inherited rather than reincorporated. To trace individual nuclei, the authors developed an open-source, semi-automated segmentation method using a customized deep learning model optimized for variability in embryo size, shape, and signal. Using this approach, most labeled cells remained in external positions (trophectoderm from where PGT-A biopsies are taken), consistent with placental rather than inner cell mass fate.

And Cambridge, indeed, just published yet another fascinating paper in which they through life imaging could demonstrate that human embryos at late preimplantation stages (i.e., for

Meaning: Unsurprisingly, the authors, therefore, note that these findings raise further questions about clinical uses of preimplantation genetic testing for aneuploidy while providing

DE NOVO MITOTIC ERRORS REVEALED IN LATE-STAGE PREIMPLANTATION HUMAN EMBRYOS BY LIVE IMAGING

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broadly applicable imaging and segmentation methods for studying diverse cellular structures in human embryos.

Quite a beautiful study!

ENCOUNTERING A TRIPRONUCLEAR HUMAN ZYGOTE AND PRODUCING A NORMAL MALE PREGNANCY Chinese investigators recently reported in the Journal of Ovarian Research a case where most of a patient’s oocytes (14/20) were immature (MI, GV), and/or had large to giant polar bodies. After fertilization with ICSI, almost all resulting zygotes (7/8) were 3PN (had 3 pronuclei) by removing one female PN in 6 of the 3PN zygotes, and two of this way zygotes, enucleated, developed into highquality blastocysts. The transfer of one euploid blastocyst after noninvasive chromosome screening, vitrification, and thawing resulted in the live birth of a healthy male, at the time of the report, 9 months old.10 A zygote is considered normally fertilized when it demonstrates 2PNs, one from sperm and the other from the oocyte, and 2PBs. 3PN zygotes, however, are not uncommon and often lead to implantation failure, miscarriages, and molar pregnancies. Many IVF clinics routinely discard 3PN embryos or are not allowed to be transplanted. Approximately 25% of 3PN embryos, however, as the literature suggests, are euploid and can lead to normal offspring. A very recent abstract at ESHR 2025, indeed, suggested that less than 50% of 3PN embryos are triploid and recommended the testing of 100

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such embryos before discarding them.11 Meaning: The suggestion that the “microsurgery” on the 3PN embryo the Chinese investigators performed was the reason for the normal birth is, therefore, by no means established. The only thing this paper really suggests is that such enucleations can be performed without likely significantly harming an embryo’s pregnancy chances. Whether such enucleations, however, improve pregnancy and live birth chances cannot be determined from single case reports.

MORE INFORMATION ABOUT DEPLETION OF ANEUPLOID CELLS (i.e., SELFCORRECTION) The here discussed paper, at first impression, appears to have absolutely nothing to do with any form of PGT (including PGT-A); it, however, very quickly discloses its significance for our understanding of self-correction in preimplantation-stage human embryos. Some proponents of PGT-A still, after initially demonstrated in a mouse model7 and later by and Rockefeller colleagues in humans,8 a very interesting paper in Cell Genomics

by Spanish investigators now reported interesting technical insights. They demonstrated that— in general human experience— depletion of aneuploid cells is shaped by cell-to-cell interactions.12

(i) Segmental monosomies are outcompeted through cumulative haploinsufficiency. (ii) Segmental trisomies of up to 1,500 genes don’t demonstrate any growth impairments. (iii) The cell competition relies on the interaction between complementary monosomies and trisomies. And, finally, (iv) the genome appears to have many dosage-sensitive loci.

Meaning: The reasons for the hierarchy in pregnancy and live birth chances after transfer of at blastocyst-stage “aneuploid “embryos, therefore, now, increasingly come into focus. No wonder segmental abnormalities practically have normal pregnancy chances, as the CHR and others have reported.

References 1. Roura-Monllor et al., F&S Reviews 2025;6(1):1-9 2. Muñoz, et al., Reprod Biomed Online 2024;48(3):103664 3. Gleicher et al., Fertil Steril 2015;104.

Suppl 3e9 4. Tise et al., Fertil Steril 2025;124(5P2):1016-1022 5. Singh et al., Fertil Steril 2025;124(5P2):964-973 6. Woodward JT. Fertil Steril 2025; 124(5P2):985 7. Bolton et al., Nat Commun 2016;7:11165 8. Yang et al., Nat Cell Biol 2021;23:314321 9. Abdelbaki et al., Nat Biotcechnol. 2025; https://doi.org/10.1038/s41587-025-02851 10. Xu et al., J Ovarian Research 2025;18:236 11. Glynn et al., Hum Reprod 2025;40(Suppl 1):deaf097.589 (abstract) 12. Fusari et al., Cell Genomics 2025 5:100894

More specifically, they demonstrated that aneuploid cells in vivo are eliminated through cell competition. As the paper summarizes their findings,

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Determining with AI follicle sizes that optimize clinical outcomes in IVF—and confirming prior CHR publications as well as current clinical practice The concept that follicle sizes at time of ovulation trigger and, therefore at time of retrieval, should not be the same in all patients (at ca. 18-23mm) as is still practice in almost all IVF clinics has, of course been a major theme of the CHR’s research and clinical practice or over a decade, leading to HIER (highly individualized egg retrieval)1,2 and the recognition that how oocyte maturity designations change with advancing female age in their ability to predict good embryo quality also had to be reconsidered.3

also apply to general populations, including younger patients.

Figure 1. Follicle sizes contributing to clinical outcomes: Normalized permutation importance values (mean ± SD) of follicle sizes (in mm) in treatment cycles averaged across all eleven clinics in the cross-validation protocol. The outcome variables are all oocytes (a), metaphase-II (MII) mature oocytes (b), two-pronuclear (2PN) fertilized zygotes (c), and high-quality blastocysts (d), respectively. The shading highlights follicle sizes that have at least 50% normalized importance.

We were especially happy about the confirmatory value of the latter statement because the recognition that follicles prematurely luteinize This work now has some indirect earlier and earlier as women age support from an interesting paper was indeed the initial discovery

by British investigators in Nature that led to the introduction of 4 Communications. In a multi-center our HIER program for especially study (n = 19,082 treatment-naive older patients, but also for younger female patients) from 11 European women with prematurely ageing IVF centers, explainable artificial ovaries.1,2 Once we recognized intelligence was obtained to identify that we were unable to stop this follicle sizes that contributed most premature luteinization in follicles to clinical outcomes. As it turned (which, of course, negatively affects out, intermediate-sized follicles egg quality in these follicles, we were most important to the number jokingly call such eggs “hardof mature oocytes subsequently boiled” instead of “soft-boiled”), the retrieved. Maximizing this logical next step was progressively proportion of follicles by the end of earlier and earlier egg retrievals. ovarian stimulation was associated As a consequence, CHR triggers with improved live birth rates. patients over age 45 nowadays quite Larger mean follicle sizes, especially routinely at lead follicle sizes under >18 mm, were associated with 10-12mm. premature progesterone elevation by the end of ovarian stimulation Figure 1 above from the paper and a negative impact on live birth below demonstrates some very rates with fresh embryo transfer. interesting details, basically confirming that the CHR’s reported findings primarily in older patients

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Age effects are, indeed, demonstrated in Figure 2 below, but unfortunately, they only differentiate between those below and above age 35. Still, extremely remarkably, especially in the older

above age 35 age group (and not that much in the younger age group under 35), one sees an almost straight line in the increase of MII mature oocytes from follicles as small as 6-12mm (b), which we suspect are the oldest patients. And since—except for the CHR—almost no other IVF clinics treat patients above age 43 with autologous oocytes, we can assume that most of these mature MII oocytes in follicles between 6-12mm, likely, came from 40-43 year-old patients.

Also quite remarkably, as we very clearly observed, the long (agonist) protocol does not do very well in such patients (c), while the short (antagonist) protocol does much better, though since we at the CHR retrieve oocytes now in older patients at quite small follicle sizes—and therefore do not have to be concerned about premature ovulation—we in most cycles do not use either agonists or antagonist but stimulate without use of either.

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Figure 2. Follicle sizes contributing to mature MII oocytes stratified. Outcome variable is mature metaphase-II (MII) oocytes in a-c. The shading highlights follicle sizes that have at least 50% normalized importance. In a first stratification approach, (a, b) represent patients that were ≤35 years old at the time of treatment (n = 5707), and >35 years of age (n = 4717), respectively. The data in (c, d) are stratified by those with a GnRH agonist (“long”; n = 5420) or GnRH antagonist (“short”; n = 3981) IVF suppression protocol, respectively. All cycles receive an hCG trigger.

A wonderful paper, we recommend it for everybody interested in ovarian physiology and clinical IVF practice.

References 1. Wu et al., J Endocrinol 2015;226:167180 2. Wu, et al., J. Ov. Res.218;11:23 3. Nicholas C. iScience 2023;26(8):107308 4. Hanassab et al., Nat Commun 2025;16:296

Finally, some discussion on routine blastocyst-stage culture as the standard of care We, of course, have repeatedly raised the question in these pages over recent years why the IVF field, including ASRM, has decided that routine extended culture to blastocyst represents the standard of care. The switch from routine cleavage stage to routine blastocyststage transfer took place slowly and was unquestionably started 102

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by a highly biased paper out of the original CCRM center, in which Gardner and Schoolcraft, in a highly selected patient population, made two incorrect and one correct claim.1 The two incorrect claims were: (i) that blastocyst-stage culture (BSC) is a good selection process to improve pregnancy and live birth rates, and (ii) that it does that better than standard morphology and cleavage stage transfer.

Though these two false claims still reverberate through the IVF field, they have been proven to be false.

As we have repeatedly noted in the CHRVOICE, not only has BSC failed as a hypothetical selection process for best embryos, but the whole concept of embryo selection, including all the decades-long unsuccessful efforts to “find” best embryos through so many different “add-ons” to IVF, must be finally laid to rest.

Where Gardner and Schoolcraft were correct was in the argument that BSC supports the concept of elective single embryo transfer (ESET) and, therefore, helps in reducing twin pregnancies. Though correct, this argument in favor of BSC is also misleading because it presumes that all twin pregnancies after IVF represent an adverse and, therefore, unwanted IVF outcome, as first suggested by Scandinavian colleagues and, for reasons we really do not comprehend, without criticism, accepted by the IVF community.

And then there was yet another argument added: We might as well use blastocyst stage culture in everybody because it is anyhow needed for preimplantation genetic testing for aneuploid (PGT-A, which, like embryo transfer, had also been moved from cleavage to blastocyst stage) to “improve” PGT-A (which, of course, never happened).

This is not the place to explain the counterargument that twin pregnancies, if statistically properly analyzed, really are not even close to how badly they have been presented regarding their maternal and neonatal risks in comparison to singleton pregnancies, initially only in Europe, but then also in the US. As is so often unfortunately the case, somebody makes a superficially attractive argument, and everybody jumps on the bandwagon, without recognizing the subtleties of the problem, usually caused by differences in patient populations that are ignored. We are discussing such issues in the pages of the CHRVOICE constantly, always pointing out how dangerous it is to accept the notion

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of treatments that are “best” for everybody.

Such treatments do not exist!

But because BSC carries with it the half-truth of fostering eSETs and, therefore, fewer twin pregnancies, it has remained the standard of care in worldwide IVF practice. eSET and PGT-A support the use of BSC and BSG; of course, they support eSET and PGT-A, a typical reciprocal, fake argument where each one of the three treatment modalities has actually failed in proving any outcome benefits (and significant negative outcome effects on at least selected patient populations have been well established).

Annually, when ASRM completes the analysis of its national IVF registry, it in recent years has always pointed out with pride further declines in twinning rates from IVF. Yet, the ASRM has not said a word in those statements about the fact that pregnancy and live birth rates in fresh autologous IVF cycles since 2010 have, year by year, been steadily declining, being now lower than 15 years ago.

And why has this been happening?

There are, of course, several reasons, but among those reasons are routine blastocyst-stage cultures and eSETs (and then there is, of course, PGT-A and all the healthy embryos that are not used or are even discarded).

It was, therefore, something of a surprise to see a recent paper from Italian colleagues in Reproductive BioMedicine Online, not necessarily a medical journal

we often address in these pages, which asked the question: where are human embryos better off during development, in vitro in our embryology laboratory or in utero with the potential mother.2 There, of course, is not one correct answer for every patient; but it seems high time to revisit all three subjects - routine blastocyst-stage culture, eSET, and PGT-A. If IVF eliminated all three tomorrow, national U.S. pregnancy and live birth rates in fresh autologous IVF cycles would instantly rebound!

References 1. Gardner et al., Fertil Steril 2004;81(3):551-555 2. Bartolacci A, de Girolamo S, FraireZamora JJ, Pagliardini L, Papaleo E. The eternal dilemma: are embryos better nurtured in utero or in vitro? Reprod Biomed Online. 2025;51(5):105103. doi:10.1016/j.rbmo.2025.105103.

Did you know that one can take a “liquid biopsy” from an embryo culture medium?

This is at least what Japanese investigators recently suggested in a paper in Scientific Reports,¹ even though such a title, of course, makes absolutely no sense, considering the fact that a “liquid biopsy” is widely considered the substitution of a tissue biopsy with a blood draw and not simply the analysis of a fluid—in this case spent media from culturing embryos.

not English) because it claimed that Raman spectroscopy of spent embryo culture medium could differentiate between poorer and better embryos.

For example, the paper claimed that media analyses can differentiate between embryos that would and would not make it to blastocyststage. The study involved two culture media: A was an early development medium, while B was the medium used for vitrification and rewarming.

Interestingly, the pH of medium A tended to be more acidic with higher- than with lower-grade blastocysts. Conversely, in medium B, pregnancy did not occur even with high-grade blastocysts when the medium was contaminated by residual vitrifying/warming agents or had slightly elevated component concentrations due to water evaporation. Furthermore, medium B, in contrast to medium A, tended to be slightly more alkaline if blastocysts had higher grades.

Though preliminary, these data do suggest that Raman spectroscopy of spent media may have a diagnostic future in IVF. Reference 1. Ishigaki et al., Scientific Reports.

2025;15:33986

But despite this obviously mistaken heading, we found the paper of interest (even though this relatively new science journal from Nature journals really deserves better editing of manuscripts from authors whose native language is 103

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And did you know that in women dyslipidemias apparently adversely affect fertility and IVF cycle outcomes?

of one good-quality embryo to lead to pregnancy is less than 5%, this would then mean that implantation failure cannot be assumed until at least 20 good-quality embryos have been transferred.

This is at least what the literature suggests,1-2 and Chinese investigators now attempted to explore the subject further in a paper in the JCEM.³ By way of background, the term “dyslipidemia” applies to abnormally increased total serum cholesterol (TC), triglycerides (TG), or low-density lipoprotein (LDL)—but also to decreased high-density lipoprotein (HDL).

In what the authors called a “retrospective real-world analysis as well as prospective study,” they investigated 5618 non-RIF (repeated implantation failure) and 881 RIF patients, with RIF defined as “implantation failure after 3 or more consecutive transferred highquality embryos.”

Even though the study included only women up to age 40 years, to define RIF—independent of age— as failure to conceive after transfer of only 3 embryos, therefore, makes absolutely no sense. And this, of course, once again means that the design of this study’s protocol was seriously flawed and any data derived from this study must not be taken seriously.

And this is, of course, where the problem with this paper starts, even though the authors’ definition of RIF is, indeed, quite popular in the literature. As, indeed, a point addressed in these pages on many prior occasions, despite considerable acceptance worldwide, this definition of RIF is basically ludicrous, with the principal reason (there, of course, are several) being obvious: Even if one (probably correctly) assumes an approximately 30–35% chance of an embryo at peak fertility (ca. female and male age of ca. 25 years) to lead to pregnancy, that anything beyond three embryos represents RIF would, therefore, only apply to women at peak fertility ages. At age 45, in contrast, where the chance 104

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But for completion’s sake, we, of course, do not want to withhold the suggested findings of this study— once more demonstrating why so much of published literature is just a complete waste of time and effort for investigators, readers of their papers, and their funding organizations. The authors concluded that RIF women with dyslipidemia had significantly poorer cycle outcomes, with the proposed reason being breached immune homeostasis in the lutealphase endometrium. To be more specific, RIF women had more dyslipidemias and significantly lower implantation, clinical pregnancy, and live birth rates.

They also had a higher rate of nonreceptive endometrial receptivity test and of endometrial pathogenic bacteria.

And—imagine—after “personalized” treatments— whatever that may mean—the reported clinical pregnancy rate in dyslipidemic women still was an amazing 73.3% and their live birth rate was—considering an allegedly

unselected patient population— an even more incredulous 60.0%. Of course, bulk RNA-seq deconvolution analysis in addition detected increased endometrial CD56dim NK cells and—by bulk—macrophage M1/M2 ratios with dysregulated immune factors.

Clearly not a very credible study and well deserving of a WORST PAPER AWARD IN ISSUE. References 1. Pugh et al., Hum Reprod.

2017;32(5):1055–1063 2. Wang et al., Medicine (Baltimore).

2020;99(13):e19665 3. Zhang et al., J Clin Endocrinol Metab.

2025;110:3230–3242 and (WORST PAPER AWARD IN ISSUE)

It is not only the ovary that declines in pregnancy efficiency with advancing female age Fertility and Sterility classifies one manuscript in every issue of the journal as a “Seminal Contribution.” That in itself—for several reasons—we find kind of obnoxious, and here are just a few good reasons: (i) Truly seminal contributions in science are rare.

To expect one such contribution per issue in any journal is, indeed, completely unrealistic and, therefore, quite obnoxious on its own. (ii) Whether a contribution is “seminal” becomes really determinable only over time. There is a reason why Nobel Prizes are usually awarded only years after original achievements. (iii) How likely will a truly seminal paper be submitted and published by a journal of F&S’s ranking? Not very much!

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Thereare several cases in history where later Nobel Prize winners had their original manuscripts describing their work repeatedly rejected before getting their papers finally published in lower-ranking journals. But even, likely the last such alleged case—Rosalyn Yalow’s (and Berson’s) manuscript describing the radioimmunoassay for measuring insulin in 1960— ended up in the Journal of Clinical Investigation,¹ a journal with much higher impact factor than F&S. Why such a lengthy introduction for an in general well-executed paper in F&S reporting that maternal age not only adversely affects IVF cycle outcomes because of ovarian (i.e., oocyte) ageing?² It is really not because we consider this an important paper for discussion. Moreover, an—of course—accompanying commentary as a “Reflections” article commented on the paper, pointing out well its shortcomings.³ Because this was the “Seminal Contribution” of the October issue and we—frankly—had planned to address this issue for quite some time.

This paper offered a good opportunity because it demonstrated the absurdity of such a classification quite well: First, the paper did not report anything new.

The authors, themselves, referenced several publications which made this point already decades ago—like in this paper based on observations in donor-egg cycles. Second, even assuming they had been the first to make this point, could that really be considered a “seminal” paper? We don’t think so!

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We already hear, of course, the principal counterargument, which likely will be something like, “Who cares what an article is called?” And we disagree because if a journal is to be taken seriously, it—first and foremost—must take itself seriously.

References 1. Yalow RS, Berenson SA. J Clin Invest.

1960;40:2103 2. Sebastian-Leon et al., Fertil Steril.

2025;124(4):635–644 3. Denham et al., Fertil Steril.

2025;124(4):645–646

GENERAL INFERTILITY Cannabis impacts female fertility Cannabis legalization and consumption is increasing, and with it use in pregnancy, raising concerns about its impact on fertility. An extensive body of literature describes the impact of tetrahydrocannabinol (THC) on sperm. Canadian colleagues previously reported that THC and its metabolites reach the ovarian follicle. They now took the logical next step and investigated the impact of THC on human female fertility through both a clinical and in vitro analysis.

In a case-control study, they demonstrated that follicular fluid THC concentration positively correlated with oocyte maturation.

THC-positive patients exhibited significantly lower embryo euploid rates than their matched controls.

In vitro, we observe a similar but non-significant increased oocyte maturation rate following THC exposure and altered expression of key genes implicated in extracellular matrix remodeling, inflammation, and chromosome

segregation. Furthermore, THC induces oocyte chromosome segregation errors and increases abnormal spindle morphology.

This study, therefore, highlighted potential risks associated with cannabis use for female fertility.

Reference 1. Duval et al., Nat Communications.

2025;16:8185

Polycystic ovary syndrome (PCOS) HOW MANY PCOS SUBTYPES/ PHENOTYPES EXIST? It has been for decades recognized that PCOS is not one single disease—but how many different phenotypes PCOS encompasses has remained controversial and generally is believed anywhere between 2 and 4 (with phenotypes on some occasions also overlapping). As we repeatedly before discussed in these pages, the CHR believes that PCOS is made up of only 2 phenotypes (as does the Mount Sinai Medical Endocrinology Group a few blocks uptown from CHR), but others still stick to 3 or even 4, as originally determined by the Rotterdam Criteria.

Now, a Chinese group identified 4 (what they called) reproducible subtypes: (i) with hyperandrogenism; (ii) with obesity; (iii) with high sex hormonebinding globulin (SHBG); and (iv) with high luteinizing hormone (LH).¹ 105

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Each subtype exhibited distinct clinical characteristics (see Figure 1).

The hyperandrogenic subtype (HA-PCOS, 25%) was characterized by high testosterone– dehydroepiandrosterone sulfate (DHEA-S), along with mild metabolic disorders. The subtype with obesity (OB-PCOS, 26%) was characterized by higher body mass index (BMI), fasting glucose, and fasting insulin level, with the highest prevalence of T2DM (7.9%), dyslipidemia (75.3%), and hypertension (28.7%). The highsex hormone-binding globulin subtype (SHBG-PCOS, 26%) had the highest sex hormonebinding globulin (SHBG) level and lowest BMI among four subtypes, primarily manifested as lower luteinizing hormone (LH) and testosterone levels. The high-LH– AMH subtype (LH-PCOS, 23%) was distinguished by elevated levels of LH, follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH).

The authors then also validated these four groups in non-Chinese populations from Europe, Singapore, and Brazil. Moreover, in the Chinese validation cohort, the average AUC of the four subtypes was 0.88 (0.87 to 0.90); an average AUC of 0.92 (0.83 to 0.95) was obtained in the US validation cohort; 0.88 (0.88 to 0.89) in the European cohort; 0.95 (0.90 to 0.98) in the Singapore cohort; and 0.82 (0.80 to 0.86) in the Brazilian cohort.

Follow-up data are shown to the right in Figure 2.

Figure 1. Classification and validations of PCOS subtypes: (a) First two components of scaled quantitative trait data, with cases grouped according to subtype by k-means clustering. (b) Case distribution in original cohort (n= 11,908). (c) Characteristics of each cluster in Chinese cohort: (i) n=2,952; (ii) n=3,138 (iii) n=3,103; (iv) n=2,715. (d-h) distribution among Chinese validation cases. (i-m) ROC for 4 sub-types in different validation cohorts.

This Chinese study represents not only a momentous amount of excellent work but also was a very important study for the CHR since it confirmed much of the CHR’s clinically reached conclusions, which already, before this Chinese study was published,² very similarly to Mount Sinai investigators based on genomic studies,³ concluded

that PCOS basically appears to represent only 2 distinct subtypes which clinically—because of overlaps—can cluster in 3 groupings.

In a way, this is also what this Chinese study demonstrates if one combines what in this study are groups (iii, low SHBG) and (iv, low

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MYOINOSITOLS IN PCOS PATIENTS

Figure 2. Follow-up data of 11,908 affected women over 6.5 years, validated across 5 international cohorts. (a) Remission of PCOS features over the study period for all 4 subtypes; (b) type 2 diabetes; (c) hypertension; (d) dyslipidemia across the study period.

LH)—by the CHR named hyper-/hypo-androgenic PCOS (HH-PCOS) and by the Sinai group reproductive PCOS—and Chinese groups (i, hyperandrogenism) and (ii, obesity), which the CHR calls “classical” PCOS, and the Sinai group “metabolic” PCOS.

execution that we found in the Chinese paper.

The question asked here was also much simpler: How do PCOS and non-PCOS patients compare in their respective ovarian aging processes? And the answer, therefore, was also quite simple: Bravo to our Chinese colleagues PCOS patients demonstrated for a study that—considering the greater declines in antral follicle number of participating universities counts (of course because they and number of patients—can only started with much larger numbers), come out of China. ovarian volume (same reasoning), AMH (of course, same reasoning), FOLLOWING PCOS PATIENTS and total testosterone (oh God!); FOR 13 YEARS but maintained better functional ovarian reserve and hormone levels And while our Chinese colleagues (now seriously?!) followed PCOS patients for only 6.5 years, Turkish colleagues followed Did we really need a study to find their PCOS patients exactly out all of this? twice as long—13 years (quite a coincidence!).⁴ Unfortunately, this study, however, did not have the sophistication and excellence of

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We, of course, have repeatedly written about myoinositol use in infertile women in these pages, making the point that—based on some reports—it represents a potentially useful supplement in anovulatory PCOS patients (classical phenotypes A and B under Rotterdam criteria) but warning about prescribing it to usually ovulatory phenotype D PCOS patients, which the CHR has come to call after age 35 (when they usually present to the CHR for the first time) high/low (testosterone) PCOS patients because they, as teens, also started out hyperandrogenic but by age 35 already enter hypoandrogenic hormone range.² And since inositols lower androgens, they in these PCOS patients are contraindicated.

But this is not why we here once again write about inositols. We do so because—somewhat unclear to us why—something of a rumor was created in reproductive medicine that myoinositol supplementation prevents pregnancy complications in PCOS patients. Why daily inositol supplementation in pregnancy should reduce gestational diabetes, preeclampsia, and preterm birth was never really clear to us, and we, therefore, are glad that Dutch colleagues used their unmatched collaborative of medical schools in the country—which together tackle the study of important medical questions probably better than any other country but China (see above)—to query this question in a randomized clinical trial.

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And the answer was—as we, frankly, would have expected— myoinositol has zero effect on pregnancy complications. We are still happy our Dutch colleagues did the study!

AND WE HATE TO DISAGREE WITH SOME OF THE MOST IMPORTANT PCOS EXPERTS But we wouldn’t be so brazen if we were not convinced that we are right (and they are wrong). And here is what all of this is about.

Not incorrectly, the authors note that PCOS is often associated with chronic inflammation, but characterization of immune markers has not been performed sufficiently well. So what did they therefore do? A retrospective study of 40 premenopausal women (20 PCOS and 20 control patients!!!).

Has anybody ever seen a study in fertility practice which, with 20 study patients, offers sufficient statistical power to answer a question? We have not! And on top—a retrospective study, with all of the inherent weaknesses of this study design. But that is, of course, not all the criticism. The most important criticism has remained the same for decades and is being perpetuated exactly by PCOS “experts” who in practically none of their PCOS studies in all of the decades since PCOS was recognized as a syndrome of several related conditions but not one disease ever have bothered to investigate PCOS patients based on the phenotype those same experts now have been fighting about for over 40 years.

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And the same, of course, happened here. God only knows what kind of PCOS patients were among the 20 study patients and how many undiagnosed lean, phenotype D under Rotterdam PCOS patients were mistakenly in the control group—as these PCOS patients more often than not go undiagnosed through life (including infertility treatment).

Online ahead of print; WORST PAPER AWARD IN ISSUE

Anti-Müllerian hormone (AMH) REGULATING CELL FATE AND THE RESPONSE TO DNA DAMAGE—A NEWLY DESCRIBED EFFECT OF AMH

Who, therefore, can be surprised that the authors did not find the “difference” between PCOS patients and controls they expected? Shame on them! This paper revealed absolutely nothing about PCOS but demonstrated very clearly why basically no progress has been made in our understanding and treatment of PCOS over more than 40 years, except for the earlier above-described facts.1-3

David Pepin’s laboratory at Harvard recently published an interesting paper in PNAS clarifying certain, so far, only poorly understood functions of AMH. That AMH can protect the ovarian reserve from some chemotherapies (Doxorubicin being the best example) has been known for some time. Now this study helped in explaining how this happens: In mesenchyme, AMH halts theca progeny differentiation and reduces apoptotic gene expression. Doxorubicin in preantral granulosa cells upregulates cell cycle inhibition and dysregulates Wnt signaling, both ameliorated by AMH. And AMH also induces Id3—a DNA repair gene.

Clearly a paper deserving of the WORST PAPER AWARD IN ISSUE, demonstrating that not only fertility journals publish at times really poor papers that should never have made it through peer review.

Meaning: As these results were obtained in a mouse model, they, of course, must be replicated in humans. But if replicable, AMH may find a new application in fertility preservation of women requiring certain chemotherapies.

References 1. Gao et al., Nat Med. 2025; https://doi. org/10.1038/s41591-025-04113-8 2. Gleicher et al., Biomedicines.

2022;10(7):1505 3. Dapas M, Dunaif A. Endocr Rev. 2022;43(6):927–965 4. Sonu et al., Reprod Biol Endocrinol.

2025;23:126 5. Pancheko-Sanchez et al., J Clin Endocrinol Metab. 2025;dgaf524.

VALIDATING AMH CUTOFF TO DETERMINE POLYCYSTIC OVARIAN MORPHOLOGY?

And it is exactly this group of PCOS women who in roughly 85% demonstrate evidence of a hyperactive immune system (autoimmunity, inflammation, excessive allergies) and in ca. 45% have autoimmune thyroid disease.²

It is always the same story when a new PCOS-related paper comes out: the title is promising and then—once one looks who and how PCOS is defined—one once

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again is disappointed. This was exactly again the experience when a recently published study by a group of European investigators from all over Europe—this time in Fertility and Sterility—published a prospective validation study of the previously suggested cut-off for AMH of 3.2 ng/mL for the determination of polycystic ovarian morphology (PCOM) under the fancy name HARMONIA study.² Studying a large Finnish population, the study assesses the above-noted AMH value for its correlation with PCOM on vaginal ultrasound. To give credit where credit is due, the study did one thing most PCOS studies fail to do: it separated individual PCOS phenotypes—in this case phenotypes A, C, and D under old-fashioned Rotterdam criteria (why not also B is unclear)—but, like most published PCOS studies do, it failed to take another crucial step in not adjusting AMH data for age. AMH values, of course, change significantly with age; to declare one single AMH value, therefore, as reflective of PCOM at all ages makes absolutely no sense.

References 1. Phuong Nguyen NM et al., PNAS. 2025;122(5):e2414734122 2. Piltonen et al., Fertil Steril.

2025;124(3):543–552

Why do eggs demonstrate increasing aneuploidy with advancing female age?

That aneuploidy in human eggs drastically increases with advancing female age has been known for a long time. That this may be a consequence of premature loss of chromosome cohesion proteins and

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the consequential early separation of chromosomes has also been widely accepted. But it has also become clear that this cannot be the main cause of the observed rapid increase in aneuploidy. Now investigators from Yale University published an interesting paper in Nature Aging in which they added significantly new insights.

Yes—that exactly has become the question and, unfortunately—for several reasons—is not answered by a recent study by Venezuelan and Spanish investigators which claims to do so.¹

Just as PRP started with reports of injections of women with primary ovarian insufficiency (POI) who really in a large majority were not Coupling what they called a truly POI patients but women with versatile cohesion manipulation lower-than-normal ovarian reserve system with quantitative high(i.e., women with premature resolution live imaging, they were ovarian aging, POA), so were able to directly observe cohesion women—as recently reported in protein behavior during meiosis Regenerative Therapy (obviously and demonstrated that premature not a fertility journal)—now being sister chromatid separation sharply injected with exosomes for the increases only when REC8 levels largely undefined diagnosis of drop below a critical threshold. This “premature ovarian insufficiency.”¹ observation suggests a nonlinear, vulnerability-triggering cohesion We, of course, would welcome a limit. good study on using autologous exosomes for intraovarian An interesting paper offering treatment of selected infertile new technology that will allow women (on PRP there, of course, for further interesting new already exists considerably more observations. information, including from CHR publications), since published Reference data on exosome treatments are 1. Leem et al., Nat Aging. 2025;5:2215– at best sparse. This, however—not 2227 unexpectedly—of course, never prevents IVF clinics from offering Treating “premature ovarian such treatments as “routine” insufficiency” and infertility treatments.

with autologous exosomes and platelet-derived growth factors History repeats itself, and it all started with platelet-rich plasma (PRP) injections into ovaries; then it was alleged mesenchymal stem cells; and the latest “fad” are autologous exosomes that are injected into ovaries of—who?

Unfortunately, this paper also did not help very much because it in many ways is a textbook example of how not to conduct a study like this: When study populations are not properly defined and the patient numbers are inadequate to offer adequate power for any statistical analysis (10 patients in each group), and no adjustments are made (not even for age), one really does not have to go any further and can basically stop

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reading. But when one overcomes this impulse and nevertheless continues, it is truly painful to discover the authors’ conclusions from their study. They really— basically without data—concluded that what they call bio-stimulation with autologous exosomes is a safe and promising treatment for improving markers of ovarian reserve.

One is left wondering how many more IVF clinics will now take this paper as evidence for the efficacy of bio-stimulation of ovaries with exosomes and just start using the procedure without discriminating in whom, why, and how. As noted before—history repeats itself— because this is how the infertility world brought PRP into routine practices which, to this day, has not led to a real understanding of who really will benefit from PRP and how PRP is best performed.

Which leaves us only with the option of awarding this paper with a WORST PAPER AWARD IN ISSUE—in the hope of at least attempting to prevent such a repeat—though without being too optimistic. But what does really one more potentially useless “add-on” to IVF really matter, considering how many useless “add-ons” have become routine practice!?

Reference 1. Navarro et al., Regen Therapy.

2025;30:309–320. WORST PAPER AWARD IN ISSUE

A two-phase model of the follicular phase We consider Claus Yding Andersen, PhD, from Denmark to be one of the most knowledgeable 110

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and clearest thinkers in the world when it comes to ovarian function, and we, therefore, were very much looking forward to reading a recent paper he penned for Reproductive Biology and Endocrinology—a journal which, as we have noted before in these pages with considerable pleasure, surprisingly frequently publishes interesting papers other journals apparently don’t want.

Described as a “Review,” it is really a hypothesis paper in which Andersen points out that the hormone FSH is secreted by the pituitary in multiple isoforms which differ in their respective glycosylation, bioactivity, and half-life. He also noted that acidic isoforms dominate early in the follicular phase, while—associated with and likely caused by rising estradiol—less acidic forms increase closer to ovulation.

Since the specific roles of these isoforms in vivo are still not well understood, Andersen undertook a narrative review of the literature which he in this paper shared with us, reaching the conclusion that the sequential dominance of FSH isoforms appears to influence distinct stages of follicular development.

More specifically, he proposed in the manuscript that acidic isoforms of FSH primarily support early follicle growth by stimulating inhibin-B production, which enhances androgen synthesis in collaboration with LH. Androgens—as we here at the CHR, of course, very well understand—in turn increase FSH receptor expression in granulosa cells, enhancing follicle sensitivity.

The picture in the later follicular phase, however, differs somewhat: Less acidic isoforms support final follicle maturation by upregulating aromatase and LH receptor expression in granulosa cells, thereby facilitating the shift from androgen to estrogen production.

This is a complicated paper to digest in content and analysis, but it is definitely worthwhile the read.

Its importance, moreover, goes beyond just—as Andersen suggests in the paper—improving ovarian stimulation protocols. It is a paper that challenges the pharma industry to – finally – after decades of complete inactivity – start offering the fertility field more specifically directed gonadotropins to welldefined patient subgroups in place of the “same for all” approach the field has been pursuing now for over 40 years.

Reference 1. Andersen CY. Reprod Biol Endocrinol 2025;23:130

REPRODUCTIVE AND GENERAL MEDICAL ENDOCRINOLOGY Subclinical hypothyroidism in infertile females Some people—apparently including the ASRM—believe that whether subclinical hypothyroidism (SCH) should be treated in infertile women has remained controversial.

Consequently, the Practice Committee of the ASRM (this time for some reason not involving the Practice Committee of SART) published a new guideline, and we have to acknowledge that we were pleasantly surprised by many

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of the conclusions and have to give the ASRM Committee full credit for a high-quality analysis, even though we found their risk analysis for treating SCH somewhat exaggerated, when stating:

concerns over data integrity. On the basis of current evidence, it is not recommended to screen or treat for asymptomatic SCH in women with infertility or pregnancy.

Although levothyroxine therapy is often considered minimally risky, it does have some associated risks.

These risks include, but are not limited to, heat intolerance, sweats, chills, heart palpitations and arrhythmia, diarrhea, weight change, hair thinning, tremors, mood changes, sleep disturbances, fatigue, anxiety, and bone loss.

In addition, the goal of achieving a TSH level <2.5mIU/L has resulted in significant delays in women receiving the appropriate infertility treatment or initiating an IVF treatment cycle. Although prior versions of this ASRM document and recommendations from other international societies state that there may be benefit and likely low harm to levothyroxine treatment for SCH, treatment does have side effects, risks, including misdiagnosis and delay in care, and associated costs.

In the absence of demonstrable benefit, practitioners are encouraged to use caution and not recommend routine screening and treatment.

Caveats to those conclusions:

The document summarized the conclusions of the guideline as follows: Most of the evidence advocating for screening and treatment of SCH in women with infertility or pregnancy is based on lowquality observational data and one clinical trial, which should be withdrawn because of significant

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Because of the quality of this analysis, we here are reprinting it in full length:

Additional clinical trials evaluating the treatment of SCH to improve offspring neurocognitive development are unlikely to change the evidence that screening and treatment do not provide benefits. Additional clinical trials evaluating the screening and treatment of antithyroid antibodies and pregnancy outcomes are needed.

Additional clinical trials evaluating the screening and treatment of SCH in infertile patients and in patients receiving IVF therapies could result in a change in recommendations.

We found it especially laudable that the guideline contains a large section addressing the question whether thyroid autoantibodies are associated with infertility and adverse pregnancy outcome. The analysis is complete and reflects the realities of what is known and still unknown on the subject.

Because the CHR sees the presence of thyroid antibodies as evidence of a hyperactive immune system and because hyperactive immune systems are almost universally associated with increased miscarriage risk,2-3 we feel strongly that so-affected patients require treatment interventions. But we acknowledge that—whether such interventions should include treatments with levothyroxine or should just be immunologic in nature—has remained unresolved.

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It is important to emphasize that the current document does not address SCH in women with a history of repeated pregnancy loss (RPL), which is covered in another ASRM Practice Committee Guideline. A population study found that antithyroid antibodies were more prevalent in women than men, increased with age, and were significantly associated with hypo- or hyperthyroidism, but antithyroglobulin antibodies were not.

However, the data are varied on whether thyroid antibodies are associated with infertility or adverse reproductive outcomes.

A systematic review and metaanalysis of 38 articles found that the presence of thyroid antibodies was associated with an increased risk of unexplained subfertility (OR 1.5; 95% CI 1.1–2.0), miscarriage (OR 3.73; 95% CI 1.8–7.6), recurrent miscarriage (OR 2.3; 95% CI 1.5–3.5), preterm birth (OR 1.9; 95% CI 1.1–3.5), and maternal postpartum thyroiditis (OR 11.5; 95% CI 5.6–24) compared with the absence of thyroid antibodies. This metaanalysis is complicated by varied definitions of SCH, heterogeneous patient populations, and combining cohort and clinical trial evidence.

Looking further into any association with miscarriage, some studies that were prospective, retrospective, and case-control in design found an increase in miscarriage rate in patients with thyroid autoimmunity even in the setting of a normal TSH level.

Conversely, a prospective cohort of 234 women screened before their first ART treatment cycle found no difference in pregnancy rates 112

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between women with and without thyroid antibodies. However, there was a higher miscarriage rate in women with thyroid antibodies. A retrospective study of 537 patients found a higher miscarriage rate in nontreated anti-thyroid peroxidase (TPO) antibody-positive patients compared with the treated group.

Cost-effectiveness analyses have demonstrated a higher cost in women with a history of pregnancy loss and a history of untreated SCH, or autoimmune thyroid disease (ATD) that was left untreated, and found universal screening for ATD to be costeffective. These data are heavily influenced by the reference data used to model the benefits of screening and treatment.

treatment (RR 0.51; 95% CI: 0.32– 0.82). However, these data were largely driven by the results of one study, which were excluded for reasons. With the exclusion of these data, there was no benefit to treating women with antithyroid antibodies. A prospective trial examining women undergoing ART treatment found a higher miscarriage rate in TPOAb-positive patients. Other studies did not find an effect on thyroid autoantibodies and ART treatment success. In another study of 487 patients who successfully conceived with ART treatments, the investigators found a 22% rate of thyroid antibodies.

Patients with positive thyroid antibodies had a similar pregnancy rate to those without antibodies.

Not all studies support an association between thyroid autoimmunity (TAI) and pregnancy loss. One prospective cohort study of 1,228 women who had a history of one or two prior pregnancy losses found no increased risk of pregnancy loss nor decrease in live births in women with TAI.

Another retrospective study of 416 euthyroid women found no differences in pregnancy and delivery rates observed between women with and without antibodies. However, women with TPOAb who failed to become pregnant or miscarried displayed higher TSH values before ART treatment compared with those who delivered and compared with women who were antibodynegative.

When examining infertility and ART/IVF treatment outcomes, there are also conflicting study results. A retrospective study showed a higher prevalence of subclinical hypothyroidism (SCH) but not of thyroid autoimmunity in patients with infertility. A systematic review and metaanalyses, which included only RCTs, focused on the treatment effect of levothyroxine on the pregnancy outcomes of women with SCH and/or TAI who underwent IVF treatment. This study found a significantly decreased miscarriage risk relative to those receiving a placebo or no

References 1. Practice Committee of the ASRM. Fertil Steril 2025;121(5):765–781 2. Gleicher N. Clin Rev Allergy Immunol 2010;39(3):194–206.

3. Gleicher N. J Autoimmunity.

2014;50:83–86

And right away a contradictory paper A paper by Chinese investigators in the November issue of the JCEM right away contradicts previously

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noted ASRM Opinion¹ by claiming that the association of anti-thyroid peroxidase (TPO) antibodies with preterm birth “has been established before” and in the present study demonstrating also a mild—though clinically not very relevant— association with anti-thyroglobulin (TG) antibodies.¹ So, what to believe?

Reference 1. Yang et al. J Clin Endocrinol Metab 2025;110(11):e3841–e3849

Hypothyroidism in general And since we are already talking about thyroid disease and hypothyroidism, it does not happen frequently that a prominent medical journal offers an up-todate review article on a specific disease. But that is exactly what The New England Journal of Medicine recently did with hypothyroidism.

So, whoever, especially after the preceding article, is interested in a general update on hypothyroidism, here is a really good one.¹ Reference 1. Chaker L, Papaleontiou M. N Engl J Med 2025;334(19):1750–1760

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REGARDING THE MALE PARTNER

Mutations sperm acquire with age

Is the role of males in fertility and reproductive health underrecognized?

A recent issue of Nature magazine offered some interesting news on mutations human sperm acquires with age. As Caroline Watson, PhD, summarized this in an Insight article,¹ “age-related mutations give sperm-forming stem cells a selective advantage during sperm production, shaping disease risk and genetic variations in offspring.”

This is at least what Aleksander Giwercman, MD, PhD, a professor of reproductive medicine at Lund University in Sweden, recently suggested in an oral presentation at ASRM 2025 in San Antonio, TX, which found wider distribution through an article in Healio.¹ We, frankly, are not sure that this really represents an area of

fertility care that—currently—is significantly underserved. This, of course, does not mean that new insights into male fertility may not be of importance and may not improve current fertility treatment outcomes, as this speaker suggested. But we quite strongly feel that the infertility field—at least currently and considering the already insufficient financial support it receives from government and private research foundations—has many other issues to resolve first (mostly relating to female infertility), which would have a much bigger impact on fertility treatment outcomes.

Reference 1. Healio. Q&A: Men’s role in fertility, reproductive health underrecognized.

Healio Primary Care. Published November 17, 2025.

EVERYTHING

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As she noted, it is now over 50 years ago that several developmental disorders (Apert syndrome, achondroplasia, etc.) were first associated with advanced parental age. They then later were demonstrated to be the results of activated genes of the RAS–MAPK signaling pathway, and by 2016 localized clusters of spermatogonial cells carrying these mutations were discovered in human testes. This discovery supported the so-called “selfish spermatogonial selection theory,” which proposed that mutations which confer a selective advantage to spermatogonial stem cells increase disproportionally in the sperm pool as those cell clones expand, increasing the risk for newly acquired mutations to be passed on from father to offspring.

Till now only 13 genes in the RAS– MAPK signaling pathway were shown involved in this, but Watson wrote her comments in response to two sequential papers in the same issue of Nature magazine.2-3 In the first, Neville et al. identified among 263 genes commonly implicated in cancer and/or developmental disorders 40 genes under significant positive selection. They basically were mutated versions of genes selected because they were 113

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conferred an advantage, either because the mutation activated the gene (gain of function) or impaired the gene (loss of function).² In another paper, Seplyarskiy et al., using a very different strategy, also identified 40 genes with more mutations than one would expect, among them 23 with loss-offunction mutations and 17 that were frequently mutated in socalled “hotspots” believed to exhibit gain of function.³ Both of these studies, therefore, demonstrated that driver mutations exist also outside of the RAS–MAPK pathway with its only 13 genes. Though only 17 genes overlapped in these two independent studies, Watson suggested that one could expect that because of different strength and statistical powers of the different methodologies both studies utilized.

Neville et al. calculated that at age 30 approximately 2% of sperm cells carry such mutations, which increases by age 70 to ca. 4.5%, many being very low-frequency mutations (99.4% were found in only 1 sperm cell).

Meaning: The proportion of disease-carrying mutations rises with advancing male age due to the accumulation of many small, positively selected clones, rather than expansion of a small number of dominant ones. Moreover— as demonstrated by Neville et al.—most genes that drive clonal expansion are ultimately depleted in the population of loss-offunction variants (selection in the long term is always purifying).

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Both groups of investigators, however, also found that advantageous mutations can arise in spermatogonial stem cells faster than purifying selection can remove them. As a consequence, analysis and genetic counseling about disease risk can be misleading if such counseling solely relies on new (de novo) mutations.

References 1. Watson C. Nature 2025;647:323–324 2. Neville et al., Nature 2025;647:421–428 3. Seplyarskiy et al., Nature 2025;647:429– 435

Now also intratesticular platelet rich plasma (PRP) for non-obstructive azoospermia? Not so quick!

It started in sports medicine, went to several other medical specialty areasincluding the treatment of male balding—before entering the infertility arena—first through intra-ovarian injections in women with low functional ovarian reserve and, shortly thereafter, as treatment for chronically thin endometrium through endometrial perfusions.

And what is this “wonder treatment?” It, of course, is platelet rich plasma (PRP).

And now it has reached male infertility as a potential treatment of nonobstructive azoospermia.¹ By captions advertised as a Narrative Review of the use of PRP in nonobstructive azoospermia, this paper is anything but that because a majority of the paper is taken up by a discussion of the pathophysiology of azoospermia and sperm retrieval techniques in azoospermia as well as PRP use in female infertility, all three, of course, subjects that

have almost nothing to do with use of PRP in nonobstructive azoospermia.

The reasons for this charade, however, become quickly obvious because there hardly exist any data to review. In other words, there really is no way to fill enough pages for even a short Narrative Review on the subject. So why not blow up the text with irrelevant stuff to fill the pages?

That Fertility and Sterility’s peer review and editorial office (likely the biggest of any medical journal in the world!) would publish this paper under this title is almost unbelievable. The poor editing of the manuscript also makes one wonder whether anybody really read the whole paper at all. But in the end this is only just more evidence that the ASRM really has to start paying attention to what currently is going on in the editorial office of its premier medical journal. It has never been as bad before!

And regarding this paper—clearly deserving of a WORST PAPER AWARD IN ISSUE. Reference 1. Cakiroglu et al., Fertil Steril 2025;124(3):417–425. WORST PAPER AWARD IN ISSUE.

For how long does illicit androgen use in males linger?

A recent paper in the JCEM offered some interesting and somewhat unexpected answers: Previous illicit androgen use caused lower testosterone secretion by testicles after hCG injection in participants

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with mean age 33 for up to two years after cessation of androgen use and likely influenced erectile function in parallel.

Reference 1/ Bulut et al., J Clin Endocrinol Metab 2025;110(11):e3709–e3718

Accutane (isotretinoin) as a new treatment for nonobstructive azoospermia?

A recent study in JARG reported interesting and—for a change— quite promising results for selected males with non-obstructive azoospermia. Here is some detail: Among 30 men undergoing isotretinoin treatment, 26 (87%) were azoospermic and 4 (13%) were intermittently cryptozoospermic.

Among azoospermic men, 24 (92%) had prior testicular procedures and 6 (23%) had a history of cryptozoospermia.

Overall, 11/30 (37%) of patients developed reliable, motile ejaculated sperm counts with Accutane treatments (20 mg BID), with men with maturation arrest patterns demonstrating the highest response (6/11 or 54%). Side effects included 30 (100%) with dry skin and chapped lips, 4 (13%) with rashes, 14 (47%) with irritability, and 5 (17%) with altered cholesterol panels.

This result should really not surprise because retinoic acid is a metabolite of vitamin A and is required for mammalian spermatogenesis. Clinically, intratesticular retinoic acid concentrations, moreover, have been reported to be lower in infertile men and in prior reports of

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azoospermia. Moreover, Accutane treatments have before been suggested to increase sperm counts in men with oligospermia and in nonobstructive azoospermia. But this was the first study that did not only investigate whether there was semen in the ejaculate after treatment—yes or no—but whether there was enough sperm in the ejaculate to avoid the need for a surgical testicular sperm retrieval.

And approximately a third of men treated with Accutane did have enough semen in a follow-up of 3–9 months.

References 1. Jessup et al., J Assist Reprod Genet 2025;42(8):2793–2799 2. Healio. Accutane improves sperm count for some infertile men in early study.

Healio Dermatology. Published September 15, 2025. https://www.healio.com/ news/dermatology/20250915/accutaneimproves-sperm-count-for-some-infertilemen-in-early-study 3. Draghici S, et al. Exp Ther Med. 2021;21(5):534

What the authors, in a discussion of their JARG paper in Healio,² however, completely ignored is the fact that isotretinoin is in males just as teratogenic as in females.³

The swinging pendulum when it comes to menopausal hormone therapy

GYNECOLOGY, MENOPAUSE, FEMALE SEXUAL MEDICINE, & TRANSGENDER CARE

And here we go again: The FDA decided to remove the black box warning for postmenopausal estrogen supplementation.¹ Postmenopausal estrogen supplementation, indeed, may be helpful in delaying Alzheimer disease,² and a recent Viewpoint article in JAMA Internal Medicine actually addressed this swinging pendulum, noting that “few medications have captured the imagination—and provoked such ire—as menopausal hormone therapy.”³ But there are lessons to learn from this swinging pendulum which do not only have relevance to postmenopausal hormone replacement therapy (HRT) but really apply to all of medicine: (i) Almost nothing in medicine is forever; (ii) Almost nothing in medicine applies to “everybody”; (iii) Medical remedies often are age-dependent; (iv) What represents “best” treatment often 115

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depends on multiple contributing causalities and their relative contributions.

Doesn’t that sound exactly how the CHR always notes infertility should be treated?

References 1. FDA News Release. November 10, 2025. https://www.fda.gov/news-events/pressannouncements/hhs-advances-womenshealth-removes-misleading-fda-warningshormone-replacement-therapy 2. Nerattini et al., Frontiers Aging Neurosci 2023;15:1260427 3. Thurston RC, Huang AJ. JAMA Intern Med 2025;5340. Online ahead of print.

PREGNANCY AND OBSTETRICAL PRACTICE The effects of ionizing radiation on future pregnancy Animal studies have demonstrated ovarian follicle damage and mutagenesis after ionizing radiation exposure. Computed tomography (CT) imaging is commonly done outside pregnancy, but risks to future pregnancies have so far not been evaluated. Canadian investigators now published a study which immediately resulted in strong responses because it concluded that exposure to preconception CT imaging may be associated with higher risks for spontaneous pregnancy loss and congenital anomalies, though the authors noted that causality remains to be elucidated and that alternative imaging methods should be considered when appropriate.

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Among several rather emotional responses, a more reasonable critique in a comment to the paper² in our opinion correctly concluded (and, as above noted also noted by the authors, that the study was not conclusive and did not prove causation). Further, the results conflict with studies that have failed to find an increased risk of heritable effects at doses associated with other radiation therapies, which were three orders of magnitude larger than those associated with medical imaging in this study.

These authors further argued that, while the topic warrants further study, there is not enough evidence yet to justify changing clinical practice based on this single study, as anticipated benefits from a necessary diagnostic imaging exam do substantially outweigh any potential radiation effect.

References 1. Simard et al., Ann Int Med 2025;178(1). https://doi.org/10.7326/ ANNALS-24-03479 2. McCollough et al., Ann Int Med 2025; https://www.acpjournals.org/doi/10.7326/ ANNALS-25-03528

The use of various biologics in pregnancy BIOLOGICS IN WOMEN WITH AUTOIMMUNE DISEASES DURING PREGNANCY In a recent paper in JAMA Network Open, investigators from several U.S. universities investigated the question whether use of biologics for seven autoimmune diseases in 6,131 patients changed during pregnancy after they had used such biologics for at least six months prior to pregnancy.¹

Considering the still quite limited knowledge about safety of biologics in pregnancy, the answer may be somewhat surprising: 71.6% of patients continued use of their medication at least once during pregnancy. Individuals with Crohn's disease and ulcerative colitis were more likely to continue use during pregnancy compared with individuals with rheumatoid arthritis, while patients with psoriasis or psoriatic arthritis were less likely to continue.

As the authors noted, continuation of biologics in patients with an autoimmune condition who become pregnant involves weighing consequences of pregnancy-related changes in disease severity and potential teratogenic effects of medications. Characterization of biologic treatment patterns during pregnancy, therefore, may provide some insight into maternal and fetal risks and benefits.

Meaning: The authors correctly concluded that the variations in decline in the use of biologics for autoimmune disease observed during the pregnancy period that rebounded only partially thereafter in use across different autoimmune conditions suggest that indicationspecific risk-benefit assessments of biologic use are needed.

TUMOR NECROSIS FACTOR INHIBITORS (TNFis) And in follow-up and, for a change, with some mildly reassuring news: The use of biologics in pregnancy is obviously increasing; yet safety data are still sparse for many of them.

In a study of 3,711 pregnancies exposed to TNFis in the Journal of Rheumatology, the authors

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observed trends to increasing continuous use in comparison to other therapies (including fewer steroids), concluding that this must reflect “growing confidence” in safety and effectiveness of TNFis during pregnancy.² While this trend and this belief is also supported by other publications addressing several other biologicals, these kind of uncontrolled real-world data are obviously very limited in the level of safety evidence they provide.

NATALIZUMAB – a monoclonal antibody has been a standard treatment for relapsing multiple sclerosis for almost 20 years and the news about using this medication in pregnancy is less favorable: A recent paper in JAMA Neurology reported that in a cohort study of 6,341 pregnant women, diseasemodifying treatments in general significantly increased the risk of relapse and this risk was especially high with natalizumab. To mitigate this risk, the use of anti-CD20 before pregnancy turned out to be the most effective treatment to mitigate this risk.³ MONOCLONAL ANTIPLATELET FACTOR 4 ANTIBODIES Monoclonal anti-platelet factor 4 (PF4) antibodies were recently shown to be a cause of persistent thrombotic thrombocytopenia.

In a research letter in The New England Journal of Medicine, US investigators from two institutions recently reported two patients with monoclonal anti-PF4 antibodymediated thrombosis, chronicintermittent thrombocytopenia, and unexplained first-trimester

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pregnancy losses, suggesting a possible link between antiPF4 antibodies and obstetric complications – clinically mimicking the anti-phospholipid antibody syndrome. The losses occurred during the first trimester, and a comprehensive work up suggested the possibility that monoclonal anti-PF4 antibodies may have contributed to the pregnancy losses.⁴ References 1. Ewig et al., JAMA Network Open 2025;8(5):e2510504 2. Flatman et al., J Rheumatol 2025;52(11):1159–1165 3. Gavoille et al., JAMA Neurol 2025;82(10):994–1003 4. Bavli NR et al. N Engl J Med 2025;393(3):307–309

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Systemic lupus erythematosus (SLE) in pregnancy And since we are already talking about autoimmune diseases in pregnancy, a little side trip to pregnancy outcomes across SLE subgroups, as recently reported in Lupus Science & Medicine.¹ That SLE represents risk for adverse pregnancy outcomes as well as cardiovascular events— especially if patients also have lupus nephritis (LN) or antiphospholipid antibody syndrome (APS)—is well known. But how maternal cardiovascular events affect pregnancy complications is not well understood, as noted by the authors.

Using a California-based birth cohort between the years 2005 and 2020, the study population was further subdivided based on whether they did or did not have LN or APS. What they found was that cardiovascular events complicated 0.2% in women without autoimmune rheumatic diseases or APS and 2.1% with SLE. Women with LN had cardiovascular events in 5.8%, women with APS in 7.8%. Here is further detail: Non-cardiac severe maternal morbidity (3.2-fold to 31.5-fold), intensive care admission (2.0-fold to 12.2-fold), 1-year readmission (2.4-fold to 6.0-fold) and death (7.0-fold to 7.9-fold). Similarly, adverse infant outcomes were higher: preterm birth (2.3-fold to 6.8-fold), small-for-gestationalage infant (1.8-fold to 3.4-fold), neonatal intensive care admission (2.1-fold to 7.9-fold) and infant death (1.6-fold to 3.7-fold), with

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highest risk estimates for SLE with LN or APS, particularly when complicated by cardiovascular events.

Meaning: LN and APS in SLE contributed to incremental risks for adverse outcomes, with the combination of LN or APS with cardiovascular events yielding the highest point estimates, underscoring the importance of disease severity but also the impact of cardiovascular events.

Reference 1. Dhital et al., Lupus Sci & Medicine 2025;12:e001507

REPRODUCTIVE AND GENERAL GENETICS Experimental cell division to generate cells with reduced chromosome ploidy—an important step toward making new autologous gametes Papers from Shoukhrat Mitalipov, PhD’s, laboratory in Oregon are quite rare; but whenever one drops, it usually makes headlines and the last one was no exception.¹ And here is what the laboratory did this time: Somatic cell nuclear transfer (SCNT—transfer of a nucleus from a somatic cell, like skin or hair, into an egg) enables the direct reprogramming of somatic cells into functional oocytes. But this newly constituted cell will have a diploid genome (double of what will be needed to make an embryo).

To address this problem ploidy has to be reduced.

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And this is what Mitalipov’s laboratory set out to do in the human experience (in mouse, this had been already accomplished

by Japanese investigators several years ago). They investigated an experimental reductive cell division process, termed “mitomeiosis,” wherein non-replicated (2n2c) somatic genomes are prematurely forced to divide following transplantation into the metaphase cytoplasm of enucleated human oocytes.

vitro gametogenesis, though—they noted in their paper—at this stage it remains just a proof of concept and further research is required to ensure efficacy and safety before future clinical applications. We are very much looking forward to hearing from Mitalipov on his lab’s progress at the annual FRMC in NYC between December 5 and 7.

However, despite seemingly successful fertilization with sperm, the SCNT oocytes remained arrested at metaphase stage, which suggested that activation of the oocyte had failed to occur. The investigators, however, overcame this difficulty with artificial activation using a selective cyclin-dependent kinase inhibitor, which successfully bypassed the arrest, resulting in induction of segregation of somatic chromosomes into a zygotic pronucleus and a polar body.

INFECTIOUS DISEASES AND REPRODUCTION

Comprehensive chromosome tracing via sequencing revealed that homologous chromosome segregation occurred randomly and without crossover recombination.

An average of 23 somatic chromosomes were retained within the zygote, demonstrating the feasibility of experimentally halving the diploid chromosome set of a somatic cell. Fertilized human SCNT oocytes progressed through normal embryonic cell divisions, ultimately developing into embryos with integrated somatic and spermderived chromosomes.

Their study, thus, demonstrated the potential of “mitomeiosis” for in

Reference 1. Mart Gutierrez et al., Nat Commun 2025;16:8340

What to expect from this year’s flu season?

So, you may have seen the TV psychiatrist and a supposedly world-leading epidemiologist selling the public on TV prophylactically medications (including antibiotics) in preparation for a especially bad flu season this year (where that information is coming from, we don’t know). Aside from the fact that prescription medications have expiration dates and one, therefore, should not buy them in advance on spec, this is an especially stupid idea when it comes to antibiotics which already are badly overprescribed and overused, leading to their ineffectiveness when really needed because bacteria already are resistant. And antibiotics, moreover, don’t work against viruses!

So what can we really expect in this upcoming flu season?

According to NBC News, health experts are increasingly worried

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about a new strain of the flu virus that emerged over the summer, causing “unprecedented outbreaks in Japan, Canada, and the UK”¹ It’s a version of H3N2 that acquired over the summer seven new mutations, which makes it to be quite different from the H3N2 strain included in this year’s flu vaccine. In the UK, flu cases are this year—due to this new strain—triple what they were last year. Japan is experiencing a 6-times as high prevalence as last year, closing more than 2,300 day care centers and schools at least partially.

And how does this virus strain so far affect the US? As of this writing, we don’t know because the CDC apparently no longer has enough staff to follow flu activity. In over six weeks, the CDC has been mum regarding U.S. flu activity!

So what to do? The CHR recommends getting vaccinated.

The flu vaccine, like the COVID vaccines, does not prevent infection but is quite effective in preventing serious disease, requiring hospitalization. We especially recommend it for immunecompromised individuals, women trying to conceive or already pregnant.

Reference 1. Edwards E. NBC News. November 12, 2025. https://www.nbcnews.com/ health/health-news/evere-flu-strainh3n2-us-response-outbreaks-canada-ukrcna243431

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And what to expect from this year’s COVID season and COVID in general COVID VACCINATIONS The SARS-CoV-2 virus appears quite active this year, even though exact numbers are not as usually available in timely fashion because of the shut-down of the government and, likely, because of the upheaval at the Centers of Disease Control and Prevention (CDC). The CHR has repeatedly stated and restated that we strongly recommend COVID vaccinations of women attempting to conceive and already pregnant.

A recent study strengthened our argument by reporting in a modeling study (not our favorite study format but better than nothing) that estimates show substantial reductions in infant and maternal hospitalizations if mothers are vaccinated.¹ The study used 2024–2025 surveillance data and was conservative in its assumptions, for example, using vaccine effectiveness estimates of only 35% against infant hospitalization and 33% against maternal hospitalization.

SEX SPECIFIC DYSREGULATION IN LONG COVID PATIENTS Canadian investigators recently reported that women with long COVID plus ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) demonstrated a very different immune system pattern than males with long COVID, characterized by heightened inflammation, altered

hematopoiesis, disrupted hormone levels, and neuroinflammatory gene signatures. In addition, they found sex-specific immune and hormonal biomarkers correlating with clinical symptoms.

Meaning: These findings call for tailored therapeutic strategies for both sexes—among those potentially hormone replacement therapy.² THE COMMON COLD PROTECTS FROM INFECTIONS WITH SARS-CoV-2 Here are some interesting and—for a change—good news: As a recent paper in The Journal of Infectious Diseases reported, rhinovirus infections (the viruses responsible for the common cold) trigger the expression of antiviral airway genes and are linked to a subsequent lower risk of COVID infections.³ The authors also suggest that this may be why children experience milder infections with the SARSCoV-2 virus than adults since frequent infections with the rhinovirus enhance this protective gene profile.

AND THIS DID REALLY MAKE THE HEADLINES: COVID-19 vaccine may boost cancer immune therapy Underscoring the still largely untapped potential of mRNA vaccination technology, an article by Phie Jacobs in Science magazine well summarized the data that probably surprised almost everybody⁴ and, roughly at the same time, was presented at the European Society for Medical Oncology Congress in Berlin and in a paper in Nature.⁵ The 119

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investigators reported that mRNA vaccines targeting SARS-CoV-2 also sensitize tumors to immune checkpoint inhibitors (ICIs), of course a revolutionary treatment that has achieved remarkable progress in a relatively short time period.

In preclinical models, SARSCoV-2 mRNA vaccines led to a substantial increase in type 1 interferon, enabling innate immune cells to prime CD8+ T cells that target tumor-associated antigens.

Concomitant ICI treatment is required for maximal efficacy in immunologically cold tumors, which respond by increasing PD-L1 expression.

doi:10.1093/infdis/jiaf374. Online ahead of print.

4. Jacobs P. Science 2025; PMID: 41129646. DOI: 10.1126/science.aed2823 5. Grippin et al., Nature 2025;647:488–497

GEROSCIENCE—THE SCIENCE OF AGING— here in its relevance for OVARIAN AGING So what is “Geroscience?”

If you never before heard this term, you are not alone. It is a relatively new field of study that focuses on the physiology of aging and how long-term benefits can be obtained from altering this physiology.¹ A recent article in JAMA, indeed, offered a Translational Review Similar correlates of vaccination (whatever this term may mean).² It responses are found in humans, is a “hot” area in medical research including increases in type I and has given rise to a whole – interferon, myeloid–lymphoid often not really “kosher” – industry activation in healthy volunteers, of clinical care. We here mostly and PD-L1 expression on tumors. refer to this JAMA article for Moreover, receipt of SARS-CoV-2 mRNA vaccines within 100 days of further explanation. With the ovary being the first human organ to “age initiating ICI was associated with out” of function, geroscience has, of significantly improved median course, potentially great relevance and three-year overall survival in multiple large retrospective cohorts. to female infertility.

This benefit is similar among patients with immunologically cold Medical therapies typically alter biologic pathways to treat or tumors. prevent specific diseases. Diseasefocused treatments, however, Meaning: Together, these results demonstrate that clinically available do not alter effects of aging on diseases and/or declining function. mRNA vaccines targeting nonIn animal models it has, however, tumor-related antigens are potent been demonstrated that treatments immune modulators capable of can alter aging’s effect on disease. sensitizing tumors to ICIs. A good example has been initial caloric restriction in mice which References demonstrated significantly 1. Loe et al. JAMA Pediatr 2025; doi:10.1001/jamapediatrics.2025.3561 increased mean lifespans (10%– 2. Shahbaz et al., Cell Rep Med 40%) compared to ad libitum fed 2025;6:102440 mice, concomitantly favorably 3. Moore et al., J Infect Dis 2025; jiaf374. affecting multiple cellular pathways

implicated in aging including nutrient sensing, protein synthesis, autophagy, and inflammation.

In obese and diabetic humans, caloric restriction was associated with a 15% reduction in all-cause mortality and a lower incidence of weight-related chronic diseases.

Rapamycin, a drug routinely used to suppress allograft rejection, increased mouse median lifespan by 249 days in females and 154 days in males. A rapamycin analogue, everolimus, improved antibody titers to influenza vaccine in older adults.

In humans, senescent cells increase in abundance with age and are characterized by growth arrest, apoptosis resistance, and an altered secretome (proteins secreted by a cell into the extracellular space). A greater abundance of senescent cells is associated with more physical impairments and increased mortality. Reducing the number of these cells in animal models extends lifespan and improves physical function, such as grip strength and mobility, and cardiac ejection fraction. However, potential health benefits of reducing senescent cells in humans remain unclear.

Meaning: Therapies that potentially inhibit aging, such as caloric restriction, metformin, senolytics, or so-called rapalogs, may, indeed, slow the development and progression of disease and functional decline in humans and—in doing so—may also extend lifespan.

References 1. Warburg M. Medscape. September 5, 2025. https://www.medscape.com/s/

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viewarticle/can-new/-science-slow-agingand-disease-risk-2025a1000nfs 2. Kritchevsky S, Cummings SR. JAMA 2025;334(12):1094–1102

A new hallmark of ovarian aging with unique immune and degradation-associated molecular signature A group of US investigators from several institutions published an interesting paper in PLOS Biology in which they claimed that multinucleated giant cells are hallmarks of ovarian aging.

Moreover, they express a unique immune and degradationassociated molecular signature. The function and consequence of these giant cells remain unknown, but such cells usually occur because of macrophage fusion and are found typically in chronic immune pathologies.

Pathway analyses suggested signatures related to degradative processes, immune function, and high metabolic activity. These cells also expressed CD4 and colocalized with T cells, suggesting interaction between these two immune cells.

Meaning: The authors concluded that these findings implicate these giant cells in modulating (or in participating in the modulation of) the ovarian “immune landscape” during aging.

Reference 1. Converse et al., PLOS Biology 2025;23(6):e3003204

Can organ age predict disease risks and lifespan?

It has been known now for already several years that a body’s organs

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can—and usually do—age at varying speeds. Using plasma proteomics, it now has become possible to study how these different organ ages reflect on disease risk and mortality, with one association having become very popular as a research goal, how the brain’s biological age reflects on Alzheimer risk.

A recent study by investigators from the Icahn School of Medicine at Mount Sinai here in NYC analyzed approximately 3,000 proteins from the blood plasma of approximately 50,000 individuals in the UK Biobank1 and identified proteins likely derived from specific organs. Their plasma concentrations were then put into machine-learning models to establish the biological age of 11 of their major organs. From these data the investigators then calculated for each individual and his/her organs their respective age gap (how much younger or older its age was than the same organ from age-matched peers).

Based on 17 years follow-up organ gaps predicted correctly heart failure, COPD, type 2 diabetes, and Alzheimer’s disease. Remarkably, a too-aged brain tripled the risk for Alzheimer, while a younger brain cut the risk by 75%. This study thus opened up a large and very interesting new research opportunity to investigators. This effect size was somewhat surprising because it matched that of the APOE genotype, which is the strongest genetic risk factor for Alzheimer’s.

Mortality risk increased ×2–3 with 2–4 over-age organs, ×4.5 with 5–7 over-age organs, and

over 8-times with over 8 organs over-age. In contrast, unusually young brains reduced risk of death by 40%, youthful immune systems by 42%, and if both acted unusually young, by 56%. While a healthy lifestyle was associated with youth, smoking, alcohol, and sleep deprivation were associated with broad organ aging. Andto demonstrate relevance to ovarian aging—so was early menopause, which in recent years has already been associated with earlier mortality in several studies.

Interestingly, however, estrogen supplementation in menopause was associated with immune system youth.

Reference 1. Oh et al., Nat Med 2025; ahead of print. https://doi.org/10.1038/s41591-025-03798

Why is Alzheimer disease more common in women?

The answer still appears to be, we don’t really know! For the longest time, the world believed to know why women had more cases of Alzheimer disease than men (approximately almost 2 out of 3): because they live longer! But as Rita Rubin recently in JAMA noted, the explanation is more complex, likely involving biological as well as sociocultural factors.¹ Women live longer with the disease, as a recent study suggested: A year after diagnosis with dementia, ca. 27% of men but only 22% of women had died.² But why they have more disease than men has really mostly remained unresolved.

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effective prophylactic measure to prevent Alzheimer; but it clearly falls short as treatment for already diagnosed disease.

As the article noted, restorative effects of SRCs are partly attributed to their exosomes, which combat cellular senescence.

Skeptics still don’t believe that postmenopausal estrogen treatments have any prophylactic function, as Rubin points out in her article, noting that the same amount of Alzheimer pathology causes greater cognitive declines in women than men. Even the APOE4 genetic variant is more “effective” in causing disease in women than men.

Meaning: Modified human mesenchymal progenitors can apparently slow down primate aging, pointing toward potential therapeutic regenerative approaches in combating age-related health declines.

Reference

1. Rubin R. JAMA 2025;334(16):1411–1413 2. Lusk et al. JAMA Neurology 2025;82(10):1048–1056

Are senescence-resistant human mesenchymal progenitor cells the answer to aging?

That is at least what a publication

by Chinese investigators in Cell recently suggested.¹ In a 44-week trial they delivered senescenceresistant human mesenchymal progenitor cells (SRCs) genetically fortified to enhance cellular resilience to aged macaques, which resulted in a systemic reduction in typical aging indicators, including cellular senescence, chronic inflammation, and tissue degeneration. Interestingly, no adverse effects from these infusions were observed, while brain architecture and cognitive function appeared enhanced and—interestingly—declines in reproductive systems were alleviated.

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Reference 1. Lei et al., Cell 188(18):5039–5061

Multilingualism (speaking multiple languages) extends health and lifespans We, of course, cannot help ourselves from once again including in this issue of the VOICE one more of Eric Topol CHR MD’s brilliant Substack, Ground Truths commentaries.¹ Once more Topol drew our attention to a fascinating subject raised by a fascinating paper,² this time the effects of learning, knowing, and/or using multiple languages on health and lifespan.

As it turns out multilingualism is a lifestyle factor directly linked to healthy aging and longevity: Based on a recent paper in Nature Aging, Topol—as usual—offers a very detailed discussion of a fascinating observation, reflected in the figure to the right.

As background, Topol noted that brain structure studies in the past demonstrated increased gray matter density in key regions (caudate nucleus and left inferior parietal cortex) linked to executive function—a feature known as

In this figure (a) demonstrates differences in gray matter density, while (b) (and (c) demonstrate how gray density relates to proficiency in a second language and age of acquisition of a second language, respectively.

“neuroplasticity.” What this means is that the brain has the ability to change and reorganize its neural connections throughout life. The figure above in (a) demonstrates changes in gray matter and in (b) and (c) how gray matter density relates to proficiency in a second language and age at acquisition of a second language, respectively.

Using 86,149 participants across 27 European countries, the investigators in the study Topol discussed developed biobehavioral age gaps, quantifying delayed or accelerated aging. Multilingualism emerged as a protective factor in cross-sectional (odds ratio = 0.46) and longitudinal (relative risk = 0.70) analyses, whereas monolingualism increased risk of accelerated aging (odds ratio = 2.11; relative risk = 1.43). Effects persisted after adjusting for linguistic, physical, social, and

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of aneuploidy. This observation alone suggested chromosomal instability (CIN) as an inherent feature of the trophoblast lineage.

They then identified potential pathways contributing to the occurrence and tolerance of CIN, including autophagy, which may support the survival of aneuploid cells.

Neural activation patterns3 in monolingual (French only), international adoptee (French with discontinued Chinese), and bilingual (Chinese–French) speakers. Bilingual brains show stronger and more distributed activation, reflecting the enhanced neuroplasticity and cognitive benefits often linked to multilingualism. (Map Courtesy of Pierce et al.)

sociopolitical exposomes. These results underscore the protective role of multilingualism and its broad applicability for global health initiatives.

THE LATEST IN BASIC SCIENCE RESEARCH RELEVANT TO REPRODUCTION

Multilingual ← 3 years younger Monolingual → 5 years older

More on chromosomal instability (and, therefore, aneuploidy) in human trophoblast stem cells and placentas

Meaning: Simply stated, learning a second language may provide 3 more years of healthy aging, while speaking only your mother tongue could shorten the healthspan by 5 years. Fascinating!

References 1. Topol E. Ground Truths. November 12, 2025. https://erictopol.substack. com/p/multilingualism-and-extendinghealthspan 2. Herman Hernandez et al., Nat Aging 2025;5:2340–2354 3. Pierce LJ, Klein D, Chen J-K, Delcenserie A, Genesee F. Mapping the unconscious maintenance of a lost first language. PNAS. 2014;111(48):1737617381.

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Aneuploidy in the placenta has over the last few years been repeatedly a theme addressed in the CHRVOICE. A recent article in Nature Communications added important new information further clarifying the picture.¹

TSCs—despite extensive chromosomal abnormalities— maintain their proliferative and differentiation capacities, findings further validated in placentas, where across trophoblasts a high prevalence of heterogeneous aneuploidy, particularly in invasive extravillous trophoblasts, was observed. This study thus challenges the traditional view of aneuploidy in the placenta.

One conclusion the authors, however, omitted in their discussion, we, in contrast, however, on several occasions have discussed in these pages, can no longer be denied: All of our current knowledge about the distribution of aneuploidies in miscarriages must be reevaluated.

The reason is simple: for decades, surgeons who have been sending products of conception for chromosomal analyses to The authors noted that diagnostic laboratories at the discrepancies in reported request of pathologists have been aneuploidy prevalence in placentas selectively submitting trophoblast stem from limitations in modeling (i.e., the extraembryonic cell and detection methods. To establish lineage) because—in contrast some better clarity, they in their to fetal tissues—trophoblast in paper used isogenic trophoblast virtually almost all cases allowed stem cells (TSCs) derived from for the establishment of cell both naïve and primed human cultures which were a precondition pluripotent stem cells (hPSCs) to for chromosomal spreads in those reveal the spontaneous occurrence days needed for karyotyping.

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But, as this paper again demonstrated, since trophoblast exhibits so much more chromosomal instability than the embryonic cell lineage from which the fetus derives, all in the literature recorded aneuploidies must be significantly exaggerated in comparison to what really exists in the fetal compartment.

Reference 1. Wang et al., Nat Commun 2025;16:3918

Has the time come to “fix” human embryos affected by monogenic diseases with CRISPR? This is a question that Heidi Ledford recently asked in a News article in Nature magazine after interviewing Cathy Tie, one of the two co-founders of Manhattan Genomics, a new start-up in New York City, located in Long Island City, which was founded to do exactly that.¹ CONFLICT STATEMENT: Norbert Gleicher, MD, Medical Director and Chief Scientist of the CHR, has AGREED to join the Scientific Advisory Board of Manhattan Genomics.

Tie, in the article teasingly nicknamed “Biotech Barbie,” is no stranger to the genetics field or to medicine in general and— certainly not—to establishing new companies. Inspired by a Peter Thiel Fellowship, she left university after the first semester and—while still 18—already founded her first company. She has started two more since and will not be 30 till next April—a birthday she is planning to

Norbert Gleicher, MD, flanked on both sides by the two founders of Manhattan Genomics—Cathy Tie and Eriona Hysolli, PhD—at the annual Double Helix Medals Dinner of the Cold Spring Harbor Laboratory at the Museum for Natural History in NYC, which this year, on November 19, honored famous scientist, inventor, and serial entrepreneur, Dr. Bob Langer and former tennis champions, Chris Evert and Martina Navratilova.

celebrate by giving a piano concert at Carnegie Hall.

As Ledford noted, her first company helped genetic testing firms in interpretation of results and her second company provided digital health care services. In her new company, she will benefit from both experiences, helped by her co-founder in the company, Eriona Hysolli, PhD, a former postdoc in the famous George Church laboratory at Harvard University and later Science Lead at Colossal, the company Church co-founded in an effort to bring back extinct animal species, including the mammoth.

Ledford correctly noted in her article that the concept of “editing” human embryos still worries many researchers, but she also acknowledged that attitudes toward this still controversial

treatment have been changing.

Tie in the interview noted that “we have the duty to patients with incurable, debilitating diseases.”

She also reiterated in several other interviews that—in contrast to some other recent start-ups mostly located in Silicon Valley in California—Manhattan Genomics is planning to “cure” embryos from lethal diseases and has no plans to “enhance” embryos, as these other companies have already started to advertise (see also below).

Considering that single gene diseases usually affect either 25% (if recessive) or 50% (if dominant or sex-linked) of embryos, even if diagnosed before transfer into the uterus (and, therefore, not used in IVF), the non-use of so many embryos in an IVF cycle already greatly reduces the cumulative pregnancy chance of an affected couple. Restoring such an abnormal

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Cathy Tie, Co-founder and CEO of new start-up Manhattan Genomics in front of the corporate logo of the new company in its new headquarter facility and laboratory in Long Island City. (Photo Courtesy of Nature/Caitlyn Gaurano)

embryo in the laboratory by “editing” (i.e., by replacing) the abnormal gene would then allow transfer of such an embryo. Every so-corrected embryo would then improve the cumulative pregnancy chance of the couple.

To do this would, of course, be especially important in older women who usually—in the first place—produce only few eggs and embryos. But even younger women can significantly better their pregnancy chances if half of their embryos do not have to be discarded any longer (see also our editorial in the CHR News section of this CHRVOICE (page 44)).

AND THE CONTROVERSY FOR GOOD REASONS CONTINUES Manipulation of the human germline remains in the headline, whether in the lay press or in science and medical journals.

Here are a few recent examples: Everything, of course, starts with accurate diagnosis of risk because, before one can—or should—edit the germline, there needs to be an objectively established need.

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The Wall Street Journal within this context recently dedicated one of its full-page Op-Ed page interviews to Katherine Stueland, CEO of GeneDx, a genetic testing company that offers newborn screening for DNA mutations “for thousands of treatable disorders.”² The obvious consequence of a societal decision to do this (most of these diseases are not only rare, but very rare, likely having a similar prevalence to the chance of having a winning lottery ticket) is to move from neonatal screening to preimplantation embryo screening.

And then there is, of course, the media buzz surrounding tech titans mostly in Silicon Valley—among those Coinbase co-founder and CEO, Brian Armstrong, and OpenAI co-founder and CEO, Sam Altman—trying to make “genetically engineered” babies for themselves and others.³ Opposition is, of course, also quite vocal: Take, for example, Marcy Darnovsky from the Center for Genetics and Society who under the very telling masthead, “Tech billionaires and rogue scientists moving to commercialize CRISPR babies,” feels that “It’s time to step up the opposition to designer babies.”⁴ And from “designer babies” it, of course, is not a big step to the concept of “eugenics,” when Joel Kotkin quite appropriately asks, “who decides what humans become?”⁵ Likely the most moving contribution to this subject came, however, from Alana Newhouse,⁶ a writer in—where else—but The Free Press, for whom the question of genetic editing was not an abstract one after giving birth to a son with

Angelman syndrome, a very rare mitochondrial disease transmitted exclusively from mothers to their offspring through their mitochondrial DNA which always, and always only, comes from the mother,⁷ when asking herself, “who am I to edit (in this case) my son’s DNA?” What else is there to say?

References 1. Ledford H. Nature 2025;647:295–297 2. The Wall Street Journal. The genetic answer to rare diseases. September 13–14, 2025:A11.

3. Glazer et al., The Wall Street Journal.

November 10, 2025. pA1 & A10.

4. Darnovsky M. Center for Genetics and Society. June 26, 2025. https://www. geneticsandsociety.org/biopolitical-times/ tech-billionaires-and-rogue-scientistsmoving-commercialize-crispr-babies 5. Kotkin J. UnHerd. July 1, 2025. The University of Texas, Austin. Civitas Institute. https://www.civitasinstitute.org/ research/beware-the-new-eugenics 6. Newhouse A. The Free Press. September 10, 2025. https://www.thefp.com/p/whoam-i-to-edit-my-sons-dna 7. Dagli et al., GeneReviews. Last revised May 1, 2025. NIH. National Library of Medicine. https://www.ncbi.nlm.nih.gov/ books/NBK1144/

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The CHR VOICE is the newsletter of The Center for Human Reproduction (CHR), an independent, academically affiliated infertility and research center located at 21 East 69th Street in Manhattan, New York, N.Y. 10021. www.centerforhumanreprod.com. Telephone +212 994 4400.

The CHR VOICE attempts to inform and engage a global community of infertility patients, infertility service providers, and researchers in reproductive medicine, physiology, and biology. The mission of The CHR is clinical care, research, and education, all at highest standards, with empathy, honesty, integrity, and equity. The newsletter is published 10 times a year (except July and August). Copyright © 2025 by The CHR. All rights reserved. Print ISSN 2836-3086. Online ISSN 2836-3094. Copyright © 2024 by The CHR. All rights reserved.

For letters to the editor, comments, and suggestions, please contact jgreenberg@thechr.com.

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