Today’s posting offers an article by David H. Barad, MD, MS, a Director of Clinical ART and Senior Scientist at the Center for Human Reproduction. In a recent lecture he attended at the Lamont-Doherty Earth Observatory of Columbia Climate School in Palisades, New York, he learned about some valuable discoveries and research that may eventually help explain how life started on Earth. Though the article mainly addresses Earth and space-related science, arguably nothing is more relevant to reproductive biology than how life started in the first place. As always, we are welcoming comments and further discussion from our readers.

The CHR’s Editorial Staff

Seeds from the Stars: Important New Insights on How Life May Have Started on Earth

By David H. Barad, MD, MS, one of the CHR’s REI physicians, Associate Editor of CHR Publications, Director Clinical IVF, Director of CHR-Research and a Senior Scientist. He can be reached through the editorial office of the _CHRVOICE and The Reproductive Times.

On a cool evening in late April, I had the pleasure of attending a lecture at the Lamont-Doherty Earth Observatory of Columbia Climate School in Palisades, New York. Founded in 1949 and perched atop the scenic Palisades overlooking the Hudson River, the Observatory has long been a leader in the world of Earth sciences. The talk was part of a free public lecture series hosted on site.

The speaker, Senior Research Scientist Kerstin A. Lehnert, PhD, presented “NASA’s Billion $$$ Samples: Space Rocks, Open Science, and the Era of AI.” Her lecture focused on extraterrestrial materials returned to Earth through NASA missions. Dr. Lehnert and her team have played a central role in cataloging these samples and maintaining a comprehensive, publicly accessible database that integrates both the materials themselves, and the growing body of research derived from them.

Midway through her fascinating lecture, she turned to the OSIRIS-REx mission to the near-Earth asteroid 101955 Bennu. This NASA-led mission was designed to collect and return pristine samples in order to better understand early solar system formation and the origins of life.

Launched in September 2016, the spacecraft arrived at Bennu in December 2018, where it conducted detailed mapping and compositional analysis using advanced imaging and spectroscopic instruments. In October 2020, it executed a brief touch-and-go maneuver, successfully collecting more than 70 grams of material—exceeding its target.

On its return, as the spacecraft approached Earth in September 2023, it released a small sample-return capsule that parachuted into the Utah Test and Training Range, while the spacecraft itself continued onward on an extended mission to another asteroid.

The most striking aspect of the returned 101955 Bennu samples was the richness of their organic chemistry. Early analyses identified carbon-containing compounds, nitrogen-bearing molecules, water-bearing clay minerals, and several classes of compounds considered important to prebiotic chemistry. In space science, the term “prebiotic” refers to “Complex Organic Molecules” (COMs): molecules that are not themselves alive, but that serve as the chemical precursors to life. These compounds represent the raw ingredients—the “recipe”—from which essential biological structures such as DNA, RNA, proteins, and cellular membranes can eventually arise.

Scientists detected amino acids, nucleobase-related compounds, and simple sugars in the Bennu samples, molecules that on Earth play central roles in biology. Importantly, these materials were recovered directly from space and returned under carefully controlled conditions, minimizing terrestrial contamination and making the findings especially compelling.

Researchers emphasized that these discoveries do not represent evidence of life itself, but rather evidence that the chemical building blocks associated with life can arise through entirely abiotic processes. This distinction is important. In chemistry, “organic” simply refers to carbon-based molecules and does not imply a biological origin. The Bennu samples support the growing understanding that complex organic chemistry may be a natural consequence of planetary and interstellar processes, rather than something unique to Earth. Primitive asteroids such as Bennu appear capable of acting as long-term reservoirs, preserving materials formed during the earliest history of the solar system.

These findings are further supported by observations from the James Webb Space Telescope (JWST), which has recently revealed what many scientists describe as a “treasure trove” of prebiotic chemistry throughout the universe. Using its Mid-Infrared Instrument (MIRI), JWST identified multiple complex organic molecules frozen within icy grains surrounding the young star ST6 in the Large Magellanic Cloud. These included ethanol, acetic acid, methanol, acetaldehyde, and methyl format—molecules considered important intermediates in the formation of amino acids and nucleotides.

Remarkably, this represented the first detection of several such “prebiotic seeds” as ices outside the Milky Way. JWST has also identified rich organic chemistry within heavily obscured galactic cores, including the first detection beyond our galaxy of the highly reactive methyl radical (CH3), an important intermediate in organic synthesis pathways.

In addition, JWST has detected polycyclic aromatic hydrocarbons (PAHs)—large, carbon-based molecules composed of fused aromatic rings—in galaxies more than 12 billion light-years away. These observations suggest that the universe was capable of producing chemically sophisticated organic compounds only about 1.5 billion years after the Big Bang. Together, the Bennu samples and JWST observations support a profound shift in perspective: the ingredients associated with life may not be rare or uniquely terrestrial but instead may emerge naturally wherever suitable physical and chemical conditions exist.

Equally important was the evidence of water-related chemistry within Bennu’s parent body. The presence of hydrated minerals suggests that the asteroid, or the larger body from which it originated, once interacted extensively with liquid water. Such environments are thought to facilitate complex chemical reactions, potentially allowing simple compounds to evolve into more sophisticated prebiotic molecules. This has strengthened scientific interest in the possibility that asteroids and comets may have delivered not only water to the early Earth, but also a rich inventory of organic materials that contributed to the emergence of life.

Taken together, these discoveries invite a profound reconsideration of humanity’s oldest question: how life began. The early Earth may not have been an isolated cradle struggling to invent biology from nothing, but rather a chemically fertile world repeatedly enriched by material arriving from space. One can imagine the young planet as a receptive and dynamic environment—oceans, minerals, atmosphere, lightning, and volcanic energy interacting with a continual rain of carbon-rich asteroids and comets carrying the molecular seeds of complexity.

In this view, bodies such as 101955 Bennu were not just inert rocks drifting through space, but cosmic couriers delivering the ingredients from which biology could eventually emerge. Whether life itself is common or exceedingly rare remains unknown, but missions such as the OSIRIS-REx mission and observations from the James Webb Space Telescope suggest that the chemistry leading toward life may be woven deeply into the fabric of the universe itself.

Today’s posting offers a look at recent news related to genetics, including a surprising review on PGT-A from some of its biggest proponents – who acknowledged some “uncertainty”surrounding the test. Also included is an unusual story about a woman in a relationship with identical twins, and how a genetic test failed to determine which identical twin fathered the woman’s baby. As always, we welcome your comments and opinions.

The CHR’s Editorial Staff

An Interesting Assessment of PGT-A From a Group of Very Well-Known Proponents

Papers – like people – sometimes offer messages between the lines, and one such paper is what we are commenting on here. Five well-known colleagues who – as strong proponents of Preimplantation Genetic Testing for Aneuploidy (PGT-A) – all have extensively published on the subject, got together and in Human Reproduction basically wrote an Opinion article in the format of a Mini Review (whatever that may mean) on the current status of PGT-A, under the heading, “Navigating uncertainty in PGT-A: aligning analytical, biological, and clinical evidence.”¹

And you may ask, - so what, - what makes this a worthwhile article to consider?

The answer is, - that there is probably more interesting stuff in this opinion article than may appear on first impression because, even the notion of “uncertainty” is already remarkable progress, considering how “certain” the PGT-A establishment has been about all of its positions in the past.

Who doesn’t remember the days when we were told PGT-A improved IVF outcomes and everybody who didn’t believe it was crucified? Or who doesn’t remember the days when we were told that every PGT-A diagnosis is binary, - either euploid or aneuploid, and whatever is aneuploid must be disposed?

And then, in 2016, a so-called society of experts in PGT-A (in reality, a coalition of mostly economically interested individuals who profited financially from increasing utilization of PGT-A) published truly absurd new guidelines because none of their prior positions were sustainable anymore and added the alleged diagnosis of “mosaicism” to PGT-A. You may have noted the wording of this last sentence with the emphasis being on “diagnosis” rather than “determination” (anybody can reach a diagnosis, but a determination is expected to reflect reality) because – as it turned out – those experts didn’t even understand the physiological definition of “mosaicism” when calling an embryo with more than just one euploid cell lineage in a tiny number of 5-maximally 10 trophectoderm cells “mosaic” (obviously, only a whole organism can be “mosaic”).

And we, of course, could go on and on about all the certainty proponents projected in their pronouncements over more than 20 years of supporting the ever-increasing utilization of PGT-A. But we, instead, want to quote from their abstract (with mild edits) because it – to a degree, surprisingly, after over 20 years of more-or-less hogwash – presented a very reasonably updated viewpoint, - even if unnecessarily complicated when spelled out:

PGT-A is widely used to guide embryo selection, yet its analytical performance, interpretive consistency, and clinical value remain active areas of debate. Advances in sequencing and haplotype-based methods have improved resolution and enabled classification of aneuploidies by their mechanistic origin. They, however, have also revealed substantial variability between platforms, laboratory thresholds, and reporting practices. As a result, the same embryo may receive different classifications depending on the analytical framework, with direct implications for transfer decisions and cumulative live birth potential. Across the available evidence, whole-chromosome meiotic aneuploidies show consistent patterns that support their clinical relevance. In contrast, diagnoses of chromosomal mosaicism and segmental abnormalities remain variable and less consistently predictive. Taken together, these observations underscore the need for validation frameworks that integrate analytical precision, biological plausibility, and outcome-anchored clinical data. Without such measures, increasing technological complexity risks widening…”

Between the lines – even if it hurts – the message is clear and can be formulated in much simpler ways:

(i) The primary purpose of IVF is the achievement of pregnancy.

(ii) The embryo cohort generated in an IVF cycle, through quantity and quality of these embryos, represents a large majority of the cumulative pregnancy and live birth chances of this cycle to achieve this goal.

(iii) Best IVF practice mandates, therefore, to maximize the chances of pregnancy and live birth by safely maximizing embryo quality and quantity.

(iv) Since, as this Mini Review acknowledged, current PGT-A does not yet allow the categorical distinction between definitely “euploid” and definitely “aneuploid” embryo, PGT-A will always result in non-use or disposal of embryos with normal pregnancy potential.

(v) The routine use of PGT-A, therefore, is not only non-sensical, - but unethical.

REFERENCE

1. Popovic et al., Hum Reprod 2026;41(5):665-676

A Case Where Even Genetic Testing Could Not Establish Paternity

So imagine, - a woman has a relationship with two identical twins and she conceives. Everybody now wants to know who the father is, including a court. And if you think that this is a made-up story, you are mistaken; it really happened, and a panel of judges just ruled that it is impossible to determine which of the two identical twins fathered the baby.

REFERENCE

1. Rudy M. FOX News. April 1, 2026. https://www.aol.com/articles/woman-double-twin-relationship-sparks-210521899.html

The Concern about Genetic Discrimination by Insurance Companies

It is interesting that out of all medical and science journals, Science picked up on this issue in a recent article on genetics and the law. And the two authors did a terrific job in explaining a very complex issue.¹ While the U.S. Congress passed in 2008 the so-called Genetic Information Nondiscrimination Act (GINA), - most of the heavy lifting regarding the subject was left to the states. In many – if not most – states, the issues, however, remain unresolved or have been only partially resolved. We clearly are all at risk of being discriminated against by insurance companies based on our supposed private and confidential genetic makeup that, likely, is at least theoretically accessible by all kinds of dark sources. Rumor has it, for example, that China is building genetic information banks not only of its own citizens but also of us, - members of the Western world.

We recommend this brief article. It is eye-opening!

REFERENCE

1. Prince AER, Eckel T. Science 10.1126/science.aee2317

Today’s posting covers topics that should be very familiar to readers: the debated use of Tylenol during pregnancy, COVID-19 vaccinations for pregnant women, and the potential impact of Long COVID on some fertility patients. Though these subjects have all been addressed numerous times in lay media at this point, it’s always worth examining the latest scientific research on these matters, as the newest updates may go underreported in some larger news publications. As always, we welcome your comments and discussion.

The CHR’s Editorial Staff

More on Acetaminophen (Tylenol) During Pregnancy and the Risk of Autism in Offspring

This is, of course, a subject addressed exhaustively in medical journals and the lay press, but the study here presented was a very large Danish nationwide cohort analysis, involving more than 1.5 million children born between 1997 and 2022 that examined whether prenatal exposure to acetaminophen (Tylenol/paracetamol) was associated with autism risk in offspring.

And the main conclusions were that (i) after adjusting for confounding factors, the researchers found no meaningful association between acetaminophen use during pregnancy and autism in children. (ii) Absence of association persisted across different pregnancy trimesters, at low and high exposure levels, and in sibling-comparison analyses designed to reduce genetic and family-environment confounding.

Earlier studies suggesting a link may have been affected by “confounding by indication” — meaning that women taking acetaminophen during pregnancy may differ medically from women who do not, and those underlying differences, rather than the drug itself, may explain prior signals.

Clinically, the article very convincingly supports the current view that acetaminophen remains one of the preferred pain and fever medications during pregnancy, when medically indicated.

REFERENCE

1. Philipsen Prahm, et al., JAMA Pediatrics. 2026, Online ahead of print. Doi: 101001/jamapediatrics. 2026.0646

More on COVID-19 Vaccines in Pregnancy

Yes, we know that everybody is tired of hearing more about COVID-19 vaccinations in pregnancy, but even though COVID is no longer the threat it used to be, it still exists endemically in the U.S., and it still is a more severe disease in pregnancy than in the non-pregnant state. Information about vaccinations, therefore, is still of importance.

This is why we here report on an interesting recent study from Norway, which examined associations between COVID-19 vaccination during pregnancy and the risk of various subsequent infections of offspring in early childhood. And the results were really interesting: COVID-19 vaccination during pregnancy protected the offspring against hospital contact for COVID-19 during the first 6 months of life, but no apparent effects were observed for other infections, demonstrating that the protection is highly specific. This is an important finding because there exists considerable evidence that under different conditions, cross-reactivity can exist with other flu-like viruses (see Figure below).

In summary, maternal vaccination against COVID-19 during pregnancy offers a waning protection to the offspring against hospital contact for COVID-19 in the first 6 months of life.

But here is more exciting news from two papers in JAMA and eClinicalMedicine (a Lancet journal), respectively: The JAMA paper, in a study of 26,584 cases, of which 19,899 were eligible for analysis, reported that vaccination prior to and during pregnancy (before diagnosis of COVID-19) was significantly associated with lower risk of severe maternal disease and preterm birth, regardless of variant time period.² The eClinicalMedicine article, in turn, involving no fewer than 69 authors from 18 countries all over the world, reported a truly astonishing finding: COVID-19 vaccination with a booster reduced the odds of preeclampsia (PE) by 30%, approaching 60% reduction among women with pre-existing morbidities.³

And here is the full story: The authors confirmed the previously suggested independent association between COVID-19 and PE (aOR: 1.45; 95% CI: 1.15–1.84), particularly in unvaccinated women (aOR: 1.78; 95% CI: 1.31–2.42). Overall, after adjusting for confounders, any vaccination offered protection against PE during the index pregnancy (aOR: 0.85; 95% CI: 0.65–1.10), further strengthened with a booster (aOR: 0.67; 95% CI: 0.45–0.99). Among women with pre-existing morbidities who received a booster dose, the odds were reduced by 58% (aOR: 0.42; 95% CI: 0.20–0.87) – mainly observed in women diagnosed with COVID-19. Adjustments did not alter the magnitude of the effect. Vaccination amongst women who received a booster dose was also associated with decreased odds of maternal (aOR: 0.68; 95% CI: 0.55–0.83) and perinatal (aOR: 0.71; 95% CI: 0.54–0.95) morbidity and mortality, and as in the JAMA study – with preterm birth (aOR: 0.67; 95% CI: 0.53–0.85).

These findings are not only remarkable in their very obvious and here-summarized detail, but, potentially, also offer important insights on a completely different level: The fact that these vaccinations demonstrate such an enormous effect on PE, increasingly understood as a condition of dwindling immune tolerance of the mother toward her fetal-placental unit – strongly implies that these vaccines affect the maternal immune system by “replenishing” its capacity for tolerance. If correct, this would suggest that PE may be preventable through timely vaccinations.

REFERENCES

1. Eide HN, et al., Pediatrics. 2026;157(4):e2025073661

2. McCkaymont et al., JAMA 2026;335(2):154-162

3. Cavoretto, et al., eClinicalMedicine 2026; 103785

Long COVID Activates Proinflammatory and Immune Exhaustive Pathways

And since we are already on the subject of COVID, here is some insight on Long COVID, which – fortunately only rarely – we also have started seeing in some infertility patients.

Long COVID (LC) involves a spectrum of chronic symptoms, and current hypotheses for the pathogenesis of LC include persistence of the virus, tissue damage, autoimmunity, endocrine insufficiencies, immune dysfunction, and complement activation. It finally appears that some mysteries of Long COVID are slowly revealing themselves. Within that context, a recent paper in Nature Immunology was a good example when it demonstrated that in so-affected patients, proinflammatory pathways are persistently upregulated. These are potentially important discoveries because they may lead to new therapeutic targets for this condition and may also allow for discovery of new potential biomarkers for the disease.¹

REFERENCE

1. Aid et al., Nat Immunol 2026;27:61-71

Today’s posting focuses on recent news related to Geroscience, alternatively called Longevity Medicine or simply the science of aging. From a potential cause of aging-related memory loss to how much of our lifespan is actually inherited, these topics deserve a much closer look by all our readers, regardless of their current age. With so many lingering questions about aging out there, it’s always encouraging to see some scientists searching for real answers. If the research can help others increase their lifespan — and not just survive, but thrive — all the better. As always, we welcome your comments and discussion.

The CHR’s Editorial Staff

It is difficult to know where we stand in the quick evolution of Longevity Medicine, or, as a recent article in The New York Times called it, Geroscience. Whatever we call it, it in many ways appears like a parallel universe next to A.I. with almost daily announcements about only recently unimaginable breakthroughs. But are they for real? The recent NYT article believed that even though Longevity Medicine is “under scrutiny” and is ripe with opportunity and opportunism, there are good ways to navigate the process.¹ We with this section want to help a little bit in this process.

REFERENCE

1. Smith DG. The New York Times. April 14, 2026. https://www.nytimes.com/2026/04/07/well/longevity-medicine-definition.html

Rockefeller University Scientists Have Mapped How Aging Reshapes Cells Across the Entire Mammalian Body

Though done in mice, this study has to be considered a force majeure, probably very soon repeated in humans. To investigate cellular alterations and epigenomic dynamics during aging, the authors constructed a single-cell chromatin accessibility atlas, spanning 21 mouse tissues across three age groups and both sexes.

What they found was pretty amazing: Approximately one-quarter of 536 organ-specific cell types and 1,828 finer-grained subtypes exhibited considerable age-related population shifts. Cellular states from broadly distributed lineages displayed synchronized dynamics with age, suggesting systemic signals that control/coordinate these changes.

Molecular analyses identified both intrinsic regulators (chromatin peaks, transcription factor activity) and extrinsic factors (cytokine programs) underlying in these shifts. Moreover, ~40% of aging-associated population dynamics were sex-dependent, with tens of thousands of peaks altered exclusively in one sex. Together, these findings present a comprehensive framework for how aging reshapes the chromatin landscape and cellular composition across diverse tissues.

But the findings went beyond that: While it was generally believed that aging meant declining functions in cells and not fewer cells, that was not confirmed. Approximately a quarter of cells also declined in numbers. Moreover, declines in cell populations appear to happen already quite early and are coordinated across even distant organs, which hints that there exists some kind of central control in this aging process, - a master switch???

Less surprisingly, the study also demonstrated profound differences between the two sexes, with women demonstrating a much broader immune activation than men with aging. And here we go again, because this observation was considered a possible hint why autoimmune diseases were so much more frequent in women than men.

REFERENCE

1. Lu et al., Science 2026;291(6788). DOI: 10.1126/science.adw6273

Is Aging-Related Memory Loss Fueled by Gut Microbes?

A News article in Nature¹ brought our attention to this paper with 49 authors, also appearing in Nature.² Following the authors’ summary in the abstract – like the preceding paper – this was also a mouse study with considerable likely implications for the human experience.

Aging leads to declining memory function, which can manifest in humans in many different ways. Brain-extrinsic factors influencing cognitive decline, such as gastrointestinal signals, have emerged as target interventions, but the underlying mechanisms have remained unclear.

By charting microbiome aging and its functional consequences throughout the lifespan of mice, the authors identified a mechanism by which inhibition of gut-brain signaling during aging resulted in impaired neuronal activation in the hippocampus and loss of memory encoding. Specifically, accumulation of gut bacteria that produce medium-chain fatty acids, such as Parabacteroides goldsteinii, can drive peripheral myeloid cell inflammation through GPR84 signaling.

As a result, the function of vagal afferent neurons is impaired, the interoceptive signal received by the brain is weakened, and hippocampal function declines. The authors then leverage this pathway to define interventions that enhance memory in aged mice, such as phage targeting of Parabacteroides, GPR84 inhibition, and restoration of vagal activity. These findings indicate a key role for interoceptive dysfunction in brain aging and suggest that interoceptomimetics that stimulate gut-brain communication may counteract age-associated cognitive decline.

Brilliant and potentially quickly clinically applicable!

REFERENCES

1. Chen E. Nature 2026;651:567568

2. Coc et al., Nature 2026;652(8109):442-450

A Bigger Part of Our Lifespan is Inherited than was Assumed

And here goes another widely held belief out the window, as a new study suggested that ca. 55% of the human lifespan is inherited; i.e., attributable to our genes;¹ and discussed in a new Commentary² in the same issue of Nature. This is not what used to be the common belief; that was only ca. 10-25%.

What now becomes the question is, - what are the involved genes and can we affect them?

In another Commentary regarding the original Nature article, this time two authors comment in Science on the (max.) 55% finding, noting that these percentages vary by disease group. So, for example, cardiovascular disease and dementia show much higher heritability than cancers.

And then, there is another important point to consider: The other roughly half is not genetic. What we eat, how we live, what our weight is, etc., of course also affects lifespan and is to a large degree under our control. So don’t give up, - treat yourself well!

REFERENCES

1. Shenhar, et al., Science 2025;391:504-510

2. Kozlov M. Nature 2026;650:283-284

3. Bakula D, Scheibye-Knudsen M. Science 2026; 10.1126/science.aee3844

Today’s posting offers a close look at timely issues related to in vitro fertilization (IVF) and the infertility field as a whole. From arguments over who gets unused embryos after a couple splits up to debates about whether Jewish law allows for the posthumous use of semen from deceased soldiers, these stories shed light on important questions that don’t always have easy answers. Surprisingly, some of these subjects have been addressed in the media on numerous occasions in the past, showing that even seemingly settled topics can still inspire heated debate or more thorough research. As always, we welcome your comments and your opinions on the best ways to resolve these ongoing issues, especially if they differ from ours.

The CHR’s Editorial Staff

Insights From 8 years of Planned Oocyte Cryopreservation at an “Egg Freezing Clinic”

There are several reasons why a recent paper attracted our attention, with the first being that the clinic that published the paper identified itself – for the first time we ever have seen this – as an “egg-freezing clinic.” We consider this an important definition because clinics that primarily only conduct egg-freezing cycles – only here and there intermingled with a real IVF cycle trying to immediately achieve a pregnancy – must lack ovarian stimulation experience because egg-freezing cycles do not offer immediate cycle outcomes beyond oocyte numbers, maturity, and morphology. For all practical purposes, they often lack experience with the most important IVF cycle outcome parameters, pregnancy and delivery rates.

But, aside from this point, egg-freezing experiences are important to publish. Despite the explosive growth in egg-freezing cycles in the U.S., reported outcome data have remained remarkably sparse and in general have demonstrated surprisingly low efficiency for the concept of egg-freezing to preserve fertility, as later use of frozen eggs in almost all studies was found to be surprisingly low.

The here-discussed study from a NYC-based “egg-freezing clinic,” therefore, added important information over an 8-year span: Between 2016 and 2023, the clinic completed 4,659 cycles for 3,138 patients, with the mean cycle start age actually decreasing from 36.9 ± 2.8 years at the onset to 35.0 ± 3.5 years in the final year of the study.

The mean length of time between freezing and thawing was 3.4 ± 1.9 years. The mean age at first thawing was 39.9 ± 3.5 years, with a median (interquartile range) of 40 (39, 42) years. Among patients who had completed at least one freezing cycle before 2020 (n = 2,163), allowing for a minimum follow-up period of 4 years, only a remarkably low 10.4% (n = 226) returned for warming of their oocytes.

Across 271 such warming cycles, the mean number of MII oocytes warmed was 15, with very good survival and fertilization rates of 90.7% and 77.2%, respectively. Among patients who underwent cryopreservation at ≤40 years of age, warming a higher number of MII oocytes was associated with increased euploid embryo yield. The cumulative ongoing pregnancy/live birth rate for the cohort was 70.3%, ranging from 58.3% for 1–9 MII oocytes warmed to 81.8% for >20 MII oocytes warmed. We here at the CHR would, of course, argue that avoiding the use of PGT-A would likely have resulted in even better pregnancy rates.

So these, then, are the conclusions:

1. We are not certain that the decline in age of patients in this study is typical. At least, at the CHR, the trend has been going strongly the other way. But we – certainly – are also not primarily an “egg-freezing clinic!”

2. The main point is clearly that the usage rates of frozen eggs has – overall and especially in young women – indeed remained incredibly low, raising the question of what can – or maybe what should – be done to screen especially younger women in ways to avoid so many, in retrospect, useless cycles of fertility preservation. And recognizing the obvious difficulties in predicting who will or will not need frozen eggs to achieve motherhood, maybe the field should search for alternative solutions. One such alternative could, for example, at a certain age, be an egg-donation option for unused oocytes, including a partial refund of egg-freezing costs and permission for the “egg-freezing clinic” to use those eggs in anonymous donor egg cycles.

3. Finally, we need more precise outcome data. While the paper-presented cycle outcomes appear quite satisfactory, they – ultimately – cannot be really judged as presented in the paper.

Nevertheless, this was an interesting paper on egg-freezing, especially since it did not come from the NYU group, which so far has been dominating this ongoing discussion.

REFERENCE

1. Klein et al., Fertil Steril 2026;125(4):671-678

Back Again Under Legal Scrutiny: Who Gets Custody of Unused Embryos When a Couple Splits Up?

We thought that courts all over the country had resolved this issue a long time ago, because who does not remember cases where older women pleaded for the use of embryos they had produced while they were still married? They often argued that these embryos represented their last chance of genetic motherhood, while their ex-husbands often refused their consent with the argument that they no longer wanted to become genetic fathers and couldn’t be forced to agree against their will. And the courts usually held that nobody can be forced into genetic parenthood.

But here we go again, as The New York Times recently reported.¹ The case the Times article reported on appears, indeed, still legally surprisingly unsettled since only approximately one-third of states have considered the issue at the appeals court level, where precedent is set.

Moreover, state legislatures are apparently getting interested in the subject: The Michigan Supreme Court in 2025 urged the state’s Legislature to consider the question of such embryo disputes. Arizona already in 2018 became the first state to pass a law requiring that – in case of such a dispute – existing embryos go to whichever party was planning on using them to have children. And in New York, the New York Times article suggested that everybody expects this case to be decisive.

And what is the CHR’s opinion? This is one of those issues where we are happy not to be the judge and happy not to have to make such difficult Solomonian decisions. But if we were forced to make the decision, we, likely, would award the parent who is ready to try to produce a child the right to do so, as long as this would not mean any form of parental responsibility – including financial responsibilities – for the unwilling parent.

But, as we already are making speculative judgment, what would be the decision if both parents want to use a single embryo to have “their own” child? It seems to us that it is only a matter of time until this potential issue will reach the courts. What then?

A modern-day King Solomon would – no doubt – split the embryo. But what could we do?

REFERENCE

1. Kitchener C. The New York Times, May 24, 2026. https://www.nytimes.com/2026/05/24/us/ivf-embryos-custody.html

Also Back Again: Is Undergoing Assisted Reproduction Procedures Like IVF Increasing Cancer Risks?

This is a question as old as IVF itself and, indeed, even older because it was already raised with the use of the first fertility drugs before IVF became a reality. In those days, they were the oral clomiphene citrate and the injectable Pergonal (the first drug derived from postmenopausal urinary gonadotropins of nuns).

But this study is worth mentioning because of its size: A multi-center cohort study of patients all over the world, it involved 417,984 women exposed to assisted reproduction procedures in Australia between 1991 and 2018, and the findings were once again reassuring: The all-cancer incidence was not different from the age-, jurisdiction-, and calendar year-matched general population of women. Incidence for some hormone-sensitive cancers (uterine, ovarian) and cutaneous melanoma were marginally higher, while incidence for cervical cancer and cancer of the trachea, bronchus, and lungs were marginally but notably reduced.

Specifically, in the total of 417, 984 exposed women, with 274 ,676 (65.7%) having used ART (median age, 34 [31-38] years; median follow-up time, 9.42 [5.08-15.42] years), and 175, 510 (42.0%) having ever used clomiphene citrate (median age, 32 [28-36] years; median follow-up time, 9.42 [5.42-13.58] years), - the overall incidence of invasive cancer was comparable with the general population for the ART (IVF) and IUI (SIR, 0.99; 95% CI, 0.97-1.02) cohorts and slightly elevated for the clomiphene citrate cohort (SIR, 1.04; 95% CI, 1.00-1.07).

For all cohorts, incidence of uterine cancer (SIRs, 1.23-1.83) and in situ and invasive melanoma (SIRs, 1.07-1.15) were elevated, and incidence of cervical cancer (SIRs, 0.52-0.61) and cancer of the trachea, bronchus, and lungs (SIRs, 0.62-0.70) were lower. Ovarian cancer incidence was elevated for the ART (SIR, 1.23; 95% CI, 1.10-1.37) and IUI/OS (SIR, 1.18; 95% CI, 1.01-1.37) cohorts. In situ breast cancer incidence was elevated for the ART cohort only (SIR, 1.24; 95% CI, 1.12-1.38). Incidence of invasive breast cancer was not elevated. Rate differences for invasive cancers with elevated incidence were all small (<1 to 6.51 cases per 100 000 person-years).

The conclusion, therefore, was that the overall incidence of cancer was comparable with that of the general population. The incidence of certain cancers appeared elevated; however, the excess numbers of these cancers were small, and there was a reduced incidence of other cancers. Causation can definitely not be inferred from this descriptive evidence.

REFERENCE

1. Vajdic et al., JAMA Network Open 2026;9(3):e261332

And Also Back Again: The Question of Whether Time Lapse is Cost Effective in Improving IVF Outcomes?

When time lapse monitoring was first introduced to embryology laboratories, the CHR – rather than purchasing one or more units of what was then called the “embryoscope” (as many clinics did) – decided to first test this new product reaching the market. Securing one of these instruments from a company for several months as a loan, for testing purposes only, we were looking to confirm claims at the time made by proponents of the product (some among them, as later tuned out, with undisclosed financial interests in the company that offered the product) that it would significantly improve pregnancy rates in IVF, shorten the staff time involvement per patient, and would also greatly enhance research on preimplantation-stage embryos. Our short study only was able to confirm the last claim, and even that in only limited ways. Moreover, we found that this new equipment actually increased the time embryologists spent on each patient.¹

We, therefore, thanked the company, returned the instrument, and have been practicing without even a single time lapse monitor ever since. And as such, the CHR is likely one of only a very small number of IVF clinics without an abundance of time lapse monitors. Indeed, by now, a large majority of embryos in IVF clinics in the U.S. are routinely monitored in the – granted, steady – environment in such units.

And while steadiness of the environment is, of course, a relatively strong argument, especially in favor of time-lapse equipment for IVF clinics with large embryology staffs, which often diverge in cycle outcomes within a program, this, however, became exactly also the principal reason we chose against converting our embryology from manual morphology to time lapse. While we confirmed that it, of course, allowed for close observations of every embryo (if one wants to do this and spend the time), it forces every embryo into the same protocol. One, of course, theoretically can still individualize, but will one really do this? We didn’t think so, and we, to this day, consider this to have been the right decision for the CHR’s highly unusual patient population. The CHR, therefore, still does not use time lapse monitoring of embryos in routine clinical practice.

As ever-increasing numbers of time lapse systems were purchased by IVF clinics and increasing numbers of manufacturers started to offer such equipment, consensus was, however, reached in parallel through several well-designed studies that – like with so many other “add-ons” to IVF practice since 2010 – time lapse monitoring actually failed to fulfill the many promises its proponents had made in convincing the field to spend millions of dollars on this new equipment (with costs, of course, passed on to patients). Many clinics, even to this day, still charge patients extra “time lapse fees” in every cycle.

And now, as A.I. is trying to secure a foothold in the IVF laboratory, the combination of time lapse monitoring with A.I., of course, looked very enticing and underwent heavy promotion by several start-ups with alleged A.I. programs that could basically “guarantee” IVF pregnancies.

We, of course, are kidding!

At least as of the time of this writing, we are unaware of even a single study having demonstrated outcome benefits for embryo selection via A.I. in IVF cycles. We, however, are aware of at least one company making this claim having gone out of business because, - as we were told by the founder and CEO, “the financial benefit for IVF clinics was not big enough for them to warrant the purchase of the A.I. product.”

And, as with several other useless “add-ons” to IVF, the IVF field once again was lucky in that – what we have come to call the “Dutch Cavalry” – recently took up (as it has done in the past for many different “add-ons,” including, for example, PGT-A) the important research question, whether time lapse monitoring represented a cost-effective service?² We coined the term “Dutch Cavalry” based on the fact that our Dutch colleagues succeeded in publishing so many important clinical studies, including large patient numbers in a very small country, and because they succeeded in setting up a unique collaborative multi-center research network involving all medical schools in The Netherlands. The study just published reported on the cost-effectiveness of time lapse monitoring with or without the use of embryo selection software compared to routine incubation and selection.²

And here is what they – for us here at the CHR completely unsurprisingly – found: The chance of having a baby within 12 months was similar for time lapse incubators and standard incubators. Time lapse incubators are, however, more expensive. The use of time lapse monitoring, therefore, - even in association with A.I. is, therefore, only unlikely to be cost-effective, - meaning that the higher costs are not balanced by better outcomes.

And for patients, this means that time lapse technology does not increase their chance of having a baby, but it does increase their costs of IVF treatment. The old-fashioned standard method of growing and selecting embryos, therefore, remains the most cost-effective option.

And why were we not surprised by these results? Because, as we just suggested in a very recent paper in Human Reproduction Open, all the evidence in the world now suggests that the concept of embryo selection – one of the earliest dogmas in IVF – simply no longer makes sense.³ Whatever technology we will throw at embryo selection (and how many investments we will make) - for basic biological and statistical reasons, embryo selection within a cycle cohort of embryos will never outbid basic, solid manual embryology in selecting the “best” embryos.

It would exceed the space we have here for this argument to go into further detail, but the absolutely correct logic behind why embryo selection – by whatever means – beyond routine manual embryology does not make sense is in detail explained in our recent publication.³ Thank you to The Netherlands for another important paper!

REFERENCE

1. Wu et al., Reprod Biol Endocrinol 2016;14(1):49

2. Kieslinger et al., Hum Reprod Open 2026;2:hoag034

3. Gleicher et al., Hum Reprod Open 2025;2:hoaf011

Does Jewish Law Allow Making Babies from the DNA (Semen) of Deceased Soldiers?

For obviously tragic reasons, this subject has occupied the Israeli public and media since October 7, 2023, to very significant degrees and has done so with considerable urgency after more than 940 young IDF soldiers in their peak reproductive years and over 210 members of Israel’s security forces lost their lives since that date. Though, of course, a problem of limited relevance to the U.S. public, it is important to recognize that ethical, religious, and legal issues that arose in Israel in obvious association with October 7, 2023, and what has followed since, also can apply to deaths outside of a war zone (for example, in NYC’s subway system, or on Chicago’s South Side).

We are here, therefore, reprinting selected passages of an article posted on Facebook by Hezy Laing, an independent journalist living in Jerusalem, in which he addressed this issue, - obviously from a religious Jewish viewpoint, which, however, as will quickly become apparent, addresses universal ethical, religious, and legal issues.

Among the most poignant stories addressing the issue of posthumous use of semen is that of Dr. Hadas Levy, a pediatrician whose fiancé, Capt. (res.) Netanel Silberg, was killed in Gaza in December 2023. Levy became the first woman in Israel to give birth to a child conceived from the genetic material of a soldier killed in the war.

Her experience, along with the roughly 250 families who have requested retrieval of genetic material from fallen soldiers, has brought unprecedented halachic questions (questions under Jewish law) to the forefront. The issue is especially pressing because sperm retrieval is extremely time‑sensitive. Success is about 75 percent within 24 hours of death and drops sharply after 72 hours.

This urgency intersects with Israeli law, which has evolved since the Attorney General’s 2013 guidelines, which said the following:

• Widows or partners may request retrieval without court approval, unless a relative objects.

• Parents must normally obtain family court approval, though, due to the narrow time window.

During the early months of the war, the Tel Aviv Family Court temporarily allowed retrieval without prior approval.

• Regardless of who requests retrieval, use of the sperm always requires court authorization.

• Widows are generally approved based on the presumption that the deceased wished to have children with them; parents must demonstrate evidence of the son’s wishes.

Halachically, the matter is, however, far more complex. Three scenarios must be evaluated separately under Jewish law: A married soldier with children, a married soldier without children (raising issues of so-called yibbum and chalitzah), and a single soldier, where the use of an unmarried woman’s womb introduces additional concerns.

These distinctions shape the positions of three major contemporary poskim (religious judges): Rav Mordechai Halperin argued that, although the deceased cannot fulfill the mitzvah of Peru U’revu after death, enabling his wish to leave a legacy may constitute chesed shel emes, similar to saying Kaddish or performing other acts on behalf of the dead. He later refined his view, but maintained that fulfilling the deceased’s will can be permissible, especially when the desire to leave a “name and remnant” is clear.

Rav Asher Weiss strongly opposed this. He maintains that there is no mitzvah after death, that “mitzvah l’kayem divrei ha‑meis” applies only to monetary matters, and that creating a child for a deceased bachelor inevitably leads to single motherhood, which he considered outside of Torah norms. He further warned that permitting such procedures could normalize parenthood outside of marriage and concluded that such requests should not be fulfilled.

Rav Zalman Nechemiah Goldberg offered a middle position: Without explicit consent, the procedure is forbidden; with clear consent or a strong umdana that this was the soldier’s wish, it is permitted. He bases this on the Torah’s valuation of preserving a person’s “name and remnant,” drawing an analogy from the rationale behind yibbum.

He further argued that the human desire for continuity is deeply rooted in Torah values and can justify posthumous reproduction when the deceased’s intent is known.

Together, these halachic, legal, and emotional dimensions have made posthumous reproduction one of the most sensitive and urgent questions facing Israel today.

REFERENCE

1. Laing H.Facebook. May 6, 2026. https://www.facebook.com/gershon.shapiro.9/posts/it-is-a-tough-call-one-that-would-require-in-my-opinion-a-sanhedrin-type-court-m/2182582522542965/

Today’s posting involves an Editorial by the CHR’s Editorial Board and, therefore, represents the opinion of the CHR and clinical as well as ethical practice principles of the CHR. For that reason, we reserve this publication format to only include the most important issues that arise in the fertility field.

The CHR has for many years been on record as a leading opponent of several so-called “add-ons” to IVF. CHR investigators have pointed out in several papers over almost 20 years that these add-ons have not only failed patients in improving IVF outcomes, but also in many instances have actually harmed IVF cycle outcomes in selected patient populations. They, of course, uniformly also significantly increase IVF costs.

Examples abound,- from preimplantation genetic testing for aneuploidy (PGT-A), polygenic risk screening of embryos (PGT-P), routine all-freeze cycles with delayed frozen embryo transfer cycles, - to many more. The CHR in many of these publications has also criticized the frequently observed silence of professional societies in the fertility field in this matter.

Today’s Editorial was spawned by an article by several prominent European colleagues who claimed that the poor IVF outcomes in poor-prognosis patients should be “fought” not with better cycle management (maybe excluding some of the above-noted harmful “add-ons” to IVF in such patients), but by simply manipulating outcome data, - so they looked better by no longer presenting outcomes to patients based on single-cycle outcomes, but based on multiple-cycle outcomes. In other words, - sell IVF to poor-prognosis patients in multiple-cycle packages (which, of course, lock patients into multiple-cycle commitments). One, therefore, wonders who would really benefit from this kind of a change? Certainly not the patient!

The CHR’s Editorial Staff

Making IVF Always More Expensive, But - Unfortunately - Never any Better in Outcomes!

The Editorial Board of the _CHRVOICE and The Reproductive Times

Sometimes it is not enough to speak quietly, and raising one’s voice becomes essential if one wants to be heard at all. In this article, the CHR’s Editorial Board does exactly that when addressing the fact that the IVF field is overrun by a stampede of great-sounding clinical ideas, - including so-called “add-ons”- offered by often prominent “experts” in the field and introduced into routine clinical practice, - simply based on the power of the names of the “experts.” And as is well recognized, expert opinion – yet deservedly - sits at the very bottom of the evidence pyramid because a good idea is, of course, cheap and not at all enough to support introducing new treatments, - even if such treatments – especially if not depending on FDA approval - at times can also become quite profitable.

Colleagues often too generously offer such opinions through the quickly increasing plethora of opinion articles in many medical journals, sometimes with clear intent, - but frequently simply out of ignorance about potential negative consequences.

This Editorial was in reaction to such a recent article in a prominent European infertility journal, which – without any cost and other considerations like time to pregnancy - claimed to introduce a new treatment paradigm with the goal of benefitting clinical patient outcomes. Though patient outcomes, of course, must be at the center of all benefit considerations, they also must not exclude risk assessments and costs. Both of these considerations, however, did not at all enter consideration in this proposal, and that must be viewed by editors as a clear warning signal before publication that other than pure scientific considerations may be - subconsciously or consciously - at the core of a new submission for publication.

We fully recognize the controversial nature of this Editorial, but, considering the uncontrolled proliferation of unvalidated “add-ons” to IVF practice since approximately 2010, the IVF field will not improve IVF cycle outcomes that have stagnated since that date overall, and for certain patient sub-groupings (like autologous IVF cycles), they have actually dramatically declined. Because of the controversial nature of this Editorial, we – more than ever – are looking forward to our readers’ opinions.

Especially our European colleagues always appear on the outlook for new ideas about IVF, - but for some reason, - those ideas never appear to improve IVF outcomes as promised. They most certainly, however, increase IVF costs. And, paradoxically, it almost appears like, – the more expensive, the quicker the new ideas are accepted by the IVF field, - even in absence of significant evidence. There is, of course, reason to wonder why this has been such a recurring theme?

When Austrian/German colleague Georg Griesinger, MD,¹ for the first time in 2007, and Paul Devroey, MD and colleagues in Brussels, Belgium² in 2011, for example, proposed so-called segmentation of IVF, a term created to denote the conceptual separation of ovarian stimulation from embryo transfer, the primary purpose was to prevent the ovarian hyperstimulation syndrome (OHSS) in IVF cycles with excessive follicle numbers. The idea of all-freeze cycles under such circumstances, then, of course, made sense.

But what followed was that the concept then was expanded to practically all IVF cycles under the dubious – and, to this day, unproven – allegations that ovarian stimulation in IVF cycles in some ways adversely affects endometrial receptivity. And, suddenly, all-freeze cycles became the “fashion of the moment” (and, yes, IVF constantly does go through such “fashions of the moment”) for all IVF cycles after they were heavily promoted by Las Vegas-based Bruce S. Shapiro, MD, and co-workers (too much gambling going on in Las Vegas, apparently!).³ But that fashion did not maintain popularity because some “real” studies very quickly demonstrated that this kind of segmentation did not – as claimed by Shapiro et al (and others) – improve IVF outcomes, but actually reduced cumulative pregnancy chances.⁴ But by adding freezing costs and additional costs for a thaw-out frozen embryo cycle, it surely raised overall IVF costs (and, of course, increased IVF clinic income) significantly, while in addition prolonging the time to pregnancy.

But that is only one “fashion of the moment” that has obviously negatively affected IVF practice (and is still going on in too many U.S. and European IVF clinics). Again, especially some European colleagues have apparently convinced themselves that they know what we should spend our money on: A.I., of course, can improve donor oocyte assessment⁵ and basically everything else in embryology, DuoStim is, of course, effective in improving egg numbers (and how about quality?).⁶ It also, of course, prevents all fresh embryo transfers and, therefore, requires an additional thaw cycle; but who cares about that?

And, yes, all embryology, of course, must be automated⁷ (because closed incubation systems really delivered on all the promised improvements the manufacturers touted) and, therefore, let’s just expand automatization to everything in the embryology laboratory (and it, of course, helps if we hold shares in a company that sells the needed equipment).

A group of prominent European colleagues recently published a commentary in Reproductive Biomedicine Online (RBMO), in which they – kind of unexpectedly – proposed to “change the narrative for poor-prognosis patients in IVF by unlocking success through a multi-cycle approach.”⁸

So, why were we interested in this subject? Not only because one of the authors was a senior associate editor of the journal (the topic of editors publishing in their own journals was recently addressed in a prior issue of the _CHRVOICE). No, - what we found, rather shamefully, was that these authors were not trying to suggest that it was time to try to improve the kind of IVF that is offered to poor-prognosis patients all over the world, - but they were suggesting the amazing – almost mind-blowing – allegedly new concept of offering them multiple-cycle packages as the solution for the patients’ poor prognosis.⁸ Not a word, however, on the fact that relatively promising treatments exist for many women above ages 42-43 that - even with autologous oocytes - still offer very decent pregnancy chances.

Most U.S. IVF clinics, however, are no longer even interested in trying to treat patients with their own autologous eggs. U.S. statistics well demonstrate this fact through the quick fall into nothing of U.S. autologous IVF cycles after age 43. This is indeed why we started this commentary with the subject of “all-freeze cycles.”

The authors, then, of course, also had to add to their absolutely “brilliant” idea of multiple-cycle packages in poor-prognosis IVF patients the following, -quoting the authors verbatim: “A multicycle approach, adopting approaches such as oocyte/embryo accumulation from several stimulations or two consecutive stimulations, - i.e., DuoStim (yes, they threw that in as well!), enables the advance planning of multiple attempts (really?). It helps shorten time to pregnancy (evidence?), reduces treatment discontinuation (evidence?), and offers support for patients facing setbacks (how?).

Poor-prognosis patients, of course, have poorer pregnancy chances than average-prognosis and especially good-prognosis patients. And, as usually one of the best-informed patient populations in all of medicine, infertility patients, of course, understand that – in practical terms – this means that they can expect to need more IVF cycles than most other patients. Multiple-cycle packages in such cases then, of course, may make sense for some patients, but, of course, only if significantly discounted.

But to make this the centerpiece of a Commentary article in a major infertility journal with not a word about how poorly poor-prognosis patients are currently treated (if at all!) in most IVF clinics is just further evidence for how much more emphasis is dedicated these days to improving the economics of IVF (for providers) rather than the execution of high-quality infertility care (for patients).

All of this must also be seen against the overall clinical realities of steadily declining pregnancy and live birth rates in autologous IVF cycles versus steeply increasing IVF cycle costs based on U.S. registry data (see figure below). Considering, under these circumstances, multi-cycle programs as the solution , - rather than advocating for better per-cycle outcomes first, appears more than just a misdirection. Since the “add-on” revolution around 2010 started to explode, these kinds of unfortunately only poorly-thought-through commentaries have, however, been fairly typical, - not infrequently driven by false narratives by European colleagues.

And the consequence?

To the best of our knowledge, autologous IVF - at least in the U.S. - has earned the “honor” of being the only widely accepted primary treatment in all of medicine which over the last 15 years has experienced an almost straight line downwards to progressively poorer outcomes (see again figure below, with background information for this figure provided as a footnote).

Three U.S colleagues recently submitted a letter-to-the-editor to Human Reproduction Open in which – describing themselves as “leaders of the Society for Assisted Reproductive Technology (SART),” a sister society of the American Society for Reproductive Medicine (ASRM) – they criticized a recently published paper in this prominent journal by CHR investigators that pointed out “the declining efficiency since approximately 2010 of (autologous) IVF in the U.S.,”⁹ as also described in the above figure. We, of course, are not permitted to reveal the content of their criticism before publication of their letter and the CHR authors’ response. But it appears appropriate to point out here that this Editorial made its points appear even more timely in view of the comments made by SART leadership in this letter and we strongly encourage the readers of this Editorial to seek out this exchange of letters, which should appear within weeks in Human Reproduction Open.

REFERENCES

1. Griesinger et al., Hum Reprod 2007;22(5):1348-1352

2. Devroey, et al., Hum Reprod 2011;26(10):2593-2597

3. Shapiro et al., Fertil Steril 2014;102;3-9

4. Wong et al., Hum Reprod 2021;36(4):998-1006

5. Cimadomo et al., Hum Reprod 2025;40(10):1886-1892

6. Vaiarelli et al., Upsale J Med Sci. 2020;125(2):121-130

7. Racowsky et al., Fertil Steril 2026;125(1):2-12

8. Vaiarelli et al., Reprod Biomed Online 2026;52(5):105465

9. Gleicher et al., Hum Reprod Open 2026(1):,hoag004

Today’s posting offers an article by Lyka Mochizuki, MSc, who, several years ago while a research assistant and research fellow at the CHR, wrote a remarkable article on PGT-A in the JARG and now – here – is revisiting the same theme. But without disclosing too much, it wasn’t then just another opinion article on PGT-A and it is not now either, and you will have to read the article to know why. We think you will find the article to be quite interesting.

And if you wondered why we so far didn’t post this week, Monday was, of course, a holiday and Tuesday we were extremely busy completing the April/May issue of the _CHRVOICE, which is scheduled to drop tomorrow.

The CHR’s Editorial Staff

THE PGT-A CONTROVERSY What Five Years Later A.I. May or May Not Change

By: Lyka Mochizuki, MSc, past Research Fellow and currently Project Manager at the CHR. She can be reached through the editorial office of the _CHRVOICE and The Reproductive Times.

This article follows a highly unusual article on the then still very acutely controversial subject of preimplantation genetic testing for aneuploidy (PGT-A) in association with in vitro fertilization (IVF) by the same author in the Journal for Assisted Reproduction and Genetics. The article was so unusual because in addressing the then still much more heated differences of opinion, she for the first time applied the concept of conflict resolution to the dispute (the author holds a MSc in Conflict Resolution from Columbia University in NYC). Now - in a different position - once again a member of the CHR team, she agreed to revisit the subject, though in consideration of the current Zeitgeist in which A.I. is changing the world and, with it, of course, medicine. We are certain you will enjoy this article and, as always, we are welcoming responses.

And as a side note, the April/May _CHRVOICE should be dropping tomorrow! Here, too, we are awaiting your responses.

In 2020, I co-authored a paper in the Journal of Assisted Reproduction and Genetics that approached the controversy surrounding preimplantation genetic testing for aneuploidy (PGT-A) through an unusual lens: a formal conflict resolution analysis.¹ Rather than entering the clinical debate as another voice for or against PGT-A, the paper examined why the debate itself had become so durable — and what it would take to move past it.

The argument was that the persistent disagreement over PGT-A could not be resolved by more data alone. It was a structured conflict between physicians and professional bodies, rooted in competing interpretations of overlapping evidence, competing incentives, and competing definitions of what counts as a successful in vitro fertilization (IVF) cycle.

Five years later, the controversy has evolved, but not resolved, and a new element has entered the conversation, - artificial intelligence (A.I.) applied directly to PGT-A. This article, therefore, asks two questions: Can A.I. resolve the conflict between physicians, or relocate it? And what would real resolution actually require?

Where the Controversy Stands in 2026

The clinical evidence has not been kind to the broadest claims made for PGT-A: A 2021 randomized controlled trial in the New England Journal of Medicine found that, among good-prognosis patients, cumulative live birth rates were lower in the PGT-A group than in the conventional IVF group.² A 2025 review described PGT-A’s clinical value as an open controversy after nearly thirty years of practice.³ A recent analysis of the UK Human Fertilisation and Embryology Authority registry found that, in routine practice, PGT-A was associated with reduced live birth rates compared to standard IVF.⁴ The American Society for Reproductive Medicine’s 2024 committee opinion concluded that PGT-A should not be recommended for routine use.⁵

At the same time, subgroup evidence has somewhat shrouded the picture when some authors suggested that PGT-A improves live birth rates in women over age 35,⁶ though ignoring the growing importance of patient selection bias with advancing female age. Successful blastocyst-stage culture – an obvious prerequisite for PGT-A – of course increasingly biases patient selection toward good-prognosis patients, as poorer-prognosis patients simply will no longer produce blastocysts. Obstetrical safety data after PGT-A use are, however, reassuring.⁷

That ambiguity has become the controversy. Physicians who emphasize per-transfer success and argue that avoidance of miscarriages is a worthwhile goal to pursue read this evidence one way. Physicians who instead emphasize cumulative outcomes and embryo conservation read it in a very different way. Both sides claim not to misread the data and my comments here are not meant to be the judge between these two opinions (even though – as a scientist – I, of course, have an opinion). What I am instead trying to achieve, is to stop both sides from yelling at each other.

What A.I. is Doing Now

A.I. has attempted to move from embryo morphology into the genetic analysis itself. A 2023 study of nearly 25,000 embryos reported that A.I.-augmented PGT-A allegedly produced higher euploidy rates, lower mosaicism rates, and was associated with higher live birth rates in subsequent transfers.⁸ [Please note industry conflict regarding this statement further explained at the end of this manuscript.] Other A.I. models are alleged to detect complex abnormalities, including triploidy, that standard PGT-A can miss.⁹ Interestingly, the MIT Technology Review named A.I.-based embryo scoring one of its breakthrough technologies of 2026.¹⁰

While the technical promise appears to be real, - reliability was, however, never the whole controversy. It was always only one layer of it.

The Layers A.I. Touches, and Doesn’t Touch

It is reasonable to assume that the PGT-A controversy has three layers and that A.I. affects them unevenly. The first is technical and is defined by how accurately can the test classify an embryo’s chromosomal status? This is likely the layer A.I. can most directly improve.

The second layer is clinical: Even when the classification is accurate, does acting on this information really improve outcomes across an entire IVF cycle? This is where most of the disagreement between physicians lives. While A.I. can improve the label, it does not necessarily resolve the question of what to do with the label. This, of course, especially applies to mosaic or intermediate results, where clinical judgment remains shaped by individual values and risk tolerance.

The third layer is structural and addresses the question, - what is PGT-A for, and who benefits from its widespread use? Somewhat surprisingly, adoption has continued to grow, - even as evidence for its routine use has weakened. The financial structure of IVF adds additional complexity: So-called “add-on” tests are often billed outside of insurance coverage. PGT-A is a good example: Considering PGT-A is still experimental, insurance companies even in covered IVF cycles usually do not include PGT-A coverage. Patients, therefore, pay for this service out of pocket and undiscounted, greatly enhancing overall cycle profitability for IVF clinics, otherwise forced to greatly discount cycle fees to insurance companies.

Moreover, while advertising IVF outcomes with reference embryo transfer rather than cycle start, success rates offered to the public are often significantly exaggerated and unrelated to increasingly accepted evidence. A.I. does not touch this layer but – if anything – A.I.-augmented PGT-A may, in itself, become a new add-on with its own opportunity for marketing.

Our 2020 paper argued that more data alone likely could not resolve this conflict and A.I. in effect means more data. It is improving the technical layer while leaving the clinical and structural layers untouched. The conflict has not been resolved, but its terrain has shifted.

Toward Common Ground

If A.I. cannot resolve the disagreement between physicians, then what can? We suggest that three steps, drawn from conflict resolution practice rather than clinical debate may be able to achieve this goal.

1. Agree on the outcome that matters most. Much of the disagreement disappears when physicians specify, in advance, whether they are optimizing for per-transfer success, cumulative live birth per cycle started, time to first pregnancy, or miscarriage reduction. These are different goals, and a test that helps one can hurt another. Naming the goal before recommending the test is the single most useful step.

2. Separate the test from the decision. A.I. improves PGT-A’s classification accuracy, but classification is not the same as a transfer decision. A mosaic or intermediate result is a piece of information, not an instruction. Building decision frameworks that treat ambiguous results as starting points for patient conversation, rather than disposal criteria, would address one of the most persistent sources of physician disagreement — and one of the most painful sources of patient harm.

3. Acknowledge the structural layer openly. The financial and competitive structure of IVF shapes which tests get offered, marketed, and adopted. Pretending those incentives do not exist makes the clinical debate harder than it needs to be. A field that openly discusses how its payment structure influences its practice patterns is better positioned to evaluate new technologies on their merits, — including A.I.

None of these steps requires a new study. They require a different kind of conversation, between physicians who currently talk past each other.

Why This Matters Beyond PGT-A

This behavior pattern is likely not unique to reproductive medicine. Across health care, A.I. is being introduced into long-standing controversies, such as mammography screening, prostate cancer overdiagnosis, and even psychiatric diagnostic categories. In each case, A.I. offers improved classifications, better consistency, and faster analysis. And in each case, the underlying disagreement persists, because tests do not exist in a vacuum. They exist inside workflows, payment structures, and definitions of success that carry their own incentives.

A more accurate test inside a contested system produces more accurate contested results. Resolving a conflict between physicians requires more than better information. It requires a willingness to revisit the goals, the incentives, and the values that shaped the disagreement in the first place.

This work, for now, at least remains in human hands.

A.I. Disclosure Notice:

This article was written with help of several A.I. platforms during the research phase. The final product was fully vetted and edited.

Industry Conflict:

This study⁸ was conducted at NYU Langone Prelude Fertility Center using CooperSurgical’s proprietary PGTai℠ and PGTai 2.0 platforms. CooperSurgical has a direct commercial interest in PGT-A. This article acknowledges that the strongest evidence for A.I.-augmented PGT-A benefits has come from studies on commercial A.I. platforms by groups with industry relationships, an observation that strengthens the article’s central argument that A.I. does not resolve the underlying conflict, but only relocates it.

REFERENCES

1. Mochizuki L, Gleicher N.. J Assist Reprod Genet. 2020;37(3):677-687.

2. Yan J, et al. N Engl J of Medi. 2021; 385(22):2047-2058

3. Coussa et al., J Assist Reprod Genet. 2025;42:179-184

4. Roberts, et al., Reprod Biomed Online. May 2, 2026:105747. S1472648326002889

5. ASRM; A Committee Opinion 2024. Fertil Steril. 2024;122(3):421-434

6. Simopoulou et al. J Assist Reprod Genet. 2021 38(8):1939-1957

7. Hyttel, et al. Hum Reprod. 2026;deag049; on line ahead of print.

8. Buldo-Licciardi et al., J Assist Reprod Genet. 2023;40(2):289-299

9. Xiet et al., Hum Reprod Open. 2025;,hoaf054

10. MIT Technology Review. May 7, 2026. https://www.technologyreview.com/2026/05/07/1136946/whats-next-for-ivf-ai-robot-pgt-gene-editing/

Today’s posting offers a broad spectrum of news for almost everybody in one or the other way engaged with the fertility field. We are addressing change in the pharma industry which over decades has failed to innovate when it comes to either female or male infertility. Diagnostics – we must say – have also not been too hot and, indeed, o several occasions have succeeded bringing to market pretty useless stuff. But there can be no doubt that change in the fertility field in general has been speeding up and we are with today’s posting attempting to offer a quick overview.

We hope you enjoy today’s postings and, as always, are looking forward to your responses.

The CHR’s Editorial Staff

News from the Fertility Pharma Industry

The Inside Reproductive Health (IRH) , made several interesting points in a recent report worthwhile mentioning here:¹

Disruptions at drug manufacturers like big layoffs at Ferring and the exit of the Organon CEO , Kevin Ali, – for at least so-far – appear not to have impacted the companies’ fertility operations (yet). But Ali’s exit from Organon, of course, appears related to the since announced pending acquisition of Organon by India’s Sun Pharma in an $ 11.75 billion all cash deal.¹ Serono’s early announcement about quite radical price reductions for their company’s gonadotropins in response to the Trump administration’s effort to lower medication pricing will, however, of course force the hand of competitors. Amazing how large the companies’ profit margins on these medications must have been if Serono could afford such big discounts!

Even more interesting, the report correctly noted that new drug R&D in the fertility arena has – to say it politely - dragged for decades. More bluntly, it basically has not existed with the reason being that, previously independent pharma companies almost exclusively active in the fertility field, were bought up by multispecialty giants who quickly discovered how small the fertility market really was in comparison to many other medical specialty areas. Investments toward the developments of new drugs, therefore, went elsewhere.

The article in IRH now suggested that, driven by newer companies in the field, this decades-long drought may now have finally ended. One such company is Granata Bio which apparently partnered with Gedeon Richter, - a very prominent European pharma company to bring an additional FSH to the U.S. market after – because of the staggering costs of FDA approvals - so-far having chosen not to enter the U.S market. These two partners also acquired Oviva Therapeutics, - a relatively new company concentrating on the ovarian aging process, finally including production of a hypoglycosilated FSH products, fitting natural glycosylating changes observed in the FSH of aging women.

The CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, - and we are certain others – suggested such adjustments – to no avail - in FSH glycosylation based on patient ages to the old-timer companies in the fertility field, Serono, Organon, and Ferring already decades ago. Their response was negative because they argued that this would only split the already existing (relatively small) market.

A company called Meitheal, in turn, has taken the lead in bringing generic fertility medications to market in the U.S (Genirelix and Cetrorelix) and is also advancing a FSH biosimilar.²

News About Fertility Diagnostics

A recent posting suggested that payor preferences as well as clinical workloads bring at-home testing to the forefront, with home semen analysis being a good example.³ The big home-testing reward for patients as well as IVF clinics would however, of course, come from the ability to monitor patients in ovarian stimulation cycles from home.

Pulsenmore, the Israeli ultrasound manufacturer that already received FDA approval for home pregnancy monitoring,⁴ in January now also announced home follicle size monitoring.⁵ But follicle size alone is, of course, not enough to determine ovulation trigger timing. For that, additional blood tests are required (estradiol, progesterone and sometimes LH). That is, - they were required:

The CHR’s investigators, indeed, recently filed a patent, describing a technique that allows assessments of follicle maturity (and, therefore, egg maturity) by using only ultrasound alone. If validated by further studies, this new patent will, indeed, allow home monitoring of patients in all ovarian stimulation cycles, including IVF cycles. Imagine what difference that would make for patients as well as IVF clinics!

News About Third-party Donations

As another report by IRH noted,⁶ the use of third-party donations in the U.S. appears “strained.” And the strain is apparently at least partially the consequence of increasing demand. The CHR fully agrees that many third-party programs including gestational carriers, surrogacy agencies, sperm banks, and egg banks -as the report noted - “simply don’t meet the operational standards required to seamlessly support the patient experience.” We have noticed especially increasing inconsistencies in donor egg quality and especially in the selection process for gestational carriers, while costs for these services are continuing to increase. In other words, patients are asked to pay more for less!

The Adoption of A.I. by Fertility Clinics

Yet another IRH report suggested that during 2025 the adoption of A.I. in fertility clinics accelerated.⁷ But that is, of course a very relative term. Our impression, indeed, is that A.I. – as of this moment of time – in infertility plays a much smaller role than in some other medical specialty areas. While that may change, we know of at least one A.I. start-up that – after a lot of initial publicity - already went out of business. It originally claimed outcome advantages for IVF from judging embryo development by A.I. through imaging systems. Advantages of its algorithm apparently were not worth time and financial investments.

In a retrospective cohort study of 858 patients, a company called Cycle Clarity apparently found that A.I.-only follicular ultrasound produced outcomes equivalence to traditional monitoring using ultrasound and hormone levels. Its website describes it as follows: Cycle Clarity is software company dedicated to improving fertility care around the world. It’s FDA-cleared patented software platform can reduce fertility ultrasound times from 15 minutes to 20 seconds while simultaneously adding standardization of follicular measurements and providing clinical decision support software to enhance decision making.

Every time in recent years when a new “add-on” to IVF was announce as “time-saving” we so-far have been disappointed and, therefore have become quite skeptical - but are looking forward to more information. Every IVF clinic these days would benefit from time savings!

Declining Reimbursements for IVF Clinics

Declining reimbursement rates have apparently been “slashing fertility centers’ margins.” Employer benefit managers and insurance companies per this report often reimburse fertility clinics only at a fraction of only around 50%.⁸

Ever poorer insurance reimbursements are, of course, nothing new, - leading the CHR already over 20 years ago to limit the insurance plans CHR was willing to accept to plans that at least covered CHR’s overhead costs per cycle. A 50% reimbursement rate form regular fee schedules very definitely doesn’t do that. In most clinics, but certainly in those which basically accept any insurance plan, cash-paying patients – without even knowing - thus subsidize insurance covered patients.

The State of the Fertility Clinic Networks

In a quarterly review IRH also summarized how fertility clinic networks, mostly owned by Private Equity, are expected to perform in 2026,⁹ - and the conclusions were not very pretty and we are quoting: (i) “Everyone is freaking out” because of fierce competition for fertility specialists.” (ii) We are already witnessing a backlash against these practice networks.

And what are the signs? A first one is that most of them are looking for buyers, including US Fertility where Amulet Capital partners was unable to sell their majority ownership and only succeeded to decrease its exposure by bringing in L. Chatterton which acquired a 42.5% stake in the company. Management and the roughly 200 physicians the company employs, thus are left with only 15% ownership. Other networks are allegedly behind the scenes – so far unsuccessfully - searching for buyers are, - Kindbody already for over a year, Inception, Pinnacle, and others also for some time.

A second reason is that individual REIs and/or small groups of physicians are returning to opening their own “little” practices. So, for example – as we previously already reported in the _CHRVOICE, three REIs from Boston IVF opened their own practice at home in straight competition to Boston IVF in Boston.

REFERENCES

1. Venkat PR, Loftus P. The Wall Street Journal. April 22, 2026. https://www.wsj.com/business/deals/sun-pharmaceutical-to-acquire-organon-valued-at-11-75-billion-8c3e0f65

2. Inside Reproductive Health. January 15, 2026, https://www.linkedin.com/pulse/state-fertility-pharmacies-2026-insidereproductivehealth-jpfac/

3. Inside Reproductive Health, January 13, 2026, https://www.fertilitybridge.com/news-articles/fertility-diagnostics-at-home-testing-2026

4. Radiology Business. November 3, 2025. https://femtechinsider.com/pulsenmore-and-clalit-health-services-launch-at-home-follicular-monitoring-for-ivf/

5. Israel.com. January 27, 2026. https://israel.com/technology/pulsenmore-clalit-launch-israels-first-at-home-fertility-monitoring-service/

6. Inside Reproductive Health, January 15, 2026. https://www.fertilitybridge.com/news-articles/third-party-ivf-patient-experience-breakdown

7. Inside Reproductive Health, January 13, 2026. https://www.fertilitybridge.com/news-articles/artificial-intelligence-fertility-care-2026

8. Inside Reproductive Health ,January 14, 2026. https://www.fertilitybridge.com/news-articles/ivf-benefits-patient-finance-2026

Where the Infertility Field Is in Attempts to Favorably Influence the Ovarian Aging Process

We have – especially in recent times – been quite critical about what Fertility and Sterility - in the format of opinion articles (which, of course includes many different review formats) has been publishing. We, therefore, were in a way positively surprised to see in the March 2026 issue of the journal and interesting and somewhat original View and Review article (this designation correctly described the article) that informed well on ongoing attempts to learn how to potentially influence to the better ovarian aging.

The article format was “original” because the paper had five distinguished authors from different institutions who apparently – separately - wrote five individual sections of the manuscript: (i) An introduction (2 authors); (ii) clinical applications and experimental modalities including platelet-rich plasma, stem cell therapy, and mitochondrial transfer (2 authors); (iii) nutrient-sensing pathways, including the growth hormone - IGF-1 and rapamycin (mTOR) pathways (1 author); (iv) partial epigenetic reprogramming and ovarian aging, including methylation, histone modifications, and chromatin organization (1 author); and (v) ovarian fibrosis as target for reproductive longevity (also discussed earlier in this section, - 1 author).

All five sections are very well written, objective, and well referenced, - a review article that not only informs but also educates.

REFERENCE

1. Eubanks et al., Fertil Steril 2026;125(3):387-398

Does Anybody in Fertility and Sterility’s Editorial Office Peer Review the Journal’s “Inkling” Articles?

This is, of course, not the first time – and with great likelihood also not the last time - that we criticize an “Inklings” article in Fertility and Sterility.

There are many, we think good reasons, why we don’t like “Inklings: (i) Based on the Merriam – Webster Dictionary, it’s a really stupid name since this noun reflects “a slight knowledge or vague notion,”¹ - certainly not what readers of F&S would expect from an allegedly authoritative editorial which is only open to submissions from the journal’s unusually large editorial board. (ii) While opinion papers may be good for improving the various citation indices of a journal, they, of course lower the scientific appreciation of the journal, especially if their publication, like in the case of F&S, greatly reduces page numbers dedicated to scientific papers. After all, expert opinion represents the lowest level of evidence in the evidence pyramid. Every kind of study, therefore, represents better evidence than an Inkling. (iii) But definitely the most compelling reason is their - only too often – not very informative content that makes one at times wonder whether Inklings are subject to even minimal peer review or – after submitted by a member of the editorial board - are automatically allowed into print.

The March 2026 issue of F&S offered again a telling example when three authors (under the obvious leadership of a senior editor of F&S who in recent years contributed opinion articles on all kinds of subjects to almost every monthly issue of the journal), practically issued an order to the troops (sorry, - we meant readers) categorically demanding to “not measure antiMüllerian hormone to predict women’s fecundity (this is how the hormone was, indeed, spelled)!”²

To further explain why this Inkling article warranted our commentary, we here verbatim cite its concluding paragraph (in its at times stylistic awkwardness):

“The routine measurement of AMH in young women for counseling them about their fecundity is fundamentally flawed. This practice, still too often and undertaken, may lead to unnecessary and unfounded fears in women whose AMH is low. Reproductive doctors (we assume that is us) and women alike should know that routine AMH dosage (??? - we assume what was meant was level or concentration) for fertility counseling provides false information and should be absolutely discouraged. Let this be a call to action (Liberté, Égalité, Fraternité???) to raise awareness within both the public and the obstetrics and gynecology communities about the limitations of AMH testing and to end the misguided practice.”

So, what are these authors really telling us with their Inkling article?

It sure sounds like we should stop measuring AMH levels in our female infertile patients. And why? Because – and we are quoting again verbatim from the article: Already “over 18 years ago, we (the meaning is only the senior author of the Inkling article) first reported live pregnancies in women whose AMH levels were undetectable and had been advised to undergo donor-egg ART (and, of course referencing themselves in a 2008 F&S publication³). The Inkling article then went on to another paper – of course again of the senior author - noting that “over 10 years ago” it reported “expected age-related decreases in AMH after (prolonged) oral contraceptive use and that time to subsequent spontaneous pregnancy was unrelated to their measure of AMH levels.”⁴

The Inkling article then cited two additional later published papers by different authors, claiming that AMH levels are unrelated to natural conception.,^5,6 - which the Inkling paper then used in support of its professional tongue lashing of us reproductive doctors for still using AMH levels for screening purposes.

And aside of the fact that medical journals (other than seemingly F&S, of course) have started to notice and address during peer review excessive self-citations, the Inkling’s argument does not make logical sense because nobody with basic understanding of AMH functions will use AMH levels exclusively to predict the future fecundity of a patient (if we at the CHR did this, we would have no patients considering how low even our younger patients’ AMH levels are). But that does not mean that women, in whom either a problem with functional ovarian reserve is already suspected or because their medical history may suggest an increased risk for premature ovarian aging (POA), should not be screened with AMH.

Let us here – coincidentally - quote from an F&S paper by CHR investigators published already in 2010 (and, of course, unreferenced in the Inkling article) under the title, - “Anti-Müllerian hormone (AMH) defines, independent of age, low versus good live-birth chances in women with severely diminished ovarian reserve.”⁷ And we quote from the abstract of this publication:

“Maximal receiver operating characteristic curve inflections, which differentiate between better and

poorer delivery chances in women with diminished ovarian reserve (DOR) independent of age, were at anti-Müllerian hormone (AMH) 1.05 ng/mL (improved odds for live birth 4.6 [2.3–9.1), 95% confidence interval: Wald 18.8, df = 1], although live births occurred even with undetectable AMH. Pregnancy wastage was very low at AMH ≤0.04 ng/mL but significantly increased at AMH 0.41–1.05 ng/mL, resulting in similarly low live-birth rates at all AMH levels ≤1.05 ng/mL and significantly improved live-birth rates at AMH ≥1.06 ng/mL (see figure below).”

So, why then does “do not measure antimüllerian hormone to predict women’s fecundity” not make any sense (beyond the strange spelling)? Because AMH – besides reflecting functional ovarian reserve (i.e., potential egg numbers in an IVF cycle) – also reflects other hormonal influences (i.e., for example hormonal contraceptives). And anybody who is aware of these associations, consequently, will not be stupid enough to refer a young women automatically into egg donation because she had a very low AMH level or may not even demonstrate any detectable AMH at a given moment.

AMH is, therefore, quite good in predicting response to stimulation but far less good in predicting pregnancy chances in IVF (especially in the longer run), But because egg and, therefore, embryo numbers are predictive of cumulative pregnancy chances (of course, also taking age and other factors into account), AMH also has relevance in predicting pregnancy chances but, of course, to lesser degrees. To basically state that AMH should not be tested to predict a woman’s fecundity, therefore, is simplistic thinking, - undeserving of an editorial opinion in a leading fertility journal.

REFERENCES

1. Merriam – Webster. https://www.merriam-webster.com/dictionary/inkling. Accessed March 17, 2026.

2. De Ziegler et al. Fertil Steril 2026;125(3)399-400

3. Fraisse et al., Fertil Steril 2008;89:723:39-11

4. Streuli et al., Fertil Steril 2014;28:216-224

5. Zarek et al., J Clin Endocrinol Metab 2015;100:4215-4221

6. Galati et al., Arch Gynecol Obstet 2024;310:2691-2696

7. Gleicher et al., Fertil Steril 2010;94(7):2824

Today’s posting addresses the increasing recognition of the importance of the food we ingest for our health. And this, of course, also includes our fertility. This issue has come into better focus with the relatively recent discovery of the so-called gut-brain axis, which has taught us how important gut health is for normal brain function. And since our brain basically controls everything in our body, - one can actually make the argument that - at least to a degree - it is really our gut that controls everything!

Because of this, nutrition has become a much more important issue in counseling our infertile patients. Therefore, the CHR, as today’s posting demonstrates, addresses nutritional issues on a regular basis in its publication.

As always, we welcome your questions and comments!

The CHR’s Editorial Staff

Does Drinking Coffee and Tea Reduce Dementia Risk and Prolong Life?

So here is the final truth: Coffee is good for you, especially in the morning. Morning coffee drinkers had a 16% reduction in death from all causes. Greatest benefits were obtained with more than 2-3 cups. The association was especially strong in regard to cardiovascular diseases. Interestingly, however, those who consumed coffee all day long (like yours truly!) did not achieve the same benefits. One wonders why?

Then there is the dementia question, and – lo and behold – Chinese research in JAMA just reported that tea as well as coffee in a study of 11,033 dementia cases followed for up to 43 years demonstrated that greater consumption of caffeinated coffee and tea was associated with significantly lower risk of dementia and modestly better cognitive function, - with the most pronounced association found at moderate consumption.

REFERENCES

1. Wang et al., Euro Heart J. 2025;46(8):749-759

2. Zhang et al., JAMA. 2026; doi: 10.1001/jama2025.27259. ahead of print.

The Effects of Fermented Foods on Our Diet

It is now no secret that fermented foods are healthy. Interestingly, they, indeed, have been a mainstay of many different cuisines all over the world. Few are, however, so reflective of a cuisine as kimchi in the Korean diet. And with Korean restaurants having become quite popular in NYC’s dining scene, kimchi is gaining more attention.

It, therefore, is of interest that Nature’s npi Science of Food recently published an article on kimchi that demonstrated that kimchi modulates human-antigen presenting and CD4⁺ T cells.¹ The results were fascinating: After 12 weeks of consumption, kimchi enhanced intercellular signaling mediated by antigen-presenting cells, increased antigen uptake, and promoted the upregulation of MHC class II–related genes through the JAK/STAT1–CIITA axis. Single-cell trajectory analysis revealed accelerated CD4⁺ T cell differentiation toward effector and regulatory phenotypes, whereas CD8⁺ T cells, B cells, and NK cells remained stable, indicating preserved systemic immune homeostasis. In short, kimchi modulates our immune system, and other fermented food products probably do so as well.

Kimchi, of course, has been known in Korean culture for its health-promoting properties.² Its fermentation is mostly the result of lactic acid bacteria (LAB), including Leuconostoc, Weissella, and Lactobacillus, which produce diverse bioactive metabolites, including organic acids, vitamins, peptides, and exopolysaccharides. They then exert antioxidant, anti-obesity, and immunomodulatory effects, synergistically influencing host physiology, including immune responses.

REFERENCES

1. npj Science of Food. 2025;9:236

2. Park et al., J Medicinal Foods. 2013;17(1): https://doi.org/10.1089/jmf.2013.3083

Eating Out Is Getting More Expensive

This is probably not news for most of our readers. Our impression, moreover, is that nothing in our economy has increased in price as much as eating out.

The restaurant business is a very tough business, - usually operating on very tight profit margins. It was hit hard by the COVID pandemic, then - mostly learned during COVID, - by significant changes in population behavior in cities like NYC. These changes led to new habits, which included frequent home deliveries, then inflation in food prices and staffing costs; and it has not gotten any easier! Moreover, consumers spent less on restaurants in 2025 than in 2024.As the headline in a recent FOX News article noted, Americans have hit menu price fatigue. In December of 2025 alone, restaurant prices rose by 0.8%,¹- annualized representing a 12% annual inflation.

REFERENCE

1. Margolis A. FOX News. February 5, 2026. https://www.foxnews.com/food-drink/eating-out-getting-more-expensive-americans-hit-menu-price-fatigue-nationwide

Healthy Eating

INFECTIOUS CONTAMINANTS -- A recent Medscape article¹ reported on hidden complexities around the world involving healthy eating. Some recent food safety incidents in Europe have renewed scrutiny of dietary risks and their global relevance. This included Escherichia coli-contaminated meat in France, causing severe disease in some cases and even one death, contaminated pizzas linked to two infant deaths, and more than 70 reported cases of salmonellosis tied to cheese consumption in 2024. The U.S., of course, also intermittently reports such outbreaks.

CHEMICAL CONTAMINANTS -- The article notes that modern diets, however, also expose populations to chemical contaminants and nutritional imbalances that contribute to chronic diseases.

FIBERS BUT NO ULTRA-PROCESSED FOOD -- The goal is always a balanced diet with a higher intake of fiber-rich foods, including fruits, vegetables, and legumes, all consistently linked to lower cardiometabolic risk across populations. Food processing has also emerged as an independent risk factor, - with especially ultra-processed foods (by the NOVA classification, products that have undergone extensive industrial processes and are formulated with ingredients such as hydrogenated oils, protein isolates, glucose/fructose syrup, and additives like colorings, sweeteners, and emulsifiers), which have been tied to metabolic dysfunction, chronic inflammation, and gut-microbiota disruption.

According to the Medscape article, data from a large French study involving more than 180,000 participants, established links between ultra-processed foods and an increased incidence of chronic diseases: cancer, cardiovascular disease, diabetes, and obesity.

CHEMICAL CONTAMINANTS -- Pesticides can leave residues in agricultural products. Choosing organically grown foods helps reduce this risk. Persistent organic pollutants including dioxins, polychlorinated biphenyls, perfluoroalkyl, and polyfluoroalkyl substances are of global concern because of their environmental persistence. They then accumulate in the food chain, especially in animal fat, and prolonged exposure has been linked to neurotoxic, immunotoxic, and endocrine effects, with possible implications for reproductive health and cancer. International dietary advisories typically recommend moderating the intake of fatty fish, dairy products, eggs, and red meat to limit cumulative exposure.

FOOD ADDITIVES and THE NEW SCIENCE OF MICROBIOTA -- Food additives are used to enhance texture, flavor, color, and shelf life, but not everything is innocent: For example, certain emulsifiers and sweeteners have been shown to alter gut-microbiota composition. Though individual susceptibility varies, emulsifiers found in many industrial baked goods and packaged breads may promote inflammatory bowel disease or metabolic disturbances, reflecting differences in baseline microbiota shaped by genetics, environment, and diet.

According to the Medscape paper, a recent French study also showed that sensitivity to this emulsifier can be predicted through microbiota analysis. In general, as repeatedly noted before in these pages, the gut-brain axis – because of the gut microbiome – has become a study subject revealing significant surprises.

REFERENCE

1. Salmon. Medscape. January 9, 2026. https://www.medscape.com/viewarticle/hidden-complexity-healthy-eating-whats-changed-2026a10000qx

Obesity-associated Inflammation

Obesity is continuing to increase in many populations, and it is associated with many comorbidities, which often coincide with a low-grade chronic inflammatory state that can be quantitated using circulating inflammatory proteins. In a here-discussed study, therefore, morning urine samples were taken from normal-weight controls (n = 30) and from people with obesity (n = 58).

Normalized protein expression data were obtained using the Olink Explore 384 inflammation panel. Of the 384 inflammation proteins, 48 proteins had a P < .05 with false discovery rate correction between the persons with obesity and the persons without obesity. Network analysis revealed 5 different clusters of proteins with several clusters associated (P < .05) with circulating concentrations of high-density lipoprotein, waist circumference, and fat distribution in individuals with obesity.

The paper, therefore, demonstrated that urine may represent a novel, noninvasive approach to measure the state of inflammation in individuals with obesity using Olink-targeted proteomics.

REFERENCE

1. Clanki et al., J Endocrine Soc. 20206;10:bvaf212

The Gut Microbiome in Obesity

That the gut microbiome (the bacterial flora in the bowels) affects human health in many different ways is now already widely accepted. A recent review, however, addressed a related subject that has not been addressed before in an organized and systematic approach,- namely, how the gut microbiome may influence dietary, surgical, and the new pharmacological interventions for obesity,- and did so very well.¹

This is, of course, a multifaceted and very complex subject (almost 12 pages of text), - much too substantial to even just summarize here; but the relevance of this relationship for potential efficacy, treatment costs, and patient-specific variability seems obvious, and we, therefore, wanted to point this very interesting Review article out to our readers with an interest in the study of obesity.

REFERENCE

1. Masi et al., Cell Rep Med. 2026;7:102573

Gut Microbiome Testing - Same Stool Sample, but Different Results

Reading this headline, every fertility service provider may immediately think about PGT-A and may be wondering what PGT-A may have to do with nutrition. But give us a minute to explain: What we are writing about here has - for once - nothing to do with PGT-A, but has a lot to do with another test, which in our opinion is oversold (in its accuracy) by the laboratory testing industry, - and that is microbiome testing. And just as the CHR’s investigators convinced themselves in 2014 and 2015 of the incompetence of PGT-A laboratories when – unknown to two testing labs – they sent them biopsy samples from same embryos,¹ - only to often get back hugely different results – here, U.S. investigators did the same for gut microbiome testing and found similarly disturbing divergences between diagnostic laboratories, which they reported in Nature’s Communications Biology journal.²

As they noted, these tests (like PGT-A) are so-called laboratory-developed tests (LDTs) – a troublesome subject we previously discussed in these pages - which “straddle the line between more strictly regulated medical devices and minimally regulated general health and wellness products“ because the FDA chooses not to review them,- a distinction that may not be readily apparent to consumers.

To assess the current state of the industry, the authors evaluated the performance of seven DTC gut microbiome-testing services using a standardized NIST–developed human fecal material. And results then revealed major discrepancies, both within and across the different service providers. Significantly, they found that variability between providers was on the same scale as biological variability between different donors.

They then attributed the observed differences to methodological variability and lack of sufficient quality control. Additionally, they highlighted that analytical performance is a prerequisite for making sound clinical recommendations, demonstrating the need for standards to ensure analytical validity and consumer confidence.

REFERENCES

1. Gleicher et al., Reprod Biol Endocrinol. 2017;15(1):23

2. Servetas et al., Commun Biol. 2026; 9:269

All the New Information About GLP-1s, - the Wonder Drugs Beyond Just Weight Loss

BELIEVE IT OR NOT, GLP-1s ARE CHANGING HOSPITAL ADMISSION PATTERNS – A very interesting recent Medscape article by Julie Peck reported that this family of “wonder drugs” has become so ubiquitous, hospitals are seeing shifts in the kind of patients admitted.¹ The article reported that a September 2025 study determined that initiating treatment with a GLP-1 receptor agonist (RA) was associated with an almost immediate decline in overall risk of having to visit an emergency room or being admitted to the hospital, and by October 2025, another study reported that patients with obesity and/or congestive heart failure who were treated with only 2.4 mg of the GLP-1 RA semaglutide (a first-generation drug in this family of medications) demonstrated significantly lower medical costs and inpatient resource utilization in comparison to similar patients who were not on GLP-1s.

In a retrospective population-based observational cohort study in adults including 24,576 new users of a GLP-1 receptor agonist (RA) and 23,600 controls, GLP-1RA initiation was associated with a lower risk of all-cause emergency department encounters or hospitalizations (hazard ratio [HR] 0.90; 95% CI 0.87-0.94; P < 0.0001).² These data obtained in a study population of patients with renal diseases confirmed similar data previously reported for patients with cardiovascular diseases.

AND THE BIGGEST CHALLENGE IN REGARD TO GLP-1s IS INSURANCE COVERAGE – And here, like with fertility medications (especially gonadotropins), the Trump administration deserves credit by having achieved huge price reductions for these drugs (monthly injectables used to run at between $1,300 to $1,400 for a 4-week pack, - and this cost has now been reduced to $350 per month).

As another article in Medscape recently pointed out, this remarkable price-drop may help future plaintiffs who may try to compel medical insurance companies to offer coverage for these drugs. As the article also noted, the argument is further strengthened by the improving cost-effectiveness of these medications.³

In 2025 – according to a New England Journal of Medicine article – only 15 Medicaid programs covered obesity treatments with GLP-1s.⁴ An immediately following article addressed the possibility that generic GLP-1s are now expected to enter the market⁵ (HIS & HERS not too long ago got into trouble with the FDA for doing that).

THE DRUGS’ CARDIOVASCULAR EFFECTS, - ARE THEY DEPENDENT ON ADIPOSITY? – That semaglutide treatment reduces major adverse cardiovascular events in overweight and obese individuals has been known for quite some time. Now, a large group of U.K. and U.S. investigators in the same study population tried to determine what the relationship was between baseline adiposity measure, treatment-induced adiposity changes, and subsequent major cardiovascular events risk.⁹

And, once again, results were somewhat surprising because what they found was that the cardioprotective effects of semaglutide (and, therefore, likely all GLP-1s) were independent of baseline adiposity and weight loss and had only a relatively minor association with waist circumference. And these findings now, of course, mandate a better understanding of what mechanisms beyond adiposity reduction may be at play.

AND HOW ABOUT CNS-EFFECTS ? – Once again, that GLP-1s have direct CNS effects is by now well-known; but who would have thought that brain stimulation matches semaglutide for weight loss? This is, however, exactly what Italian investigator, Anna Ferrulli, MD, and collaborators recently reported in Obesity.¹⁰

She already in 2019 reported in Diabetes, Obesity and Metabolism that 5 weeks of high-frequency deep transcranial magnetic stimulation (dTMS) is safe, effective, and well-tolerated for inducing weight loss in obesity. The treatment reduces body weight for up to 1 year by modulating the dopaminergic pathway, reducing impulsivity, and improving gut microbiota. She now demonstrated that treatment with transcranial magnetic stimulation produced a comparable reduction in body weight to that observed with the GLP-1 semaglutide (at the dose of 0.5 mg/week). dTMS, therefore, represents another promising intervention for the treatment of obesity and type 2 diabetes.¹¹

GLP-1s AND PREGNANCY – In attempts to improve pregnancy rates, in many fertility clinics, GLP-1 treatments now increasingly by several months precede fertility treatment beginnings. Weight loss of as little as 2% of bodyweight can already improve outcomes and a weight loss of 5% virtually guarantees improvements in pregnancy rates, as Australian investigators already decades ago demonstrated.¹² But a word of caution may be in place here.

A recent cohort study of primarily obese women published in JAMA produced some surprising findings: Use of GLP-1s – subsequently pre-pregnancy or in early pregnancy discontinued – was associated with more gestational weight gain and higher risk of preterm delivery, gestational diabetes, and hypertensive disorders of pregnancy.¹³

We have a very hard time believing these findings because they are not only counterintuitive, - but to a significant degree contradict physiological logic.

As the authors, themselves, noted, their study also contradicted in many aspects two other large recent retrospective studies, and they also appropriately acknowledged the significant limitations of their study. The CHR, therefore, – at least for the moment – reserves judgment on whether pretreatment of obese patients – if their ages allow for the time – and termination of GLP-1s before or early during pregnancy attempts represents a good, neutral, or bad strategy for obese women trying to conceive. Time will tell shortly,- we are convinced!

And how about using GLP-1s for postpartum weight loss? That, too, appears to be a rising utilization wave, according to a recent Research Letter by Danish colleagues in JAMA;¹⁴ but the paper really does not offer any data of interest beyond the observed increased utilization.

The CHR’s concerns about GLP-1 use in association with pregnancy are not about maternal outcomes, – but about potential effects on the fetus and – postpartum – effects on the maternal milk for the newborn. But wouldn’t it be amazing if we could use these drugs safely through pregnancy and into the postpartum period?

AND – FINALLY – SOME POTENTIALLY REALLY GREAT NEWS ABOUT GLP-1s – One of the alleged principal problems of GLP-1 use to lose weight has been that stopping the medications within the first year results in the reversal of practically all weight loss. What these studies, therefore, suggested was that, like other diabetes drugs, GLP-1s – for persistent weight loss – also have to be taken for life if one wants to maintain the weight loss.

Now, a small retrospective study of 30 adults in Obesity, however, suggested otherwise:¹⁵ Patients who plateaued their weight on either semaglutide or tirzepatide, once they reduced the frequency of administration of the GLP-1 from weekly to usually every other week – as it turned out – were neither affected in their weight nor in metabolic criteria that had improved under weekly treatment.

These data – though only based on a small study size – are fascinating because they suggest that maintenance of weight loss and metabolic gains may be possible, – even if the medication is only administered every other week, – and who knows – maybe only once a month.

And, yes, there is also interesting news regarding the also allegedly unavoidable muscle loss that happens along with weight loss. And that, too, may not be as bad as reported because – as it tuns out – if muscle loss is measured appropriately and correctly, there practically is no serious muscle loss because the body, of course, needs less muscle after significant weight loss.

More on all of that to come, – and we are quite certain that the news will remain good and astonishing. GLP-1s have the opportunity to reshape the world and significantly reduce the burden of overall health service needs.

REFERENCES

1. Peck J. Medscape. January 13, 2026. https://www.medscape.com/viewarticle/how-weight-loss-medications-are-changing-hospital-admissions-2026a1000156

2. Yau et al., Diabetes Care. 2025;48(9):1524-1528

3. Freehoff Y. Medscape. December 24, 2025. https://www.medscape.com/viewarticle/two-new-developments-may-help-future-plaintiffs-compel-glp-1-2025a1000z61.

4. Dusetzina et al., N Engl J Med. 2026;3934(2)105-107

5. Gondi et al., N Engl J Med. 2026;394(2):107-110

6. West et al., BMJ. 2026;392:e085304

7. Sun Q. BMJ. 2026.392:r2586

8. Lapid N. Reuters Health Information. Updated January 22, 2026. https://www.reuters.com/business/healthcare-pharmaceuticals/many-patients-may-keep-off-lost-pounds-after-stopping-glp-1-us-data-suggests-2026-01-22/

9. Deanfield et al., Lancet. 2025; 406:2257-2268

10. Ferrulli et al., Obesity (Silver Spring): 2026; 34(2):317-322

11. Ferrulli et al., Diabetes, Obesity Metabolism. 2019; https://doi.org/10.1111/dom.13741Digital Object Identifier (DOI)

12. Clark et al., Hum Reprod. 1995; 1095;10(10):2705-2710

13. Maya et al., JAMA. 2025;334(24)2186-2196

14. Bliddal, et al., JAMA. 2025;334(24):2227-2229

15. Wong et al., Obesity. 2026; https://doi.org/10.1002/oby.70137

Today’s posting is quite different from our usual material because 2026 is not only the Semiquincentennial, i.e., the 250^th anniversary of the United States Declaration of Independence - but also the 25^th anniversary of the CHR’s formal move from Chicago to New York City into its current location. To celebrate this event, the CHR is planning an Anniversary Gala on September 9, with all the proceeds benefitting the not-for-profit Foundation for Reproductive Medicine (FRM), which supports postgraduate medical education and research at the CHR and elsewhere and has done so for decades.

The FRM, therefore, is in 2026 co-sponsoring with the CHR two major events in NYC, - the above-noted Gala at one of the city’s premier event spaces, Guastavino’s, on September 9 and - as usual - the annual international Foundation for Reproductive Medicine Conference (FRMC) between December 4 and 6 at the Metropolitan Club.

This, of course, means a lot of extra work for the CHR, as well as the FRM, which we very much want to support. Consequently, we felt a brief rehash of the CHR’s history was timely and asked the CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, to use his periodic “A Piece of My Mind” article to tell in brief the stories of the CHR and the FRM. He, after all, several decades ago, founded both organizations.

And the purpose is, of course, to invite our readers to both of these events, with the appendix after the article offering the links to make reservations and/or request further information.

The CHR’s Editorial Staff

A PIECE OF MY MIND - The Upcoming 25^th Anniversary of CHR-NY

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.

In September, the CHR will celebrate a quarter of a century in its current location in NYC with a very special Gala - obviously a very special occasion with very significant meaning for the CHR’s future. Having had the honor of establishing the CHR as an academic faculty practice at Mount Sinai Hospital in Chicago in 1981 as Chairman of the OB/GYN department, I have led the CHR organization ever since, - initially moving it out of its academic model into a private economic model in Chicago and later moving - for reasons explained below - the main practice from Chicago to NYC. This “A Piece of My Mind” article is meant to inform our readers about the CHR’s plans for the future.

Background

Though private since approximately 1990, the CHR remained “academic” in its goals as well as structure, - likely, indeed, more so than many - if not most - academic institutions. This is well documented by hundreds of peer-reviewed publications, and many discoveries that have changed clinical infertility practice and led to the CHR’s worldwide recognition as a leading last-resort fertility center for patients with repeated IVF failures. In parallel, the CHR (through its investigators) has also become one of the most cited fertility provider organizations in the medical literature in the world.

The CHR’s research program would not have been possible without financial help from the not-for-profit Foundation for Reproductive Medicine (FRM), which has steadily supported the CHR’s educational and research activities. Though the foundation has over the years been mostly funded by the CHR, tax-deductible donations mostly from the CHR’s patients and outside grants have also greatly contributed to the CHR’s educational and research efforts.

In planning the CHR’s 25^th Anniversary in NYC, all financial net-proceeds from the Anniversary Gala on September 9 will, therefore, go to the FRM (tickets and donations are tax-deductible according to the law) to continue support of educational events like the annual Foundation for Reproductive Medicine Conference (FRMC), - this year on December 4-6 again at the Metropolitan Club. The proceeds will also continue to support basic science as well as clinical research mostly at the CHR, though at times also at other fertility service providers.

After many years at the helm of this wonderful organization, the time has now, however, come to think about transitioning the CHR into its future under the next generation of leadership. This year, the CHR, therefore, initiated a carefully thought-out 5-year transition period toward new leadership and a principal purpose of this article is, therefore, to be transparent in all aspects of this process.

An important aspect in this transition is to secure the future of the CHR as a leading research center in the fertility field. Considering, however, the fact that - though working closely with several academic institutions in the world, - in NYC, for example, with Rockefeller University, in Europe, with the city of Vienna’s Medical University, and in Israel, with several of the country’s universities, - the CHR is not part of a university or a major hospital organization per-se.

Maintaining the CHR’s ability to conduct important research into the future as a free-standing fertility center is, therefore, a crucially important goal of this transition process. And the responsibility for financially supporting this ability – as in the past – will continue to rest with the FRM, a not-for-profit foundation, which over the years, has been providing the financial support for most of the CHR’s postgraduate education efforts as well as its research program.

To establish the beginning of an endowment for the FRM in supporting education and research at the CHR into the future, we, therefore, committed all net income for the upcoming 25^th Anniversary Gala of the CHR in NYC to the FRM and we hope that you – our readers – will help us in doing so by joining us in those festivities on September 9 at one of NYC’s most amazing event spaces, - Guastavino’s at 409 East 59^th Street (see below) for a night of good food, music, and entertainment, as well as purpose. With the event organized by the FRM in collaboration with the CHR, tickets and donations are tax-deductible according to the law. CHR babies above age 14 are welcome for free.

The gala will honor a leading pioneer in reproductive biology research in the country, Prof. David F. Albertini, PhD, upon his upcoming retirement after more than 15 years as editor-in-chief of the Journal of Assisted Reproduction and Genetics (JARG), the first journal in the world dedicated to in vitro fertilization (IVF). He for several years also served as Director of the CHR’s Division of Laboratories and is still a Visiting Senior Scientist at the CHR. And at the same time, the Gala will also announce and honor the CHR’s “Patient of the Year.”

A Little Bit of History

With the formal opening of our new infertility center in its current brownstone location at 21 East 69^th Street in Manhattan on September 10, 2001, the CENTER FOR HUMAN REPRODUCTION (CHR) celebrated its formal move from Chicago to NYC. Before that, in an agreement with Columbia University, CHR had farmed out the running of its new NYC program to the Columbia University’s IVF faculty, - a business relationship that from the beginning did not work out well and therefore after only one year was terminated.

It was this decision that, indeed, ultimately led to the CHR’s move to NYC after its founding roughly 20 years earlier in Chicago as the OB/GYN faculty practice at Mount Sinai Hospital, where I was the department’s Chairman. The CHR’s IVF program became one of the earliest in the nation and was the first in all of the Midwest. IVF clinics in 1981 were still such a rarity that the Chicago Tribune, the city’s leading newspaper, over two consecutive days published two full pages about the opening of the CHR’s IVF clinic.

In collaboration with Columbia University, the original NYC location of the CHR was in a rented space on Madison Avenue, just a few blocks below our current location on 69^th Street. That space, since then, has been occupied by another prominent IVF clinic.

The Opening Party

Though the move into the CHR’s current location took place in late July of 2001, things were not settled enough for a formal opening party until September 10. On that day then, however, over twice as many guests as expected showed up because an international embryology conference had brought many colleagues from all over the world to NYC. Once they found out about our party, many came to celebrate with us and we, of course, welcomed them with open arms. We, indeed, considered this coincidence a wonderful omen for what was to come for the CHR, - and we were not incorrect!

For the next day - the infamous September 11, 2001, - we had scheduled a GrandRounds event at The Russian Tea Room, for which over 200 local gynecology colleagues had registered. Unsurprisingly, of course, this event never took place!

Now, almost 25 years after these two forever unforgettably linked days, the CHR will, on September 9, 2026, be celebrating its 25^th Anniversary in NYC with yet another, - even bigger party, - this time a Gala with good food, dancing, and other entertainment at Guastavino’s. And this time, we are hoping for even more guests, - a good number again from overseas - even without a medical conference in town.

After 25 years at the current location, the CHR is today a very different organization from what it was then. In this quarter of a century, the CHR, because of its research and clinical accomplishments, has evolved from a well-known U.S. fertility center to a worldwide recognized fertility center of last resort, - recognized as such not only by patients and colleagues, but also by practically all current AI platforms.

Some of the Most Special Research Accomplishments of the CHR Over the Years

• The first IVF center in the Midwest (in Chicago) and one of a small number of first-generation IVF clinics in the U.S.

• I was given the honor of being appointed as the founding Editor-in-Chief of the world’s first IVF journal, The Journal of In Vitro Fertilization and Embryo Transfer (J IVF-ET), later renamed to its current name Journal of Assisted Reproduction and Genetics (JARG), a position I held for almost 20 years. I was followed in this appointment by David F. Albertini, PhD, a past Laboratory Section Head at the CHR and now for many years a Visiting Senior Scientist. And he, of course, will also be the principal science honoree of this year’s 25^th Anniversary Gala in September.

• Concomitantly, I was also appointed as the Founding Editor-in-Chief of the American Journal of Reproductive Immunology (AJRI), which I also led for almost 20 years.

• The CHR became one of the leading clinical and research centers in Reproductive Immunology in the world, with such giants of the field as Alan Beer, MD, and Carolyn Coulam, MD, joining the CHR in Chicago.

• The CHR performed the first vaginal egg retrieval in the world, - reported in The Lancet, which radically changed IVF practice by taking IVF out of the operating room (egg retrievals until then were performed by laparoscopy only).

• The CHR performed the first transvaginal tubal catheterization procedure to unclog obstructed fallopian tubes and, shortly thereafter, reported a multicenter study of this new procedure in the Journal of the American Medical Association (JAMA), which established beyond reasonable doubt that an ambulatory procedure without anesthesia could in many cases replace major tubal surgery.

• After moving to New York City, the CHR was the first to report the benefits of androgen supplementation in hypo-androgenic infertile women, - a subject addressed since then in over 40 peer-reviewed publications and awarded several U.S. patents.

• In 2006 – after recalculating published studies by Belgian investigators – the CHR’s investigators were the first to argue that the chromosomal testing of embryos (then called preimplantation genetic screening, PGS, and now called preimplantation genetic testing for aneuploidy, PGT-A) did not - as claimed - improve IVF cycle outcomes and in older women, indeed, could reduce pregnancy chances. Their paper was, however, uniformly rejected by medical journals until Dutch colleagues reported a prospectively randomized study making exactly this point in The New England Journal of Medicine, at which time the Editor-in-Chief of Fertility and Sterility, who previously rejected the paper, recalled and published it in 2008. The American Society for Reproductive Medicine (ASRM) only in September of 2024 in a formal policy statement for the first time recognized that PGT-A did not improve any IVF cycle outcomes in unselected patients.

• In 2009, I was honored by the British Fertility Society as an IVF pioneer by being invited to deliver the Patrick Steptoe Memorial Lecture, one of the Society’s most prestigious distinctions, “Recognizing major contributions to reproductive medicine.” This lectureship is awarded only to internationally recognized leaders in the field, and pioneers in IVF and reproductive endocrinology.

• In 2015, the CHR’s investigators were the first to report that the intrafollicular metabolism of ovarian follicles was speeding up with advancing female age, resulting in progressively earlier luteinization of follicles, - only preventable by progressively earlier retrievals. In doing so, the CHR broke a dogma in IVF that existed since the earliest days of the procedure, - that IVF cycles should be triggered only once the lead follicle reaches a size of 18-23 mm.

• In 2023, CHR investigators, moreover, were the first to report that nature also appears to support earlier egg retrievals as women age by breaking another IVF dogma that existed since the earliest days of the procedure, - namely that the different maturity grades of oocytes, - MII (mature), MI (mildly immature), and GV (very immature) - maintained their levels of functionality with advancing age in producing good-quality embryos by demonstrating that mature MII oocytes (in IVF routinely the desired maturity grade to this day) progressively lost this ability while severely immature GV oocytes progressively improved their ability to produce good-quality embryos (mildly immature MI oocytes maintain their ability, though demonstrate a mild trend toward improvement).

• In 2025, the CHR’s investigators filed a patent that describes a sonographic phenotype of follicles that allows judgment about a follicle’s (and its oocyte’s) maturity and thereby further improves the timing of ovulation trigger and egg retrieval. In conducting this research, the investigators discovered that a third longstanding IVF dogma had been broken, which assumed that the largest follicle always contained the most mature oocyte.

Many more “firsts” have been reported in all those years in over 500 peer-reviewed CHR publications in reproductive immunology and on genetic subjects (the CHR, for example, has reported important findings regarding the FMR1 gene, - also called the fragile X gene) and regarding a variety of widely used IVF practices often called “add-ons” to IVF.

The Single Most Important CHR Accomplishment

Likely the most important contribution of the CHR to infertility practice – and still not recognized by far too many colleagues - has been the fact that the CHR never accepted the widely-held notion in the IVF field in the U.S - and really worldwide - that women after ages 42 to 43 practically no longer have reasonable pregnancy chances with their own (autologous) eggs and, therefore, at those ages, should be automatically advanced into third-party egg donation.

By not accepting this notion, the CHR was forced to improve IVF outcomes in older women and/or in younger women with premature ovarian aging (POA). As a consequence, the CHR – in contrast to most other IVF clinics – slowly “learned” through in-house research (all published) how - egg by egg and embryo by embryo - IVF cycle outcomes could even be improved in old women. The CHR’s so-far oldest patient who delivered an autologous child after IVF (of course, also reported in the literature) was two weeks short of her 48^th birthday when transferred. She, to this day, has remained the oldest patient having had a healthy delivery following this type of IVF in the medical literature, even though a slightly older CHR patient conceived but – unfortunately – miscarried.

Now serving the by-far oldest infertile patient population in the U.S. (our median patient age in the last 3 years was between 44 and 45 years vs. 36 years for all U.S. IVF clinics) – and likely in the world – the CHR has been successful in improving pregnancy rates in women who have at least one cleavage-stage (day-3) embryo for transfer from 8% in 2022 to 10% in 2023, and to 12% in 2024 and 2025 (the manuscript reporting these improvements is in Reprod Biomed Online).

While these are, of course, much lower numbers than achieved in younger infertile women, they significantly exceed widely quoted rates that many colleagues use in their discussions with women above age 42-43 (the pregnancy chance often quoted is only 1% to 2%). These numbers, of course, establish a radically wrong paradigm for patients, which can be difficult to overcome when it is presented as fact by their treating physicians since it, of course, then fully supports the argument new presenting patients at the CHR almost always quote to have been exposed to, - that “third-party egg donation represented their only reasonable remaining pregnancy chance.”

We are “fighting for every egg and embryo,” which has been a principal motto at the CHR over many years. While following this motto has been a slow and rather arduous fight within the community of providers of fertility services, it - nevertheless - has been highly rewarding, and not only for the worldwide patient clientele the CHR has come to serve over the years, - but for us - the CHR staff - who feel especially rewarded for having had the privilege of learning and applying new treatments that between 2022 and 2025 allowed the CHR to increase patients’ chances to conceive with their own eggs by one third!

And the Circle Closes – Transitioning the CHR to a New Generation, while Expanding Educational and Research Support Through the Not-for-Profit FRM

We very much hope to see many of our past and current patients, colleagues, whether in labs or on the clinical side, whether collaborators or friendly competitors and, of course, as many friends and purveyors as possible at our 25^th Anniversary Gala on September 9 at Guastavino’s. And, as already noted, if your CHR babies are over 14 years old or if you yourself reading this are a CHR baby, you are invited for free and we will have special tabs for CHR babies (even if still in the uterus).

Not only is the Gala going to be a fun event with great music in a spectacular space and with very good food, but – hopefully, like the FRMC, it will become an annual event. Now in its 8^th year, the FRMC for several reasons greatly impacted the fertility field internationally from the very beginning. There were the mottos, “Think differently” and “Hear it for the first time,” clearly distinguishing the conference from everything else offered anywhere in the world.

And then there was the principal idea behind the conference, - over two-and-a-half days bringing together leading basic scientists and clinicians in one (fancy) room of the Metropolitan Club with clinicians learning what was new in research laboratories and basic scientists from those laboratories learning what knowledge clinicians needed developed in their labs.

Such a conference did not exist anywhere else in the world before the FRMC came about, though some have - with limited success - started to try to copy some of its features since then. But certain ideas are hard to duplicate, such as choosing the right topics and faculty of speakers. And apropos speakers, getting invited as a speaker has achieved a certain cachet, reflecting recognition of the impressive nature of a speaker’s work. To be invited as a member of the faculty club has, therefore, become quite popular.

That the conference always takes place on the weekend following Thanksgiving, smack in the middle of the pre-Christmas/Chanukah shopping season, also does not hurt (who does not want to shop in NYC at that time?). Of course, it’s also an expensive time to organize a conference in NYC because of high venue costs.

The annual FRMC and the hopefully soon-to-be annual FRM Gala, this year celebrating the CHR’s 25^th Anniversary in NYC, are the two big FRM events of 2026; but they are not all the foundation is doing. There are the almost monthly GrandRounds that bring prominent speakers to the CHR, - often later also participating in the FRMC. And then there are the fellowships the FRM sponsors intermittently at the CHR. The CHR, for example, would not have had the opportunity to discover what a star Sonia Gayete-Lafuente, MD, PhD, really was in the field of infertility – and, therefore, hire her into a senior attending physician position at CHR – were it not for the FRM fellowship she held for two years before that.

The CHR, therefore, over the years has become increasingly dependent on the FRM. Considering the notably increasing growth of the CHR over the last year, the CHR had to be hyperactive to meet its educational and research needs. In the appendix to this article, readers, therefore, will find the links for attending this year’s 25^th Anniversary Gala on September 9, 2026, and/or registering for the 2026 FRMC between December 4 and 6, 2026. The Gala offers individual seating (if you have preferences with whom you would like to sit, - please let us know; we will do our best to accommodate you) or, if you want to invite your whole family, your office, or just a bunch of friends, tables that seat either 8 or 10 people.

The more we see of you, the happier you make us!

The appendix also offers information about other FRMC-related topics, like the abstract submission deadline and link, and the greatly reduced early bird registration fees for the FRMC (along with various other discounts).

Finally, the FRM very much welcomes donations to the foundation’s general endowment fund, which, of course, are deductible according to the law. If you have questions regarding reservations for the Gala, registrations for the FRMC, or potential donations to the FRM, please contact Lyka Mochizuki, MS, who is our case manager for both events. She can be reached by email at lyka@thechr.com or by telephone through the CHR operator at (212) 994 4400.

As we already noted in an earlier section of this article, the CHR and, therefore, with it the FRM, have in 2026 started a 5-year transition period toward a next generation of leadership and we are hoping in the process to expand the current footprints of postgraduate educational activities and research support in an attempt to take advantage of the truly unique patient population the CHR has come to serve.

We are certain that no other IVF clinic in the U.S. or anywhere else in the world serves a similarly selected patient population, especially because the CHR’s patients are on average almost 10 years older than patients in all other U.S. IVF clinics (and probably also in clinics elsewhere in the world). The CHR, therefore, has many unique opportunities for research, and so do pharma and other industrial companies with a commercial interest in the infertility field.

We are looking forward to seeing you at both events. The gala will offer good food, fun, and dancing; the FRMC will be hard work but also plenty of fun at our social events.

APPENDIX

25^TH ANNIVERSARY GALA

Date: Wednesday, September 9, 2026 • 7pm

Venue: Guastavino’s, 409 East 59th Street, New York, NY

Table Reservations (seats of 8 or 10): 8 -- $6,500) 10 -- $8,000) for family members, colleagues, and/or friends here: https://givebutter.com/chr-25th-anniversary-gala-5eogtt

Individual Seating ($750 per person):

Please indicate any seating preferences with others when you register and reserve here: https://givebutter.com/chr-25th-anniversary-gala-general-admission-4icmdx

“CHR babies” above age 14 are welcome to attend free of charge — please email gala@thechr.com or call (212) 994-4400 to arrange your tickets. Tickets and donations are tax-deductible as determined by law. The Foundation for Reproductive Medicine is a 501(c)(3) organization, EIN 81-4615550.

General donations to the Foundation are also welcome at: https://www.zeffy.com/en-US/donation-form/because-every-family-deserves-more-time-help-us-fund-the-research-that-gives-it-to-them

2026 FOUNDATION FOR REPRODUCTIVE MEDICINE CONFERENCE (FRMC)

Dates: December 4–6, 2026

Venue: Metropolitan Club, 1 East 60^th Street, New York, NY

CME-accredited for up to 20 AMA PRA Category 1 Credits™. RNs and NPs can earn 20 CBRN-approved CE credits.

Registration: Early-bird and several other discounts are available here: https://whova.com/portal/registration/GM2LL8NP2n7gCLCnO9y-/

Interns, residents, and postdocs – with a certification letter from their department or laboratory – are offered free registration.

Abstract Submissions:

Deadline: September 18, 2026. Previously unpublished submissions are accepted in basic reproductive biology and clinical reproductive endocrinology and infertility, following standard ASRM abstract format. Submit via email to jtapper@thechr.com. Accepted abstracts will be given a 15-minute time slot for an oral presentation (10 minutes presentation, 5 minutes discussion) on Saturday, December 5.

A BEST POSTER AWARD OF $1,000 will go to one or up to 3 submitted posters.

For more information, visit https://www.foundationforreprodmed.com/ or contact Lyka Mochizuki, MS, Project Manager of CHR and FRMC, at gala@thechr.com or (212) 994-4400 ext 4435.

We in our most recent posting on May 8 noted that medicine in general is complicated. Today’s posting makes the same point for reproductive medicine by offering a potpourri of interesting recent articles from the medical literature. We on purpose also included some clinical papers to balance out some of the hard science in other papers. But in combination, all of today’s discussed papers demonstrate the amazing breadth of reproductive biology and medicine. We are so lucky!

The CHR’s Editorial Staff

Prophylactic Salpingectomy to Prevent Ovarian/Peritoneal Cancer

Now that it is well established that a considerable majority of serous ovarian cancers - once believed to be of ovarian in origin - are really of tubal origin, - the question of whether to perform opportunistic and/or prophylactic bilateral salpingectomies has once again come to the forefront. And an answer to this question is what a huge group of investigators from all over the world recently investigated and in a Research letter reported in JAMA Network Open.¹

In this retrospective cohort study from British Columbia, the investigators added up data from preliminary studies, thereby demonstrating added evidence of effectiveness for tubal such removal. Patients who underwent the surgery reduced their risk for mucinous cancers by almost 80%. In a secondary outcome, they also reported significantly fewer high grade serous mucinous malignant tumors.

Clearly a milestone!

And related, - the European Society of Gynaecological Oncology just published a Consensus Statement on the subject, identifying 230 studies on the topic, of which 129 were deemed relevant to consensus statement development. Consensus was achieved on 18 statements, with grades of recommendation ranging from B to D and levels of evidence from II to V.

Opportunistic salpingectomy was found significantly associated with a lower risk of subsequent tubo-ovarian carcinoma, with no adverse short-term impact on ovarian function. The procedure appears safe across surgical approaches, with little additional operative time. Existing evidence does not indicate harm to ovarian function or premature menopause, although long-term evidence is not available.

Salpingectomy is feasible during both gynecological and nongynecological procedures and should be considered in women undergoing gynecological surgery and, where possible, in women undergoing selected nongynecological pelvic or abdominal surgeries.

REFERENCES

1. Sowamber et al., JAMA Network Open 2026;9(2):e2557267

2. Piek et al., JAMA 2026;335(10):894-902

Immune Cells That Prepare the Uterus for Pregnancy

We have repeatedly pointed out before in these pages that pregnancy is primarily not – as widely assumed - an endocrine but an immune phenomenon. The reason is simple: Many days before an implanting embryo makes contact with the maternal vascular system and, therefore, receives systematic maternal contributions for its development, the mother must locally develop tolerance to the embryonic fetal semi-allograft [it is a full allograft in cases of gestational carrier or donor oocyte pregnancy].

Now a study by Australian investigators reported that seminal fluid expands the uterine gamma/delta T cell population in early pregnancy in mice.¹ CD4⁺ and CD8⁺ T cells accumulated in the endometrium after mating. The cells that expanded, however, in abundance accumulated after mating were a distinctive type of T cells called gd T cells, which have characteristics of both innate and adaptive immune cells. These cells also had characteristics of elevated activation and proliferation, suggesting that it is seminal plasma rather than sperm that may be critical for preparing the endometrium for implantation.

The concept that seminal plasma may enhance the chance of implantation in IVF cycles is nothing new.² In prior human studies, seminal plasma infusions into the uterus usually, however, were done at time of oocyte retrieval. These data may suggest that the endometrium requires more time to achieve the desired effects on endometrium, further suggesting that seminal plasma infusions may have to be performed around ovulation.

If also confirmed in humans, this could be a breakthrough!

REFERENCES

1. Foyle et al., Mucosal Immunol 2026;19(1):P1650-1665

2. Crawford et al., Hum Reprod Update 2015;21(2):275-284

Could Human Embryos Achieve Diapause?

Some mammals can interrupt the establishment of pregnancy, - a process called embryonic diapause that is active in hundreds of mammals, from mice to moose. But how they do it has not been discovered. Now a study by the laboratory of Alexander Tarakhovsky, PhD, at Rockefeller University in NYC and collaborators from Harvard and Glaxo SmithKline in a paper in Genes & Development reported that transcriptional depression of negative regulators of MAP kinase supports diapause by maintenance of diapause ES cells in pluripotent state.¹

Nutrient deficiency during pregnancy can induce embryonic diapause characterized by systemic changes that minimize reliance on external energy sources while ensuring survival. These changes do not affect the pluripotent state of embryonic stem (ES) cells, allowing normal development once diapause ends. The investigators in this paper identified a transcriptional mechanism that maintained ES cell pluripotency during diapause.

Inhibition of mTOR, which induces a diapause-like state in ES cells, rapidly upregulated genes encoding negative regulators of the MAP kinase (NRMAPK) pathway, a key driver of ES cell differentiation. Elevated NRMAPK expression and associated suppression of MAP kinase activity are also hallmarks of ES cells driven into diapause-like states by long-term inhibition of BET proteins, which regulate differentiation- and growth-promoting gene expression. Suppression of NRMAPK in diapause-like ES cells lead to differentiation and termination of the diapause-like state. Mechanistically, diapause-associated NRMAPK activation involved mTOR or BET inhibition-triggered release of the transcriptional repressor Capicua (CIC) from NRMAPK gene promoters.

This data highlighted a key role for mTOR- and BET-controlled transcriptional regulation of MAP kinase activity via negative regulators in maintaining the pluripotent state of diapause ES cells and potentially other metabolically dormant stem or stem-like cells.

This is, of course, a potentially groundbreaking mouse paper with not only a variety of potential implications for human pregnancy, but also for cancer treatment since cancer stem cells are known to survive in a diapause-like state in tissue. Though more speculative, one other possible application comes to mind, - the years-long survival of primordial follicles in ovaries in resting stage.

A fascinating paper! We had scheduled its senior author for GrandRounds at the CHR on May 5. Unfortunately, he had to cancel and we hope to reschedule after the summer break.

REFERENCE

1. Zhang et al., Genes & Development 2026;40:319-327

Improving the Functional Ovarian Reserve (FOR) Even in POI Patients

Japanese investigators just demonstrated in an article in PNAS that in addition to hormones, mechanical stress plays a role in in maintaining the balance between dormancy and activation of these follicles.¹ External pressure on oocytes directly leads to nuclear import of the transcription factor FOXO3, which induces changes downstream in signaling that suppress follicle activation and growth.

And in a Research Article in Science Summary, Lin et al reported that finerenone (Kerendia®, Bayer) – by the FDA categorized as alone in its drug class as a nonsteroidal MRA that selectively a potently blocks MR (mineralocorticoid receptor for aldosterone) overactivation (see figure below) and is considered an antifibrotic drug. The investigators systematically screened 1,297 compounds from an FDA-approved drug library before identifying finerenone.

After initially demonstrating that the drug promoted follicular development in mice with no adverse effects on oocyte quality, early embryo development or offspring health, they now demonstrated that clinical administration of 20mg twice weekly promoted the development of follicles in patients with primary ovarian insufficiency (POI) under age 40, yielding mature eggs and viable embryos.

They were also able to demonstrate that the drug reduced collagen depositions (i.e., fibrosis) within aged ovaries, thereby reducing stromal fibrosis-mediated restriction of follicular development and producing a more permissive microenvironment for follicle activation and growth.

The investigators in addition identified other oral FDA-approved antifibrotic drugs, including nintedanib (Ofev® and Vegatev®), - an oral tyrosine kinase inhibitor slowing idiopathic pulmonary fibrosis and systemic sclerosis-associated lung disease by blocking growth factor receptors), ruxolitinib (Jakafy®, - a Janus kinase – JAK – inhibitor used to treat myelofibrosis, polycythemia, and graft vs, host disease -GVHD) and others also effective in inducing follicle growth. Finerenone appears, however, so-far to have the least side effects.

The authors from these studies concluded that anti-fibrotic drugs could be in general repurposed to treat POI.

This remarkable article was followed by a Perspective article by two Miami-based scientists, in which they extensively reviewed the literature in support of the hypothesis that ovarian fibrosis inhibits follicle development and that, therefore, anti-fibrotic drugs can, indeed, be expected to help.³

Here is a little more detail: It is well established that even women in full menopause still have follicles in their ovaries. So how come they no longer respond to stimulation? Research in 2024 and 2025 demonstrated that increasing inflammation (every ovulation is basically an inflammatory event) and collagen deposition (due to the following fibrosis), render the ovary stiffer, which, in turn, increases intraovarian pressure, which leads to poor follicle response to gonadotropins. This increasingly fibrotic and stiff microenvironment then prevents follicles from expanding and from responding properly to stimulation. The results are anovulation and infertility (see figure below).

Under normal healing conditions in response to injury, tissue remodels with tissue regeneration without permanent damage. Cyclic changes in the production and degradation of extracellular matrix (ECM) are part of normal cyclic process of ovarian follicle development. As the ovary ages, the accumulation of ECM may prevent the usual enzymatic cleavages of the ECM necessary for normal tissue remodeling, which scars the tissues, leading to the loss of normal ovarian functions. As tissue fibrosis is frequently accompanied by innate and adaptive inflammatory processes, increased fibrosis in the ovarian stroma can then disrupt normal folliculogenesis in patients and do so earlier than normal in patients with POA or POI. In addition, there is evidence that age-related changes in the ovarian microenvironment may damage the proper primordial follicle assembly with stem cells, and the loss of primordial follicles may itself accelerate the aging process.

According to the already above referenced review article,⁴ approximately 60% of women with low ovarian reserve – whether due to physiologic or premature ovarian aging - have undetectable basal stromal blood flow in at least one ovary, while only 6% of women with good ovarian reserve have undetectable flow in at least one ovary, suggesting that alterations in the ovarian stromal vasculature may be associated with the pathophysiology of ovarian aging. This assumption was several years ago indeed confirmed by the CHR’s Visiting Senior Scientist, Pasquale Patrizio, MD, - when he still was at Yale University (he is now at much warmer Miller School of Medicine of Miami University).⁵ Normal aging in association with ovarian tissue fibrosis was also in parallel demonstrated to be associated with blood vessel damage.

In summary, a more comprehensive picture of ovarian aging is becoming apparent, which suggests that therapeutic intervention geared at mechanical processes caused by fibrosis during ovarian aging may be clinically successful in treating “older” ovaries. The CHR is getting ready to initiate a finerenone (Kerendia®, Byer) trial, but that will still take a few months to get started because it – first - will have to be taken through an IRB approval process.

REFERENCES

1. Nagamatsu et al., Proc Natl Acad Sci 2026;123(3):e2526249123

2. Lin Z. Science 2026;391.eadz4075. DOI: 1.1126/science.adz4075

3. Duncan FE, Babayev E. Science. 2026;391(6785):552-553

4. Molinari et al., Mol Hum reprod 2016;22(8):866-876

5. Chang CL. Int J Molec Sci 2023;24(19): 1475

A New, Very Promising Primate Monkey Embryo Model

The number of published stem-cell-based embryo models is by now so big that it is almost impossible to follow them all. Chinese investigators, however, now published in Nature a stem-cell-based monkey embryo model that self-organizes into a comprehensive body plan and, therefore, could lead the way to more sophisticated models of early human development.¹ In a Commentary to this paper in the same journal, two scientists from Washington University School of Medicine in St. Louis, therefore, described this paper as a “leap forward” that should allow the development of similar human models.²

They note that the ultimate test of any model would, of course, be human implantation, - a procedure that is ethically and rightly still unthinkable. A monkey model, however, could allow this and – once there is enough monkey data available to strongly suggest safety, - who knows?

REFERENCES

1. Li et al., Nature 2025;649(8095):161-172

2. Kong X, Theunissen TW. Nature 2026;649:34-35

Is Autism Not Really a Male-dominated Disorder?

A recent paper in the BMJ involving 2,756,779 liveborn children in the Swedish medical birth registry produced quite surprising results by demonstrating that the male to female ratio of autism decreased over time and with increasing age at diagnosis.¹ They concluded that the ratio, therefore, may be substantially lower than believed so-far and, indeed, may (at least in Sweden) be very similar between the sexes. The reason is that women are diagnosed later than males. Why that would be, is still undetermined. The paper also does not inform of differences in severity of the condition. We for the time, therefore, reserve judgment on this issue!

REFERENCE

1. Fyfe et al. BMJ 2026;392:e084164

In our next posting in the coming week we then intend to return again to more specific clinical subjects addressed in the recent medical infertility literature, - even though the today discussed issues very obviously have considerable relevance to the clinical practice of infertility.

The CHR’s Editorial Staff

LOW FUNCTIONAL OVARIAN RESERVE (LFOR) – What it Is and What it Is Not!

By David H. Barad, MD, MS, one of the CHR’s REI physicians, Associate Editor of CHR Publications, Director Clinical IVF, Director of CHR-Research and a Senior Scientist.

Dr. Barad here addresses an important issue in explaining the term ovarian reserve (OR) in its various applications and implications. The terminology can be confusing, starting with the fact that OR reflects all remaining follicles in ovaries and the eggs they contain. A large majority of follicles and eggs exist, however, as very primitive and very small, so-called primordial or resting follicles, - and only a small minority at any given time, - after having been recruited out of this primitive resting stage – become visible on ultrasound as they grow in the ovary toward maturity. It is this part of the OR - called functional ovarian reserve (FOR) – that is important in fertility treatments and is evaluated during IVF cycle monitoring in every patient.

This afternoon, I met a patient who came to our consultation carrying more than lab results, - she carried the weight of having been told that her chances of pregnancy with use of her own eggs were essentially gone!

Based on hormone tests showing low ovarian reserve (OR), she had been advised that in vitro fertilization (IVF) with her own eggs was not an option and that – if she really insisted on continuing to try with autologous eggs – only lower-cost intrauterine inseminations (IUIs) made sense going forward. In other words, - she was refused the chance of an IVF cycle because of her alleged low functional ovarian reserve (LFOR). In two earlier such IUI attempts, one had resulted in an ectopic pregnancy that not only required treatment but – as an undesirable consequence of her LFOR - forced a significant pause in her once more trying to conceive. Even after the ectopic pregnancy experience – potentially suggesting tubal disease - she, therefore rather paradoxically, was still because of LFOR refused IVF by her treating physician(s), even though IVF in women with LFOR in most cases is a much more effective treatment than IUIs, and – in addition - was urged to continue relying on her likely diseased fallopian tubes.

As she told her story, what was bothering her and why she had come to the CHR for a second opinion became quickly obvious: what bothered her was not only her tubal pregnancy; but – after asking several A.I. platforms a few relevant questions, she had started to wonder whether she had allowed a set of numbers assessing her so-called FOR to define her future fertility.

So, what are the tests doctors use to assess FOR, and what do they actually tell us? The most commonly used measures are FSH (follicle-stimulating hormone), AFC (antral follicle count), and AMH (anti-Müllerian hormone). Each of these three tests provides information on FOR but does so from different viewpoints, and none should, therefore, be interpreted in isolation.

FSH is a hormone produced of the pituitary gland that signals the ovaries to begin growing out of their dormant state (as primordial follicles) freshly recruited follicles. As the ovaries’ general ovarian reserve declines with advancing female age and fewer follicles are available for recruitment out of resting stage, the body tries to compensate by producing higher levels of FSH in an effort to stimulate the ovaries harder. Rising FSH is, therefore, not a sign of the ovaries “failing,” but rather of the body pushing harder to get an FSH response.

The AFC., in contrast, is assessed by ultrasound at the beginning of a menstrual cycle and represents the number of so-called small antral follicles visible in the ovaries at that moment in time. Each of these follicles is assumed to contain an at that point an extremely immature egg and, together, they offer a snapshot of how many follicles may be available to respond during the coming cycle. Importantly, AFC can vary from month to month, between ovaries, and even between individuals assessing the ultrasound exam. The AFC, therefore, just reflects what is visible, and not necessarily what is possible. A lower count , therefore, may suggest fewer follicles to work with, - but it does not necessarily predict whether one of those follicles can and/or will develop well enough to mature a healthy egg that after fertilization can produce a healthy embryo, and/or, ultimately, will result in a successful pregnancy.

Finally, AMH is produced by the cells surrounding developing follicles, including indeed the earliest small antral follicles. Because AMH therefore reflects the cumulative activity from such a broad assembly of follicles (many not even yet visible on ultrasound) AMH is often used as a general marker of FOR. One way to think about the meaning of AMH values is to consider what the sound produced in gently shaking a closed box of candy will tell about f how much candy may be inside. But it will not tell you which piece you may pick up next, or how much you will like it.

Because FSH, AFC, and AMH are each looking at ovarian function from different angles, it is not unusual for them to tell slightly different stories. One test may appear more concerning while another more reassuring, and that can be confusing for patients (and at times also for some of our colleagues). These differences do not mean that one test is “right” and the others one is “wrong.” Rather, they reflect the fact that ovarian function is dynamic and varies from cycle to cycle and - especially at more advanced ages – can quickly change.

Hormonal signals and what is visible on ultrasound in a given month, and the activity within smaller follicles do not always move in perfect synchrony. For this reason, experienced clinicians interpret these tests together, and in the context of a patient’s age, history, and prior responses, - rather than relying on any single number (including, of course, age) to define prognosis or guide care.

When these tests are placed into context, they stop being verdicts and start becoming tools that help shape a thoughtful treatment plan, - rather than defining what is or is not possible.

A LFOR in a patient, therefore, should consider how treatment should be approached, - and not whether treatment should be pursued at all!

LFOR usually means that fewer eggs may be available in any given cycle. This, of course, influences how medications are selected, how closely cycles must be monitored, and how expectations should be set appropriately from the outset. It also usually means that care in many of patients with LFOR – whether because of advanced age or because of premature ovarian aging, POA – must be more individualized and, at times, more iteractive, as each IVF cycle provides more information in refining the next cycle. In this context, the FOR guides strategy and planning but not outcomes.

LFOR however almost never automatically means that pregnancy is impossible, that treatment is futile, or that a negative outcome is predetermined. It, therefore, is difficult to understand how many of our colleagues in a case like here addressed can reach the conclusion that IVF is not even worth attempting. The patient, after all, did spontaneously conceive despite her LFOR, - even if it was a tubal pregnancy!

None of here discussed tests of FOR can predict egg quality in a given cycle, the potential of an individual embryo, or whether pregnancy will occur or not. They also cannot account for the natural variability that exists from month to month. While LFOR affects overall probabilities, it does not eliminate them, and it should never be used to close doors prematurely, - as, unfortunately, only too often happens in many IVF clinics.

In routine clinical IVF practice, patients are only too often told that a diagnosis of LFOR automatically excludes them from IVF treatments with use of their own eggs. In the case I described earlier, laboratory values were used to narrow options rather than to guide a broader conversation about strategy and risk.

Decisions like these are often driven by rigid thresholds applied to complex biological circumstances which simply don’t make sense, because probability in these cases is mistaken by the treating physician for certainty. While FOR testing is invaluable for planning care, using these measures as absolute gatekeepers can lead to options being closed prematurely, sometimes without fully accounting for individual circumstances, prior outcomes, or alternative approaches.

If – as noted before – OR reflects how the ovaries are functioning rather than final outcome, then LFOR also shapes how treatment can be thoughtfully individualized.

At the CHR, we therefor use the term FOR to describe not just the number of follicles suggested by testing, but the ovary’s current ability to access and recruit follicles in a given cycle. In other words, a LFOR reflects how the ovary is functioning at that moment in time, - not its fixed or permanent state. The concept of LFOR is that with individualized treatment we have the potential to change the ovarian response.

Because ovarian function is often influenced by the hormonal environment, treatment planning at the CHR includes thoughtful preparation before starting stimulation. In selected patients, this can involve pre-cycle therapies such as dehydroepiandrosterone (DHEA), other androgens, or human growth hormone supplementation (both synergistically with the hormone FSH enhancing follicular growth and maturation) , with the goal of optimizing follicle recruitment and response with the goal of improving LFOR.

We are also actively studying additional approaches aimed at improving how follicles are accessed and how individual follicles function, including carefully designed pre-treatment strategies and metabolic support. What remains unknown is which patients are most likely to benefit from these approaches, how durable any effects may be, and how best to individualize their use. But we are also hard at work to determine these parameters prospectively. The next guest article by Eriona Hysolli, PhD, offers some potential directions.

While none of these strategies can guarantee outcomes, they reflect a broader philosophy: FOR testing should guide how care is tailored, - not limit whether care is offered. At its best, fertility care is a partnership, in which medical expertise and patient goals are weighed together as decisions are made.

For patients facing fertility decisions, it is important to remember that test results are tools meant to guide conversations, not to shut them down. A finding of LFOR should prompt thoughtful planning and open dialogue, - not an automatic narrowing of options. Like fertility itself, - fertility treatments are rarely straightforward, and uncertainty is often part of the process. But uncertainty is not the same as impossibility and is – after all – in humans also integral to spontaneous conception attempts.

Identical treatment protocols for everybody, therefore, by definition cannot make sense and will end up hurting individual patients who deserve time, explanation, and a care planning that reflects their individual goals and values. When decisions are made collaboratively, with clarity and compassion, patients will move forward in their treatment journey feeling heard and truly supported. If treated with rigid protocols, they will perceive themselves – correctly – on an assembly line.

READING LIST

1. Gleicher N. Weghofer A. Barad DH. Improvement in diminished ovarian reserve after dehydroepiandrosterone supplementation.

   Reprod Biomed Online 2010;21(3):360-365

2. Gleicher N, Weghofer A, Barad DH. Defining ovarian reserve to better understand ovarian aging. Reprod Biol Endocrinol 2011;9:23

GUEST COMMENTARY

A NEW METHOD OF GENETIC RISK ELIMINATION IN FEMALE INFERTILITY - The Possibility of Gene Corrections in Oocytes

By Eriona Hysolli, PhD, was a Co-founder of Manhattan Genomics, and is a Member of the CHR Publications’ Editorial Board.

With correction of gene defects in embryos already being a serious goal of research in several academic laboratories and start-ups, Dr Hysolli in this brief commentary on a recently published Chinese paper in Cell Genomics points out that gene defects – theoretically – can also be corrected in oocytes and, when affecting fertility, therefore in the future can play an important role in fertility treatments via in vitro fertilization (IVF).

Introduction

A recent paper published in Cell Genomics by Chen et al, tackled the genetic link of female infertility.¹ While most attention goes to the power of prenatal genetic testing for monogenic disorders, aneuploidy, and polygenic scoring to choose the healthiest (and perhaps in the eyes of many - controversially - the best) embryo, not much attention is drawn to the genetic risk for early developmental defects of the oocyte and embryo that fail to produce a viable embryo in the first place.

This is now a key research area in reproductive medicine with several important questions left to answer: (i) How strong is the genetic link to female infertility, which blocks couples from producing viable

Embryos? (ii) Can we genetically screen oocytes, for infertility risks, - so that a clearer path to prevention and treatment can be charted earlier? And (iii) are there preventative correction pathways we can pursue?

Several genes have been correlated with female infertility in the past. In this study, a larger cohort of ~3600 women in China, who had failed two IVF/ICSI cycles with failures categorized as oocyte defects, abnormal fertilization, and embryo arrest, consented to whole exome sequencing of their blood samples. Sequence analysis revealed that approximately 13% of the cohort presented with - among a few other pathways - sequence mutations in key domains of genes involved in spindle assembly, cell cycle and check points, zona pellucida, maternal mRNA regulation, mitochondrial function, and homologous recombinations,.

As one example, TUBB8, encodes a primate-specific β-tubulin involved in human spindle assembly. Mutations in this gene have been characterized before, - but key was its overrepresentation in these datasets across the three categories of defects.

To capture the human phenotype in IVF/ICSI failure, the researchers conducted mouse functional studies in a few key targets involved in cell cycle regulation, - N-glycosylation and chromosome segregation - which showed embryo developmental arrest upon injection with mutated mRNA (CNTD2, SPDYC) or mRNA knockdown (DDOST, INCENP).

Infertility, of course, remains a complex issue. These findings are an important step toward clarifying the genetic contribution to female infertility and can be crucial for managing fertility treatments in the future.

While only roughly 13% of the cohort exome sequences had distinct mutations, hundreds of genes were

implicated, and more work on non-coding regions, epigenetic landscape, and paternal contributions is needed to comprehensively understand infertility overall; but a new path to a better understanding of human infertility has clearly emerged with this study.

Correction of Mutations in Oocytes and Embryos to Improve Fertility Outcomes -

The concept of germline gene correction has recently been making a powerful comeback in reproductive medicine conversations as well as in public discourse. The emergence of companies like Manhattan Genomics,, Preventive Bio and Bootstrap Bio, has created hope that avoidance of genetic diseases in future generations may become possible using powerful and precise editing technologies like base and

prime editors.

But the high mutational burden in the oocyte genome that contributes to developmental oocyte

as well as embryo defects can also be targeted using the same tools. IVF already can allegedly screen an embryo for PGT-M (monogenic defects), PGT-A (aneuploidy) and PGT-P (polygenic defects). But embryo screening, of course, requires substantial embryo numbers, which infertile women do not always produce in IVF cycles. The number of oocytes in an IVF cycle, however, almost universally exceeds the number of embryos. Corrections at oocyte stage, therefore, would produce obvious numerical advantages.

Gene editors or gene therapy to tackle infertility-producing genetic risks can make a significant impact when coupled with knowledge from omics analysis and better prediction algorithms. When used

thoughtfully and appropriately, gene correction or gene therapy for infertility risk at the oocyte and/or embryo stage ultimately will ensure more embryos for transfer into the patient’s uterus. And conception with such an embryos makes the genetic change also permanent for future generations, thus allowing them to avoid significant future infertility risks.

Such oocyte editing has already been established in multiple livestock species as well as non-human primates. It is time we move – at least in the research arena - towards integrating genomics into IVF cycle planning, and even bolder, open the path of exploration to gene correcting intervention of oocytes and embryos for infertility management and disease prevention in the human experience.

REFERENCE

1. Chen et al. Genetic Landscape of Human Oocyte/Embryo Defects. Cell Genomics 6, 101012

   January 14, 2026. https://doi.org/10.1016/j.xgen.2025.101012

General Medical News with Implications for Infertility Practice

Even the AMA Now Recognizes the Need to Rebuild Trust in Evidence-based Health Information

It was nice to see at least one recent communication from the American Medical Association (AMA) that is not only driven by politics and/or ideology: In a press release on March 5, 2026, the AMA reported the results of a new public opinion survey by the Annenberg Public Policy Center which “high-lightened the widening trust gap in the nation’s health information landscape and underscore the importance of trusted medical voices grounded in science.”¹

Considering the increasing politization of the AMA in recent years, this press release is almost an oxymoron, - but better late than never and better incomplete than not at all. A probably, however, more realistic inside into the AMA’s thinking comes likely from the press release’s last two sentences and we quote: “The AMA continues to advocate for science-driven health policy and clear communication grounded in the best available evidence in support of patients and physicians. The AMA recognizes the need for a strong health system that can foster and sustain a healthier future for everyone across our nation.”

Two comments regarding these two sentences: (i) Of course no “mea culpa” from the AMA for so many obviously – at least in retrospect – harmful AMA policies and practices in the recent past, - including at times quite disastrous comments and recommendations during the COVID-19 pandemic or the AMA’s quite aggressive initial support for medical gender transition for children and young adults. And (ii) Do we read the last sentence correctly by interpreting it as the AMA now supporting a national government “owned” health system?

If that is a yes, - many of the CHR’s Canadian patients may be the most unhappy, - no longer being able, after quickly crossing the border, to get medical services in the U.S. - including even simple blood tests - their own national health care system either does not offer at all or only with incredibly long delays. This is, indeed, how government – managed national health systems attempt to control costs, - constantly declining service quality.

REFERENCE

1. AMA. Press Release. March 5, 2026. Httpd:///www.ama-assn.org/press-center/ama-press-release/survey-shows-need-rebuild-trust-evidence-based-health-information

Why Is It So Difficult to Stop Pointless Medical Interventions?

This is, of course, a question we – here at the CHR – are constantly asking – too many times indeed – considering the many treatments in infertility practice which are routinely used, even though no evidence exists for any real clinical utility. The probably most consequential is, of course, preimplantation genetic testing for aneuploidy (PGT-A) where even the ASRM finally reached the conclusion that PGT-A does not confer any outcome benefit on IVF cycles.¹

Yet over half of all U.S. IVF cycles – even often including donor egg recipient cycles – now routinely involve donor oocytes from very young donors – strong evidence that many colleagues now consider PGT-A a routine part of IVF. A good number of clinics by now, indeed, refuse treatment if patients object to the utilization of PGT-A.

But this problem does not only exist in the fertility arena (though it is, likely more prevalent than in most other medical specialties), - but, as a recent Opinion article in the BMJ pointed out, also exists elsewhere in medicine.² And, based on his own behavior, the author – an intensivist - made a very interesting point in his commentary: “ You can (yourself) publish all the evidence and (may) still struggle to unlearn a habit.”

He described at least part of the problem as structural because the ability to charge for one’s activity rewards the activity, - as the feedback loop on harm is in general only very faint. The article also notes that in 2019 NHS in the UK published a list of 17 interventions judged inappropriate outside of defined circumstances, leaving the impression that this publication would result in decisive change. Yet nothing happened at all after the guidance was issued! Does this sound familiar to what is happening in infertility practice?

We could probably list 17 such interventions with ease in infertility practice alone! And more relevant information on this issue in the next commentary.

REFERENCE

1. Practice Committees of the ASRM and SART. Fertil Steril 2024;122(3):421-432

2. Morgan M. BMJ 2026;392:s374

Causal Inference in Medical Practice – How Certain is A the Cause of B?

Because of the preceding commentary, we here once more are bringing to attention two articles in the BMJ which disagree with each other to a degree on causal inference in medical research.^1,2

So what is causal interference and why does it relate to the unavoidable uncertainty in medicine and science in general?

It is basically the process that determines whether an event A is caused by another event B or not; and that is, of course, a question asked in medicine and science all the time. It has, however, also been studied in philosophy, machine learning, psychology and, of course, statistics.³ It practically always boils down to the degree in which causal interference is based on controlled and uncontrolled observations.

You by now may be asking why would the BMJ publish two such contradictory essays regarding this subject, why we would spend valuable space on discussing , and what the two essays disagreed on?

To answer both of these two simple questions let us start with how Alex Broadbent, a Professor of Philosophy of Science at Durham University in South Africa explained the principal issue: Once a year he has been baking a Christmas cake, using always the same recipe. Yet the results always varied and that, in his mind, of course, raises the question, - why?

At least two hypotheses could explain the reason(s) for the observed variability,: A first he proposed was not a very serious one, - what he called “naughty elves” (a funny but not a very likely explanation). But a second hypothesis made more sense, - namely that ingredients he used and/or how he had handled them in the baking process had been inconsistent (likely the correct explanation).

He, therefore, first-of-all would have to figure out what exactly had caused these differences and, - unless he then perfectly succeeded in adjusting the process of baking uniformly every year (of course with great likelihood an unachievable goal for a human), one has to conclude that variability is unavoidable.

And this conclusion, of course, leads automatically to a second question: What are all those variabilities that arise? And the answer, of course, is that, simply from observation (even assuming we observe ourselves) we can never fully register and, therefore, consider and perfectly adjust – all of those variabilities. Broadbent, therefore, perfectly logically concluded that ”no method ever can take observational data and mechanically deliver causation.”

In other words, no observational study can ever with absolute certainty establish causality! And quoting him again: “Uncomfortable as it may be to admit, the nature of causation isn’t fully understood, and thus no satisfactory definition has been found. Perhaps the most useful thing philosophy (therefore) can offer doctors, confronted with huge numbers of complex studies, is the reminder that some questions really do remain open.”

The second essay by Timothy Feeney, MD, MPH, currently a postdoctoral research fellow at Boston University and Paul Zivich, PhD, assistant professor in the Department of Epidemiology at the University of North Carolina, in Chapel Hill followed a different line of thought but in reality really ended up not too far from Broadbent..

They in their essay concluded that researchers must “fully understand the underlying assumptions to uncover cause and effect” (so-far they make sense).

Though – at least on the surface this sounds more optimistic and doable than Broadbent’s “pessimism,” – and was presented as a contrarian opinion to the first paper, we – frankly – don’t see much of a difference between the two papers. Quoting this time verbatim from their paper, how they described the paper’s “key point” will explain why we reached this conclusion: ”Health researchers in medical care can’t solely rely on statistical analysis to uncover relations between cause and effect (we agree). To do this, they claim researchers need to have a clearly defined question and must articulate a so-called ‘estimand’ corresponding to this question.“

We, of course, never before even heard the term “estimand.” The authors, however, graciously defined the term as “the quantities a study aims to estimate” (note the word “estimate,” of course – once again – eliminates all certainty).

And to continue quoting them: “The researchers then must be able to translate from observed data to that causal ‘estimand’ and conceptualize an appropriate way of collecting the relevant data.” And one more quote: “The investigators (of, course) must critically understand the underlying assumptions and know how to design a study to obtain the estimates of interest. Only after the ‘estimands’ are formally defined can researchers consider how these ‘estimands’ might be learnt from observations of the world, a process often referred to as ‘dentification’ that entails mapping an ‘estimand’ to observed data.”

In short – while all of these efforts may come close to certainty, the authors’ own words once more reflect the fact that getting closer does not mean establishing causation beyond doubt (i.e., establishing proof). Sisyphus’s bolder is still rolling back down the hill before reaching the top of the mountain!

REFERENCES

1. Broadbent A. BMJ 2025;391:r2615

2. Feeney T, Zivich P. BMJ 2025;391:r2618

Though we, of course, do not want a health care system like in - for example - Canada with its unbelievable difficulties in even getting just simple testing done (the CHR’s Canadian patients often cross the border, - just for blood draws), it is undeniable that U.S. health care has become too expensive.

That our today’s posting therefore addresses issues within the business of medicine should not surprise. And even though many principle problems, of course, apply to all of medicine, small specialty areas like infertility will, of course – as here presented today, have at time their own peculiarities,

As always, - let us know what you think!

The CHR’s Editorial Staff

Even the Endowments of the Ivy League Are Staying Away from Investing in Private Capital

Yes, - investment money is not available as easily as it used to be: Even Ivy League universities, which in recent years heavily invested especially in Private Equity (PE), are holding back, as a recent Wall Street Journal article pointed out.¹ As the article noted, PE in past years considered the endowments of major universities among its largest and most loyal clients. But with returns struggling to even match broader stock-market benchmarks, - those days are over.

As the article noted, Princeton University lowered its expectations regarding its endowment’s returns, Yale trimmed its portfolio, and Harvard announced cashing out of some private-market investments. More to come here on this subject in the near future!

REFERENCE

1. Gillers H. The Wall Street Journal, February 15, 2026. https://www.wsj.com/finance/investing/the-ivies-are-having-second-thoughts-about-investing-in-private-equity-de04e52a

Direct to Consumers Drug Advertisements Once Again Under Discussion

The New York Times recently addressed in an article by Paula Span direct to consumer marketing of medications, - a debate dating back to 1997, when the FDA loosened restrictions and allowed advertisements of prescription drugs. As the article noted, research demonstrated that these ads influence prescription rates and – except for New Zealand and the U.S, - no other country allows such advertisements (and in the U.S., the AMA has been strongly opposing this kind of prescription drug advertisement).

One expert is quoted in the article as noting that, “often really good drugs sell themselves.” Drugs without added therapeutic values are then the ones that require “to be pushed” and these are the medication we then see on TV.

And in this rare instance, we, indeed, do agree with the AMA because we do not understand how such advertisement can benefit anybody. Starting with the consumer, what does she/he have there to gain? If the patient has to tell the doctor which medication to prescribe, the only thing we can recommend to the patient is to choose another physician! And to the physicians who need to be told by their patients what to prescribe, - maybe it’s time for retirement, - or at least some serious CME.

And then there is also the issue with food supplements!

They by now may very well represent a majority of all adds on television (it’s at least close!) claiming all kinds of “miraculous” benefits. This industry also needs a serious review sale of food-supplements, indeed, also should undergo review Dietary supplements now represent a $65-70 plus billion (yes, billions!) and by 2030 is expected to exceed $130 billion. And if you define the field even broader by, for example adding sports nutrition and functional products, the market size in 2025 already represented approximately $113.6 billion.

Watching the daily onslaught of advertisements on television, the hubris in this marketplace, indeed, appears even more out of control than on the pharma side and, of course, is mostly not under the control of prescribing physicians.

REFERENCE

1. Span P. The New York Times. February 17, 2026,. pD3

The Disappointment with Highly Touted Blood-screening Tests for Multiple Cancers – just another example for the predatory behavior of the genetic testing industry

Especially over the last year, the medical literature reported on several proposed blood tests for early cancer detection claiming to be able to detect individual cancers or even a whole bunch of them together before cancers produce symptoms or other tests can reveal them. Early detection in almost all cancers, of course, promises better cure rates and expectations for these tests, therefore, have been very high.

The New York Times and other news outfits between, however, earlier this year suddenly reported that claimed outcome benefits turned out not to be what had been represented. And if this makes you think of other widely touted tests in medicine that greatly overpromised (like, for example preimplantation genetic testing for aneuploidy, PGT-A, among a good number of other examples in the infertility field) you would not be mistaken.

One of the most prominent among those cancer screening tests has been the so-called Graiil’s test, so named after the company, Grail Inc., which has been selling this test - also called Galleri - to the public since 2021 at a cost of US$ 949 per blood sample. This company, however now – after five years on the market with this test and claiming it detected several cancers early – finally concluded a prospective study with very disappointing results.¹

In a very large prospective study conducted in the UK in collaboration with the country’s National Health Service, the blood test basically failed to achieve the main goal of the study, – accurate and early cancer detection.² And one, therefore, really must ask on what basis this test was sold to the public for over five years?

Here is some background: This tests – like practically all of these early detection cancer tests – looks in blood for tiny amounts of cancer-associated DNA. Galleri supposedly does it for over 50 different cancers, - of course an amazing achievement, - if it works!

As noted above, the study, however, offered only disappointing results and, according to Reuters, Grail’s shares as a consequence lost 50% of their value.³ But here is the real scandal: Selling the test to the public under – as now well established – exaggerated promises since 2021, Grail in 2025 alone, according to STAT, sold 185,000 tests which produced US$ 136.8million in revenue for a by the FDA still unapproved test.

And you now may rightly ask, - how is this possible? And the answer is simply exactly the same as for too many other tests currently sold by the laboratory testing industry to the public with often greatly exaggerated claims – and this is especially prevalent when it comes to the genetic-testing industry.

The infertility field, of course, excels in this regard because of the number of tests offered which not only do not improve IVF outcomes, - but in certain patient populations, indeed, have the opposite effect. The most obvious such test is, of course, preimplantation genetic testing for aneuploidy (PGT-A). But, since the CHR’s opinion on PGT-A utilization in IVF is already well known to our readers, we will not go here into further detail.

But all of this does not yet answer the very obvious question, how does the laboratory testing industry get away with offering diagnostic tests to the public with unsubstantiated claims? Where is the FDA in all of this? How come, companies can offer to the public tests without prior approval by the FDA, - when the FDA does approve so many other tests?

Once again, the answer is simple and has been discussed in these pages before: For the longest time, the FDA - supposedly voluntarily – excluded so-called “laboratory developed tests” (LDTs) from the agency’s otherwise very detailed review processes of medical tests. This decision was made decades ago, since the FDA did at that time not want to have to review all the routine tests developed in small offices of country doctors (i.e., therefore called “laboratory-developed”). In other words, the FDA never expected that the definition of a LDT would be (ab)used by the laboratory testing industry for the establishment and sale of tests on a national scale to circumvent the need for FDA approval.

But this is exactly what has happened. By 2024, the FDA, indeed, publicly acknowledged that things had gotten out of hand in regard to LDTs and announced that the agency would – selectively -start reviewing LDTs. PGT-A was, however, not included in the initially published list of to be reviewed tests, and to this day not even a single PGT-A laboratory had its test reviewed, - even though there are significant differences how different PGT-A laboratories perform PGT-A assays.

Not a single test on the initial review list has, however, undergone an FDA review since because the laboratory testing industry, of course, wasn’t happy that its widely sold LDTs now might have to undergo FDA approval, where clear outcome benefits, of course, are a core criterion for approval. And so, they sued the FDA, and a federal judge in Texas ruled against the FDA, - opining that Congress did not intend for LTDs to be regulated by the FDA and that the agency exceeded the FDA’s authority under the Federal Food, Drug, and Cosmetic ACT (FDCA).⁴

If Galleri is really a LDT, it, therefore, may be worthwhile buying shares in Grail Inc on the dip because, - if medical establishment and laboratory testing industry – like with PGT-A – simply ignore negative outcome findings - with the Galleri test supported by continuous false marketing claims - Grail’s stock price should quickly recover and, indeed, improve with continues and increasing use of the test. PGT-A is, of course, a good example for a lousy (and often misleading test) can still remain in wide-spread use and, indeed, find increased utilization!

REFERENCES

1. Robbins R, Kolata G. The New York Times . February 21, 2026. pA1. https://www.nytimes.com/2026/02/20/health/cancer-detection-test-grail.html

2. Herper M, Chen A. STAT News. February 19, 2026, https://www.statnews.com/2026/02/19/grail-cancer-test-galleri-results/

3. Chaudhury K, Sunny ME. Reuters. February 20, 2026. https://www.reuters.com/legal/litigation/grail-shares-plunge-after-major-cancer-screening-trial-misses-main-goal-2026-02-20/

4. Jones Day. April 2025. https://www.jonesday.com/en/insights/2025/04/judge-blocks-fda-regulation-of-laboratorydeveloped-tests. Accessed on February 21, 2026.

Getting paid for Providing Medical Services

In the end financial pressures are always dumped on health care providers and patients, with everybody else reporting record profits. It is almost difficult to determine where to start: Delayed payments by Aetna and Cigna to a group of anesthesia providers resulted in a federal lawsuit against these two gigantic national insurance companies.¹

And the claims are simple and straight forward: 33 NorthStar anesthesia providers are claiming in their lawsuits that they are seeking $4.1 million for allegedly unpaid Independent Dispute Resolution (IDR) Awards. And once the insurers paid with delays, they did so without paying interests.

Experts, moreover, predict that through the rapid introduction of A.I. by insurance companies in fulfilling claims, the insurers will find additional creative ways to withhold payments from providers. Everybody is, indeed, expecting a surge in in claim denials to providers in 2026.² Rep. Greg Murphy, MD (R, NC), in a hearing on health insurance companies noted that “health insurance companies have destroyed the healthcare industry and have made an entire industry around denying care for profit.”

Murphy accused insurers of “systematic denial and delay of care,” noting his own personal experience of having a medication denied eight times. He slammed the vertical integration of some of the big insurers, which now own pharmacy benefit managers (PBMs) and lots of physician practices and in many markets - in doing so - have “destroyed competition.”

Yet at the same time, Murphy noted that these companies have record profits and high executive compensation (though being a CEO has become quite dangerous and can led to death by murder). He also, accused the industry of “deceiving and extorting taxpayer dollars through Medicare Advantage plans”.

REFERENCE

1. Force.TJ; January 5, 2026. https://patriotcompli.com/northstar-anesthesia-providers-sue-aetna-and-cigna-over-4-1m-in-alleged-idr-underpayments/

2. Ladon M. American College of Health Data Management. January 20, 2026. https://www.healthdatamanagement.com/articles/how-to-prepare-for-a-surge-in-claim-denials-in-2026?id=136219

The problem With Influencers in Medicine and Elsewhere

There, of course, are influencers for everything on the Internet. And why not also for medical issues? Jessica Grose, an Opinion Writer for The New York Times (their description) took a somewhat circular way toward discussing the issue by starting with the Epstein Files and – more specifically – with Peter Attia, MD.¹

We don’t want to waste our time here on the Epstein Files, and Attia is very obviously a scum bag because, as the Files beyond reasonable doubt revealed (and as reported by Grose in her article) he was not only one of Epstein’s peripheral acquaintance but – as he himself described in an e-mail – an Epstein “friend,” who lamented that he “can’t tell a soul how outrageous Epstein’s life really was.” In short, he apparently knew exactly what was going on around Epstein and – still – was committed to secrecy which, of course, raises the question of participation.

Google describes him as a Canadian-American author, former researcher, and CBS News contributor known for his work in longevity medicine. He’s also the founder of Early Medical and has trained at Stanford, Johns Hopkins, and the NIH. Attia is known as a “longevity influencer” and “celebrity doctor.”

A PubMed search, however, revealed not a single peer reviewed publication with his name as author or even co-authors. Though he graduated Stanford University School of Medicine ( a very highly ranked medical school), and from there trained for 5 years in general surgery at John Hopkins Hospital (once again a very prestigious appointment) from where – according to Google – he moved into a two-year fellowship in surgical oncology at NIH. Yet - according to Grose – he left his residency before completion (difficult to understand, - considering his stint as a fellow at NIH but also confirmed by Google) and, therefore, never was eligible for board certification. He, however, as of 2026, is licensed as a physician in Texas, California, Oregon, and New York.

Interestingly, after dropping out of residency, he left medicine and worked at McKinsey & Company and at an energy company before returning to the medical field by opening a medical practice in San Diego that describes him as a specialist in General Surgery.

Yet what he is really nationally known for is an alleged special expertise as a longevity physician! He in an interview claimed to have fewer than 75 patients, - among those several celebrities (Hugh Jackman, Chris Hemsworth, etc) who paid him hundreds of thousands of dollars annually for “bespoke medical care.”

Grose in her article used – out of all people – Attia to demonstrate “the big lie propping up big wellness.” It, of course, seems appropriate to question how a non-practicing physician -surgeon (if this is what he is) with not a single peer-reviewed publication to his academic research record can make a career in geriatric medicine – or should we say longevity medicine, where even a major television network hires him as an “expert.”

How society defines “expert” (and not only in medicine) is, of course of great importance and one can it only describe as a difficult to explain paradox that at a time when society holds “experts” at likely the lowest esteem ever, chooses to follow “pseudo-experts” which so may influencers are. Just a thought!

Why Berri Weiss at CBS as one of her first hires chose to recruit Attia as a “news contributor ” – yes a medical news contributor – is difficult to understand, especially as – we here at the CHR – are among her biggest admirers of what she (with wife and sister) accomplished at THE FREE PRESS. In a way she as well as CBS, therefore, were lucky that all the media attention Attia received after release of the Epstein files led to his resignation as one of CBS’s “expert” medical pundits.²

MEDIA HEADINGS AFTER ATTIA’s RESIGNATION FROM CBS

Attia was not the only “expert” physician-scientist with special Epstein relationships as a recent article in Nature magazine noted.³ The academic “expert” class apparently loved Epstein and – at least so-far – did so primarily because of his generous donations (where all of his big money came from is still quite unclear); but who knows?

REFERENCES

1. Grose J. The New York Times. February 7, 2026. https://www.nytimes.com/2026/02/07/opinion/peter-attia-epstein-health-influencer.html

2. Astor M, Mullin B. The New York times. February 23, 2026. https://www.nytimes.com/2026/02/23/well/peter-attia-cbs-epstein.html

3. Garisto D. Nature 2026;650:529-530

By Dr. Sonia Gayete-Lafuente at the Center for Human Reproduction (CHR) and the Foundation for Reproductive Medicine an Attending fertility specialist, physician scientist, and Director of Medical Education and a Visiting Researcher at Rockefeller University in NYC. She can be reached through the CHR’s editorial office or directly at sgayete(at)thechr.com

BRIEFING: Across modern cities, from New York to London to Barcelona, an increasing number of highly educated, accomplished women in fertility clinics are increasingly hearing the same question, - “why did you wait so long?” – followed by “now you are too old to try with your own eggs!” And only too often that statement concludes the discussion.

Those women hearing this, however, are rarely uninformed or careless. Many are highly educated professionals, physicians, scientists, lawyers, engineers, academics, entrepreneur, - women who have spent decades navigating demanding career paths and achieving levels of independence that previous generations often fought hard to achieve, - but often failed. In many ways, they indeed are, the embodiment of the promise that women can “have it all”. But now in medical consultation, that promise meets biological reality and, increasingly, institutional boundaries as well.

Unfairly, delayed motherhood is often framed as a miscalculation, a personal mistake. In truth, it, however, reflects something much bigger and more important, - the collision of modern social timelines and the inherent natural demands of reproductive biology.

In this article of The _CHRVOICE, we therefore explore the complex intersection of modern womanhood with reproductive biology, and why current prevalent infertility practice in most IVF clinics in the U.S. and elsewhere in the world refuses autologous IVF (IVF with use of their own eggs) to women after after age 43 years, - a policy that deserves careful scientific and ethical reflections.

The Promise and Burden of “Having It All”

Over the past half-century, women have entered an unprecedented era of intellectual, professional, and economic participation. In most privileged places, that also included an era of unprecedented physical freedom. In many countries, women now graduate from universities in greater numbers than men (especially in medicine) and occupy leadership roles across medicine, science, business, and public life. If they wish, they live by themselves, purchase property, marry multiple times or not at all, and travel the world.

Alongside these advances emerged a powerful cultural narrative, the idear (or should we say, - the ideal) of the “Superwoman.” She succeeds professionally, remains healthy and productive, nurtures relationships and enjoys the beauty of life flawlessly and freely. And when the moment feels right, she builds a family. In short, the message has been simple and seductive, - “ you can have it all as a woman!”

What this utopian narrative, however, rarely acknowledges is that female reproductive aging remains biologically constraining in ways that modern professional timelines, economic structures, and social expectations often cannot accommodate. Advanced training with educational pathways extend well into the thirties, career establishment, financial stability, and partnership formation - currently the main reason for planned egg freezing - almost entirely overlap with women’s most fertile years. These realities naturally delay family-building and unfold unpredictable, - just as the rapidly-evolving world we live in does.

For those of us practicing reproductive medicine, these “Superwomen” are often the patients sitting across from us in consultations. They used to be rare; now -at least at the CHR – they likely already are a majority. And increasingly many arrive after the age of 43, when their chances of conceiving with their own eggs are by many colleagues considered “too limited” to still offer them treatments with use of their own eggs. They claim medical futility as the reason for their refusal, - a message that, of course, can hardly be more deeply painful to receive.

Imagine another medical field would act this way! Imagine a medical oncologist would refuse treating advanced stage IV cancer patients because only a few may ultimately survive or cardiologists and surgeons would treat only good-prognosis patients, while those with poorer chances would be denied care and told to go elsewhere. Wouldn’t that be unbelievable and wouldn’t everybody be up in arms and consider such treatment (or actually non-treatment) not only to be unethical but misleading because one, of course, in every medical specialty requires better knowledge and skills for the more difficult cases?

Genomics as a Risky Boundary for Ageism

Reproductive genomics has transformed infertility care. The study of meiotic errors, embryo culture, and preimplantation genetic testing have given clinicians powerful tools to explain reproductive failure in the context of advanced maternal age. These technologies allow us to quantitatively estimate ovarian aging, the likelihood of embryo aneuploidy, and live birth rates.

Offering such knowledge to patients correctly, in principle empowers them; but, in practice, this is not always what happens because what matters in offering information to patients are not only the numbers, - but also how those numbers are presented. Women aged 43 and older seeking autologous IVF often report that these genomic explanations - even if scientifically accurate (which is also not always the case) - are presented as definitive endpoints rather than as information to guided decision-making.

Patients routinely describe consultations in which discussions of declining functional ovarian reserve and percentages of chromosomal abnormalities quickly transition into firm statements of treatment refusal from a medical provider who is presumed to objectively inform (i.e., the term, -“informed consent”) rather than impose her/his opinion on a patient. Many patients, despite understanding the offered statistics perfectly, still wish to retain the right to attempt treatment.

Rigid age cutoffs for treatments are not only illogical (there are younger women with older ovaries and vice versa) but introduce a phenomenon into infertility practice called ageism, - only rarely discussed openly in the field, - yet frequently brought up by the CHR’s patients who in over half of all cases seek treatment at the CHR because they elsewhere (and often in more than one clinic) where given no choice but third-party egg donation. There are even IVF clinics where receptionist refuse appointments after a certain age if patients are not willing to consent to use of donor eggs, even before they get a chance to see a physician. We don’t know of a better example of structural ageism embedded within access to care.

This must be revisited. Responsible medicine requires limits, based in the core ethical principles of non-maleficence, autonomy, justice, and beneficence; principles that should also remind us to approach such decisions with humility, recognizing that the authority to define those limits should not – and cannot - rest only in physicians’ judgements.

When Biology Meets Policy: IVF After Age 43

From a biological standpoint, the facts are well established. With advancing maternal age, oocyte numbers decline, mitochondrial function deteriorates, meiotic errors increase, the proportion of aneuploid embryos rises and, consequently, chances of pregnancy decline sharply. By the mid-forties, the probability of generating a euploid embryo from an autologous IVF cycle becomes very low. This is one of the main reasons why at age 25 approximately 1/3 embryos will lead to pregnancy, while at age 45 (the numbers are then not as well established) the chance drops to 1/15-20 embryos.

These realities form the foundation of responsible counseling in reproductive medicine. Yet an important distinction often disappears in clinical practice: low probability is not impossibility. A treatment with a low chance of success may still carry profound personal and ethical legitimacy for a patient. For some women, even a small opportunity of genetic parenthood remains meaningful enough to pursue freely, after thoughtful informed consent. And many other women may have no other options because their religion or their believes do not allow them to even pursue third-party egg donation.

How can we – as a medical specialty – simply abandon them?

In most clinical IVF settings, women over age 43, however, to this day still encounter categorical refusals of autologous IVF. As already noted, even in New York City, cycles are declined before medical evaluation, solely based on age. Clinics may enforce strict age thresholds prioritizing their success metrics and commercial pressures, while patients are incorrectly told that treatment would be unethical or even futile.

In addition to personal frustration, this generates an institutional biased self-fulfilling prophecy: Because these patients are often not offered treatment, fertility specialists have limited experience in managing them; as a result, the small number who do undergo treatment rarely achieve success, feeding the narrative of unequivocal futility, and leading to further discrimination.

The value of trying is, in contrast, well-illustrated by the CHR’s data, a center internationally, of course, widely recognized for treating women of advanced maternal age. In 2025 at the CHR, women aged >43 years who underwent IVF with fresh embryo transfer achieved an 8% clinical pregnancy rate (significantly higher than < 2% reported nationwide), - data to be soon published in RBMO (Reproductive BioMedicine Online). Additionally, we must remember that only practice makes perfect and, most importantly, that everyone deserves medical care.

Reframing Delayed Motherhood Beyond the Myth

We should avoid public discussions of delayed motherhood that carry subtle undertones of blame. Women are too often portrayed as having “waited too long”, as if reproductive timing was purely a matter of personal choice or miscalculation, rather than a structural consequence of modern social and professional systems. Let’s stop the shaming.

The “Superwoman” narrative promised that ambition, independence, and motherhood could coexist seamlessly - as if women could transcend every biological boundary through discipline and careful planning. In reality, many women carry the burden of delayed motherhood while trying to balance careers, relationships, finances, and personal identity under nearly impossible conditions. These women are our sisters, daughters, friends, coworkers, and patients.

The woman who walks into a fertility consultation after age 43 is not simply stubbornly confronting biology; she may instead be carrying the weight of years of responsibility, circumstances, and hope. Rather than viewing these patients through the narrow lens of probability alone, we must recognize the broader human story that brought them to where they are in their lives and engage more compassionately with their realities.

Innovation at the Edges of Reproductive Science

This necessary reframing starts by understanding the “Superwoman.” With this in mind, at the CHR, financially powered by the Foundation for Reproductive Medicine (FRM), we have initiated a new study examining how the concept of “genomic futility” has emerged as a rationale for excluding women aged 43 and older from IVF with use of their own eggs. Through interviews with women across four countries of diverse policy -the U.S., the U.K., Singapore and Japan-, the project explores how women experience age-based exclusion, how they understand genetic parenthood, and even how they view emerging technologies such as stem-cell therapies or in-vitro gametogenesis (IVG) as potential alternatives to using donor eggs. By integrating genomics, social science, and bioethics, our study aims to generate patient-informed ethical principles to guide future evaluation of reproductive technologies for women currently excluded from IVF due to age.

Hopefully, the stories of these “Superwomen” may help expand social awareness, improve fertility education, and, ultimately, challenge policy within the fertility community. In the end, perhaps real progress is not to push “Superwomen,” but to build a world where women are simply supported to thrive, however they choose to live.

INTERESTED IN SUPPORTING RESEARCH AND EDUCATION AT THE CHR AND ELSEWHERE, PLEASE DONATE TO THE NOT-FOR-PROFIT FOUNDATION FOR REPRODUCTIVE MEDICINE, AT

https://www.zeffy.com/en-US/donation-form/support-independent-fertility-research-before-year-end.

ALL DONATIONS ARE FULLY TAX-DEDUCTIBLE UNDER THE LAW.

READING LIST: This reading list balances clinical authority (ACOG 2025, ASRM Ethics 2022), data that challenges the status quo (Gleicher 2015, Selter 2023), relatable social science (Smith 2022, King 2023), and forward-looking practical guidance (Mahajan 2025).

ACOG Committee Statement No. 22: Anticipatory counseling regarding ovarian-factor fertility decline (2025). The latest guidance from the American College of Obstetricians and Gynecologists on how doctors should talk with women about fertility and age. It emphasizes early, supportive conversations rather than last-minute warning.

Gleicher N, et al. “Older women using their own eggs?” (Reproductive BioMedicine Online, 2015). A landmark report from the Center for Human Reproduction documenting successful IVF pregnancies, including a live birth, in a woman transferred 2 weeks short of her 48^th birthday, - and still the oldest autologous IVF birth in the medical literature, challenging the widespread belief that treatments over age 43 are futile..

ASRM Ethics Committee. “Provision of fertility services for women at increased risk of complications” (Fertility and Sterility, 2022). An important ethical statement from the American Society for Reproductive Medicine exploring when clinics may limit treatment and why patient autonomy and informed consent should remain central to these decisions. It affirms that determinations to decline treatment must be made in a “medically objective and unbiased manner.

Selter JH et al. “Survey assessing policies regarding patient age and provision of fertility treatment in the United States” (Journal of Assisted Reproduction and Genetics, 2023). A revealing survey showing that nearly 74% of U.S. fertility clinics enforce a maximum maternal age for autologous IVF (in this study the median cutoff was 45 years but national registry data in the U.S. demonstrated very significant autologous IVF cycle drop offs already after age 43).

Smith KS et al. “Knowledge of fertility and perspectives about family planning among female physicians” (JAMA Network Open, 2022). A powerful qualitative study showing that even female doctors, who fully understand fertility decline, delay having children because of training demands and workplace culture. Of those surveyed, 71% had delayed childbearing and 67% had altered their career for family-building reasons.

King Z et al. “Barriers to family building among physicians and medical students” (JAMA Network Open, 2023). A large qualitative study of over 2,000 physicians and medical students revealing cultural, organizational, interpersonal, and individual barriers that push family building later in life, reinforcing that delayed motherhood is a systemic issue, not a personal failing.

Mahajan NK. “Optimizing advice and approaches for elective fertility preservation” (Best Practice & Research Clinical Obstetrics & Gynaecology, 2025). Up-to-date review on egg freezing as a proactive option, including the finding that freezing ≥20 mature oocytes before age 38 gives a 60–70% possibility of pregnancy. It also addresses the ethical dimensions of elective fertility preservation, including the medicalization of reproduction and social inequity.

Today’s posting is a first for The Reproductive Times since it is the first time, we (of course with permission) are reprinting an article verbatim from another publication, - in this case form Inside Precision Medicine. There were in principle two reasons for asking for this permission: First, the subject of intervening into the genetics of embryos, fetuses, and newborns had become “hot” and, by that, we mean “hot” in a good sense.

That stands in contrast to 2018, when Jiankui He, PhD, in China became an international “celebrity” for – in secret – allegedly having edited the germline of several human embryos before transfer, with several so-edited embryos allegedly leading to normal births (those cases were never reported in the medical literature and, therefore, cannot be judged). He was rightly criticized worldwide (and allegedly convicted to three years jail time) for having acted unethically, unprofessionally, and ultimately apparently illegally under Chinese law.

But in the 7-8 years since, much has changed, - not only because of greatly improved medical technologies but also because of a clear changes in public sentiment. While editing the germline of an embryo, of course, is still a very controversial and sensitive issue, it now is openly discussed in prestigious institutions (a debate organized by the Hastings Center for Bioethics in Westchester, NY, and an online symposium by Harvard University Law School are just two recent examples).

Which brings us to the second reason for asking for the permission to reprint the article: It was simply perfect in explaining the relevant issues by in unbiased fashion giving voice to several experts on the subject (including the CHR’s Norbert Gleicher, MD) and doing so in easily understandable language. We hope you agree and let us know what you think on the subject

The CHR’s Editorial Staff

The following article by Jonathan D. Grinstein, PhD, - North American Editor at Inside Precision Medicine and host of the Behind the Breakthrough podcast, - covering latest trends in biopharma - initially appeared on April 7, 2026, in Inside Precision Medicine. We liked the article so much that we asked for permission to reprint it here. And we liked the article not only because it – among several experts – also featured the CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, but because it, comprehensively, covered a currently increasingly relevant subject in reproductive medicine, now at the core of many debates,- some in print, - others in several recent public events.

A woman lies on an exam table, holding her partner’s hand tightly with anticipation, as a technician glides an ultrasound probe across her abdomen. On the screen, shifting staticky shadows resolve into a skull, a liver, and the flicker of a beating heart. For many families, this moment brings joy and relief. For others, it’s paralyzing, as doctors detect signs that something is wrong.

A single nucleotide change can cause neurodevelopmental delays and dimorphism, failing livers, and arrhythmia-ridden hearts. For decades, medicine could only identify these conditions, usually after birth. Prenatal screening has made it easier to detect progressive diseases like Duchenne muscular dystrophy, which degenerates and damages muscles before symptoms typically appear in childhood. But treating before birth could preserve tissue prior to the onset of irreversible deterioration.

Once unthinkable, genetic diseases can now be treated before birth. Fetal genetic intervention—including early screening, in utero gene therapy, stem cell transplantation, and even embryo editing—aims not just to diagnose disease but to correct it at its earliest stages. It is a rapidly advancing frontier, defined by technological promise and profound ethical questions.

IT STARTS WITH DETECTION

Jennifer Hoskovec, vice president of medical affairs at BillionToOne, has spent more than 20 years in prenatal genetics, an era dominated by risk assessment rather than intervention.

Historically, prenatal genetic screening has fallen into two main categories. Aneuploidy testing determines the risk of Down syndrome and other trisomies, sex chromosome abnormalities, and specific microdeletions. Screening is essential for these de novo mutations, which have no U.S. Food and Drug Administration (FDA)-approved genetic interventions. High-risk Down syndrome patients may receive a fetal echocardiogram, closer ultrasound monitoring, or tertiary care delivery with neonatal support. The standard practice is to screen, monitor, and manage.

The second category involves inherited recessive conditions like cystic fibrosis (CF), spinal muscular atrophy (SMA), and phenylketonuria. If both parents are carriers for the same genetic mutation, then their child has a 25% chance of being affected. Testing typically requires samples from both parents. If both are carriers, chorionic villus sampling (CVS) and amniocentesis can detect fetal abnormalities in the first and second trimesters, respectively. However, getting each partner to follow up is a major hindrance. “When people go through a screening process and are found to be carriers, less than 50% of their partners complete the testing,” Hoskovec told Inside Precision Medicine. “Half of U.S. carriers of these genetic conditions, whether common or rare, don’t know what it means for their pregnancy. That limits their ability to get diagnostic testing because we do not have all the pieces of the puzzle.”

Hoskovec’s team developed a workaround: a single-gene noninvasive prenatal test that analyzes fetal cell-free DNA (cfDNA) circulating in maternal blood. Around nine weeks into pregnancy, fragments of fetal DNA shed from the placenta can be sequenced and quantified. If a mother is a carrier for a condition like CF or sickle cell disease, the test looks for a second variant that is not present in her DNA and forms evidence of paternal contribution.

“For example, if a mother has [the] sickle cell trait, we first sequence the full beta-globin gene in the cfDNA, which contains a mixture of maternal and fetal DNA,” Hoskovec said. “We look for a second not present variant in the mother that would indicate paternal contribution.”

Despite not replacing CVS or amniocentesis, Hoskovec said the result is highly sensitive, identifying 95% of affected pregnancies in the conditions it covers. Crucially, it does not require partner testing. “This is a steppingstone,” Hoskovec explained. “This earlier detection will likely accelerate the field by increasing the number of eligible patients for clinical studies and registries, improving equitable access across ethnic groups, and advancing precision medicine in prenatal care.”

AVOIDING GERMLINE EDITING

As screening opens the door, fetal surgeons and gene therapy researchers are taking their first steps through it. A pediatric surgeon at the Yale School of Medicine, David H. Stitelman, MD, believes prenatal treatment has benefits. The fetus is small, so it can receive higher doses based on weight. As its immune system is still developing and more tolerant, stem cells are growing quickly and organs are still being formed, so problems can be fixed before they become permanent. Because the placenta exchanges oxygen, lung conditions like congenital diaphragmatic hernia can be treated during fetal life. But once a newborn takes a first breath, defective lungs can spell immediate crisis.

Fetal therapy is not new. Specialized centers have performed open fetal surgery for spina bifida and diaphragmatic hernia lung growth, and blood transfusions for fetal anemia dating back to the 1960s. What is new is the molecular toolkit. Stitelman’s lab is investigating gene editing methods that use the cell’s repair machinery to fix one- to three-base-pair DNA errors. Another team, led by pediatric and fetal surgeon Tippi MacKenzie, MD, at the University of California, San Francisco, is using viruses to replace genes for lysosomal storage diseases and fetal stem cells for alpha thalassemia.

Some diseases require only modest correction. In hemophilia, one percent normal clotting factor expression improves outcomes greatly. Increasing the expression of functional CFTR protein to 15% of wild-type levels may cure CF or at least make it manageable. Even a small number of liver cells corrected in hereditary tyrosinemia can boost growth and repopulate the organ. However, some situations, such as congenital cancer syndromes, may require nearly 100% correction. At present, Stitelman’s team achieves single-digit percentage editing in models of CF and beta thalassemia. “We’re in the optimization phase,” Stitelman told Inside Precision Medicine. “We are testing different nanoparticles and generations of editing strategies to incrementally reach therapeutic levels.”

Stitelman draws a clear ethical boundary: this is somatic editing, not germline editing. The aim is to treat the fetus as a patient, not to create heritable genetic changes. Instead of editing embryos in vitro, systemic therapeutic agents are delivered to avoid reproductive cell damage.

Unintended germline modification remains a concern. Editing a target gene could inadvertently disrupt developmental genes and affect future generations. But, Stitelman argues, medicine always carries risk. “In 1950, children with leukemia all died,” said Stitelman. “Today, some forms have a 98% long-term survival rate with chemotherapy. We know chemotherapy can cause germline mutations, yet we accept that risk because it saves lives. With gene editing, the issue is not zero risk but understanding and quantifying the risk. Ideally, there would be no measurable off-target effects. In the places we have examined, we have not seen off-target effects.”

ONE PREGNANCY, TWO PATIENTS

In a landmark trial in 2011 known as the Management of Myelomeningocele Study, investigators found that fetal surgery for severe spina bifida (myelomeningocele) achieved better results than postnatal repair. Surgically closing the spinal defect in utero improved motor function and reduced the need for shunting to relieve hydrocephalus. The benefit was so clear that the trial was stopped early and influenced how doctors treat structural birth defects.

At the University of California, Davis, biomedical engineer Aijun Wang, PhD, is working closely with fetal surgery pioneer Diana L. Farmer, MD, to evolve fetal intervention from heroic surgery to cellular and molecular therapy. Wang and Farmer launched the Cellular Therapy for In Utero Repair of Myelomeningocele (CuRe) trial, combining fetal surgery with stem cell transplantation. The goal is to not only close the spinal defect but also restore neural tissue and improve long-term function.

The lens that Wang has used to focus his research is fetal and maternal safety. “The fetus is the patient, but treatment inevitably carries some risk to the mother,” Wang told Inside Precision Medicine. “Open fetal surgery, in particular, poses significant maternal risk. Genetic treatments introduce additional uncertainties because the long-term effects of DNA modification are not fully understood. Safety must remain the highest priority.”

Genetic medicine delivery is a critical challenge for all life stages, but the stakes are particularly high for a developing fetus. In fetal development, targeting stem cell populations is especially important because these cells are highly active, proliferating, and migrating. If edited successfully at the right developmental window, their progeny will carry the correction. The problem would be if the edit was not just unsuccessful but detrimental.

Wang’s lab focuses on delivery systems, particularly lipid nanoparticles carrying mRNA-encoding gene-editing enzymes. For genetic manipulation and high-throughput screening, Wang’s lab utilizes mouse models. Fetal sheep are used for scaling and dosing, while human organoids are used for human-specific editing and functional outcomes.

“In our clinical work, we have engaged with the FDA and conducted extensive preclinical studies,” said Wang. “Using multiple complementary models is essential. Combining small animal models, large animal translational models, and human organoid systems provides a comprehensive framework for product development, from early screening to human-focused therapeutic design.”

Although the field is highly exciting and progressing rapidly, Wang warns against premature application, which could be dangerous. Safety, developmental biology, ethical considerations, and multidisciplinary collaboration are all essential. “Despite the excitement in the field, we must proceed cautiously,” said Wang. “There is strong potential for correcting specific mutations, especially point mutations, using precise gene editing approaches such as base editing. However, safety evaluation must precede rapid clinical application.”

Effective progress requires a village of physicians, surgeons, researchers, engineers, and ethicists working together. Scientific progress requires caution, responsibility, and thorough evaluation before clinical use.

THE EARLIER, THE BETTER

If fetal intervention treats a diagnosed fetus, embryo editing operates even earlier—at the blastocyst stage in in vitro fertilization (IVF). Norbert Gleicher, MD, a fertility specialist known for treating some of the oldest and most difficult IVF patients in the United States, approaches genetic technologies with caution. Due to biological mosaicism, sampling limitations, and his belief that many abnormal embryos self-correct or develop normally, Gleicher opposes preimplantation genetic testing for aneuploidy.

But when it comes to single-gene diseases, he sees a different calculus. Couples with recessive mutations may have one-in-four embryos affected, and in dominant or X-linked diseases, half may carry the mutation. For patients who produce few embryos—especially older women—discarding affected embryos can mean losing precious chances at pregnancy. “If you can cure an embryo rather than discard it,” Gleicher told Inside Precision Medicine, “that makes a lot of sense.”

For single-gene diseases, Gleicher believes genetic editing with CRISPR or other platforms is the most straightforward intervention. He points to the 2025 work at the Children’s Hospital of Philadelphia on Baby KJ as a recent milestone. Even partial correction, which Gleicher believes is likely the case with Baby KJ—though no liver biopsies have been extracted—can transform prognosis. Gleicher said, “Correcting some cells was enough to clinically cure the baby, at least for the time being, from symptoms of a disease that historically kills affected children within a few years. However, we do not know whether the treated baby, who likely still has many affected cells, might become symptomatic again later in life.”

To Gleicher, success in a newborn is all the more reason to apply genetic intervention to fetal stages. “If this can be successful in a full human being, imagine how much easier it would be at the blastocyst stage, or even earlier at the cleavage stage, when the embryo consists of only six to eight cells,” said Gleicher. “If [CRISPR] is applied at that point, correcting those six to eight cells would mean that all their daughter cells would also be corrected. The result would be a normal baby at birth. That is the much stronger argument in this case.”

Just because something is possible, it doesn’t necessarily mean it should be done, and Gleicher establishes a clear ethical boundary. Editing to prevent a devastating single-gene disease is one thing. Editing for traits—eye color, intelligence, polygenic risk scores—is another. Polygenic predictions explain only a fraction of trait variance, and embryo implantation itself is uncertain. To him, offering polygenic selection in IVF is not only scientifically dubious but also ethically troubling. “It is surprising that professionals, particularly in genetics, would suggest such an approach,” said Gleicher. “It is worse than snake oil, because while snake oil may occasionally work by accident, this carries a real risk of causing serious harm.”

A PRETTY PENNY

What ultimately restricts fetal genetic intervention is timing. Early screening increases experimental trial eligibility, and early treatment may preserve organ development before irreversible damage. In conditions like CF and SMA, where postnatal gene therapies are expensive and delivered after injury, fetal intervention could change outcomes. Frontline screening can identify high-risk pregnancies at 11 weeks without family history or ethnicity, expanding trial access.

Yet, fetal genetic interventions require specialized teams, advanced delivery systems, counseling, and long-term follow-up. Without careful planning and reimbursement policies, only a few top-tier centers could progress, widening the gap. Ethical scrutiny remains inseparable from progress. Innovation must balance maternal risk, fetal benefit, and future consequences with safety, appropriate use, and clear limits. As prenatal care shifts from prediction to prevention, restraint and evidence will determine its future.

Jonathan D. Grinstein, PhD, earned his PhD in biomedical science from the University of California, San Diego, and a BA in neural science from New York University.

And then our posting switches straight into the recent infertility literature addressing three interesting papers, - though, as you will find out, - “interesting” for very different reasons.

Let us know what you think. We always try to say it as we see it, - well recognizing that nobody, including us – will always be right and, certainly, not everybody will always agree. But we try very hard to communicate common sense, humanity, and empathy and do it with as much transparency as is possible.

Our readers’ reactions and responses are, therefore, of great importance to us and we can’t wait for you comments to today’s posting.

The CHR’s Editorial Staff

When a couple face infertility struggles and reproductive treatments, their relationship often enters a new emotional and physical frame. What was once spontaneous desire, touch, and intimacy slowly shifts as medical routines take over. Sex becomes scheduled around ovulation, paused during procedures, or just deprioritized altogether. Hormones, injections, ultrasounds, and uncertainty can chip away at sensuality until closeness feels like another item on a long list of obligations. In some instances, it can even feel stressful, triggering, and painful. Yet beneath this clinical reframing of intimacy lies this truth: our bodies are wired for healing through closeness. Intimacy -whether sexual or not-, can soothe the nervous system, soften grief, and remind couples that their connection is still alive under the treatments. A central player in this biology is a small but potent molecule: oxytocin, often called “the love hormone”, maybe more accurately understood as “the safety hormone”.

We here explore not only the restorative chemistry of oxytocin and the neuroscience of pair bonding, but also the often-overlooked role of sexual healing: how closeness, in its many forms, can become a quiet but powerful source of resilience during fertility treatment, and why reclaiming intimacy on your own terms may be one of the most radical acts of self-care you can practice while cycling in treatment.

Why Fertility Treatment Disrupts Intimacy - and Why this Is Completely Normal -

Here’s what nobody tells you when you start IVF: your sex life is about to become collateral damage. Not because your relationship is failing or because you’ve stopped loving each other, but because your nervous system is doing exactly what evolution designed it to do under sustained threat – to prioritize survival over pleasure.

As your body becomes medicalized, monitored, injected, and hormonally manipulated, - it begins to feel more like a science trial than a source of sensuality. Physical discomfort from ovarian stimulation, egg retrievals, biopsies, or pregnancy loss can make even gentle touch feel unwelcome. Meanwhile, emotional baggage accumulates, - grief after failed cycles, fear of disappointment, the relentless uncertainty of what comes next.

Research confirms what you’re experiencing: Studies have shown that 60-80% of couples undergoing IVF report significant sexual dysfunction, with women experiencing decreased desire, arousal, and satisfaction, and men showing surprisingly high rates of erectile dysfunction - far exceeding rates in couples who conceived spontaneously.

Partners often respond differently to this stress. One may withdraw emotionally; the other may focus on staying “strong” or hyper-practical. Desire fades not because of relationship problems, but because chronic stress fundamentally rewires sexual responses. Studies using daily assessments showed that higher subjective stress directly correlates with lower sexual desire and arousal, with these effects particularly pronounced in women. But this does not only affect women: One striking study found that among IVF couples men demonstrated dramatically lower sexual function scores compared to controls not in IVF cycles, both before pregnancy and up to one year postpartum. Sex becomes scheduled, paused, or quietly avoided.

And as this shift is not pathological, but a predictable human response to prolonged emotional demand. What matters is understanding this change as part of the treatment experience and not as a failure of connection or love.

The Molecule of Love and Safety: How Oxytocin Builds Bonds -

Oxytocin is a nine-amino-acid long neuropeptide that acts as both a hormone and a neurotransmitter. It is best known for its role in motherhood, during labor and early bonding, but its influence stretches far beyond those moments. So calling it simply “the love hormone” underestimates its evolutionary sophistication.

Oxytocin is released during any affectionate touch, warm conversation, during kissing, orgasm, and even as a response to simple gestures like eye contact or holding hands. When it rises, the body and brain receive a clear message: You’re safe.

You’re held and you can let go, - with feedback into more oxytocin release, thereby further enhancing the connection. Through this message, oxytocin calms the stress response, lowers cortisol, eases anxieties. and promotes what researchers call “allostasis,” - the ability to adapt and recover from challenges.

This matters profoundly for couples navigating infertility, as it enhances trust and positive communications, reduces stress levels during conflict discussions, helps regulate sleep, reduces pain perception, and even influences the immune system – all notably important in a shared context of intense uncertainty.

The evolutionary story is fascinating. Research on prairie voles - one of the few mammalian species that, like humans, form lifelong pair bonds - revealed that oxytocin and its receptors are essential for partner preference formation and bond maintenance. Interestingly, species that don’t pair bond have different patterns of oxytocin receptor distribution in their brains; and it seems that our capacity for selective attachment, for choosing one person and staying connected through hardship, is neurochemically mediated by this single molecule.

During fertility treatment struggles, oxytocin’s calming and bonding effect becomes particularly valuable. Studies of couples in early romantic attachment show that higher oxytocin levels predict better interactive reciprocity (synchronized positive affect, affectionate touch, mutual gaze) and even predict which couples will stay together. And in stressful contexts, oxytocin reminds our nervous systems that connection itself is a form of care.

Sexual Intimacy Beyond Reproduction -

Many couples begin to see sex as losing its purpose once timed intercourse ends or IVF begins. Some couples report this as an irony of fertility treatment: the very act that brought them together becomes medicalized, scheduled, and stripped of spontaneity. Yet sexual intimacy has always served functions beyond conception. Erotic touch and orgasm produce some of the highest natural surges of oxytocin in the body, higher than almost any other naturally occurring stimulus. This is why sex can feel grounding, soothing, and connective even when it’s not tied to reproduction, although paradoxically a lot of couples may not feel like it at all in context of stress. However, the absence of sexual intimacy during treatment can feel like losing an essential coping mechanism precisely when you need it most.

The research on infertility and sexual function reveals a bidirectional relationship: infertility-related emotional and relational stressors predict lower sexual desire, arousal, and satisfaction in both partners, with effects crossing between partners (your distress affects your partner’s sexual function and vice versa). But here’s the hopeful finding: sexual desire and sexual activity are associated with lower subsequent stress levels, suggesting that intimacy - when it feels safe and is mutually chosen - can actually buffer against the emotional toll of treatment. So, how do we address this?

The Healing Power of Touch Without the Pressure

Not all couples feel ready or able to engage in sexual activity during fertility treatments. Pain, fatigue, grief, hormonal shifts, or recovery from procedures may make intercourse difficult or undesirable. For those who are ready after all, encouragement at the safe moments of the process (for example, avoiding the few days after egg retrieval or embryo transfer) is always welcome; and for those who aren’t, - here’s the good news: oxytocin is released through many forms of non-sexual touch as well.

As already noted, simple gestures such as a long hug, holding hands in the waiting room, resting together quietly, gentle stroking of the arm, etc., can raise oxytocin levels and reduce emotional tension. Recent ecological momentary assessment studies (where people reported experiences in real-time throughout their day) showed that even just an affectionate touch is, indeed, significantly associated with decreased anxiety and stress, and increases oxytocin levels with measurable effects by lowering the stress hormone cortisol and inducing higher happiness in individuals and between couples.

Our understanding of the neuroscience of oxytocin release through touch independent from sexual activity has recently come into more focus through quite elegant studies” Our skin contains specialized nerve fibers called C-tactile afferents, - unmyelinated, slow-conducting nerves, found only in hairy skin, which respond optimally to gentle, slow stroking touch (approximately 3-5 cm per second is the speed of a comforting caress). These nerves appear to have evolved specifically to signal the rewarding value of physical contact in nurturing and social interactions.

When activated, they trigger oxytocin release, reduce physiological arousal, and carry positive affective value. A groundbreaking 2023 study moreover showed that affectionate touch doesn’t just affect immediate oxytocin levels, but creates context-dependent adaptive responses, supporting that regular affectionate touch with your partner and may actually recalibrate your stress response system in general.

In fact, these small, consistent moments often matter more than grand romantic gestures. They help couples stay emotionally connected when words feel insufficient or energy is limited. During fertility treatments, intimacy is often rebuilt through repeated, low-pressure acts of tenderness rather than dramatic efforts at “fixing” lacking desire.

Reframing Intimacy as Care, - Not Performance –

As the “Inferto-Sex Syndrome” - a term coined by researchers to describe all constellations of sexual dysfunctions that can emerge during fertility treatments, affects both partners profoundly, many couples benefit from shifting their view of intimacy away from performance and toward mutual care. For you, this may mean:

- Spending intentional time together without expectation of having sex.
- Exploring slow and non-penetrative touching.
- Simply sharing physical closeness without a specific goal.
- Acknowledging that desire and sex may return gradually - or may not, - and even that is okay.

Most interestingly – and sometimes quite surprisingly - when pressures are removed and infertility-related relational stressors are navigated together, - intimate curiosity and tenderness often take over after all. Intimacy approached with kindness rather than obligation, supports both emotional resilience and relational stability during treatment, ultimately helping couples open up, maintaining more positive perspectives even during challenging times.

The Clinician’s Role: One Sentence That Can Change Everything –

Here is a final thought especially for clinicians: Although intimacy is profoundly affected by fertility treatments, it’s rarely addressed with patients by physicians in office settings. Yet a brief and compassionate acknowledgment from a clinician can have a powerful impact.

Research has demonstrated that couples want their sexual health addressed as part of comprehensive fertility care, while most report that it “never” has come up. Clinicians don’t need to offer sexual counseling to make a difference, but normalizing fluctuation in desire, acknowledging physical discomfort, and recognizing connection as part of healing opens space for patients to feel seen as a couple.

Short comments like, “partners frequently notice changes in intimacy during treatment,” - can immediately reduce shame, provide validation, normalize the situation or address the elephant in the room. Asking, “how are you two coping together?” signals that the relationship matters, not just the outcome. Couples may still not share intimate details with clinicians, but a comment like this could, at least, remove tension and open a door for couples to talk about it among themselves, and thereby reconnect.

On Valentine’s Day, the - perhaps - most radical act of love is simply holding your partner, touching each other with tenderness, releasing the pressure to perform, and trusting that your nervous systems - wired for connection across millions of years of evolution – knows very well how to find its way back to couple hood.

READING LIST

• Amiri M, Khosravi A, Chaman R, et al. Sexual function and satisfaction in couples with infertility: the role of personal and relational characteristics. J Sex Marital Ther. 2021;47(2):110–123.

• Bright K, Dube L, Hayden K, et al. Effectiveness of psychological interventions on mental health, quality of life and relationship satisfaction in infertile couples: a systematic review protocol. Syst Rev. 2020;9:25.

• Carson SA, Kallen AN. Diagnosis and management of infertility: a review. JAMA. 2021;326(1):65–76.

• Handlin L, Novembre G, Lindholm H, et al. Human endogenous oxytocin and its neural correlates show adaptive responses to social touch based on recent social context. eLife. 2023;12:e81197. doi:10.7554/eLife.81197.

• Leeners B, Tschudin S, Wischmann T, et al. Sexual dysfunction and disorders as a consequence of infertility: a systematic review and meta-analysis. Hum Reprod Update. 2023;29(1):1–19.

• Luk BH, Loke AY. A review of supportive interventions targeting individuals or couples undergoing infertility treatment. J Sex Marital Ther. 2016;42(6):515–529.

• Sater M, Al-Kindi R, Al-Makhmari A, et al. Impact of assisted reproduction treatment on sexual function of patients diagnosed with infertility: a systematic review. Sex Med Rev. 2022;10(3):433–445.

AND NOW SOME PAPERS FROM THE FERTILITY LITERATURE

Does functional ovarian reserve affect miscarriage risk?

This is an interesting question which – somewhat paradoxically and likely because everybody believed to know the answer – has not been properly addressed in the literature. And – as not infrequently in medicine and in science in general – when everybody believes to know the right answer – this consensus then proves wrong.

This is – at least partially – the case here as well: everybody, of course, believed that the lower the functional ovarian reserve (FOR) of a woman is, the lower are her pregnancy chances with treatments and the higher, moreover, - once she does conceive – will be her miscarriage risk.

But, as a paper by British investigators now clarified the picture further.¹ Using 16 retrospective studies involving 43,147 patients, they found in a meta-analysis that low AMH levels – as expected – were in principle associated with miscarriages in comparison to medium and high AMH levels. But once patient age was considered, this risk disappeared in women above age 35. And the same dynamics were observed when antral follicle counts were used to define FOR.

This, of course, then raises the question why this association is statistically lost after age 35 and the answer to this question is why we liked this paper so much: This paper points out what likely has been the most substantial error in IVF practice since its beginning - and still unfortunately lasting, - namely the failure to recognize that, especially in female fertility everything changes with advancing. The assumption that a 25- year-old woman can – or should be - be treated like a 35-year-old or even a 45-year-old woman is simply ridiculous. But that is, unfortunately, still what is happening in most infertility clinics, though, at least in some regards the IVF has recognized this fact: For example most clinics do consider a woman’s age in how they stimulate ovaries; but IVF clinics (except of course the CHR) then still trigger all patients at identical follicle sizes(overwhelmingly always between 18 and 22-23mm. This, of course, ignores the fact that all metabolic processes in follicles speed up with advancing female age. If this is not properly considered, the consequence with advancing female age will be larger and larger percentages of overmature oocytes which never produce pregnancies.

The authors try to explain the observed age-35 cut-off with increasing miscarriage rates with advancing female age due to increasing aneuploidy of embryos. But while statistically this, indeed, may be a contributing factor, the more basic message of this paper – at least in our opinion – is that female patient age must be considered in practically everything we do in treating female infertility.

REFERENCE

1. Kasavern et al., RBMOnline 2026; 52(1):105041

Can Ovaries Unlock Secrets of Aging and Longevity?

It seems that everybody has suddenly discovered the ovaries as research subjects for general aging and longevity studies. Articles on the subject are popping up everywhere, - the last one in TIME.¹ And all of them are correct: The ovaries are, indeed, for several reasons amazing organs to study aging and longevity, - not the least because – as the TIME article noted – they age like all other organs in the female human body, - just ahead all other organs which, of course, offers an opportunity to study what produces this difference.

So much for general aging; but what about longevity? The two, of course, are related but they don’t have identical meanings. What recent research has demonstrated is that ovaries have many more functions than just being the “egg-factory” for fertility. Like we have learned by now in many areas of medicine, organs which we never associated with each other are connected in so many different ways that were unimaginable only a relatively few years ago. And ovaries in women are a terrific example for this interconnectivity, often revealed by what happens to women who go through menopause.

They, suddenly, are also seen as “testing organs” for potential general anti-aging treatments and the article, quoted an ongoing rapamycin study, - this time at Northwestern University in Chicago (we previously mentioned in these pages an ongoing rapamycin study at Columbia University here in NYC). The Chicago study was headed by Kara Goldman, MD, (years ago on the faculty at NYU). And , yes, the CHR also just announced a registered rapamycin study in women with low functional ovarian reserve (FOR) and we are inviting IVF treatment resistant women beyond ages 42-43 years to participate in this new venture.

The article offers no sensational news but provides an updated overview on the subject which, of course, is not only relevant for aging and longevity medicine but also for fertility practice. For the CHR this subject has been at the core of most research for over 15 years, when the CHR reached the conclusion that the aging ovary was the most essential subject in human fertility medicine and decided to make it a core subject of research as well as clinical practice.

One of the most important discoveries the CHR then made within this context as a consequence of this decision was the fact that – as women age - all processes within their ovaries speed up, explaining why menstrual cycles shorten as women get older. This discovery then led to a radical practice change at the CHR with the introduction of HIER (highly individualized egg retrieval), leading to progressively earlier egg retrieval with advancing female age, - a practice which nowadays dominates the CHR’s IVF practice and distinguishes IVF practice at the CHR from almost all other IVF clinics in the world, - even though the CHR’s investigators published this concept years ago in two publications and repeatedly discussed it in these pages and elsewhere.

And while there are general principles that apply to most women (who then have average menopauses at ca. ages 51), roughly 10% of women age their ovaries ahead of time, a process the CHR has given the name premature ovarian aging (POA).² While so-affected women may still enter menopause around age 51, they, of course, have increased risk for early menopause and in 10% of the 10% (i.e., in 1% absolute) of so-called primary ovarian insufficiency (POI), - also often called premature ovarian failure (POF) when menopause occurs before age 40.

That with advancing age everything in the ovary is happening quicker, may very well be a general principle of aging,- well worth investigating.

REFERENCES

1. Mosbergen D. TIME. January 13, 2026. https://time.com/collections/the-age-of-longevity/7338546/ovaries-unlock-secrets-longevity/

2. Gleicher N, Barad DH. Fertil Steril 2006;86(6):1621-1625

On How Not to Do It - Another Totally Biased Expert Opinion Paper

If there is something that never should be in the title of a serious scientific paper these days, - then it is the phrase “expert opinion.” And the reason is not only because expert opinion is rightly considered the lowest levels of scientific evidence, - but because medical “experts” got a really bad name during and after the COVID pandemic. And how some of them have now become salesmen on television, does not improve their image. Yet this is exactly what two prominent female embryologists recently did in a Views and Reviews section in Fertility and Sterility (F&S), claiming in the process to having rethought embryology dogma.¹

Really? We don’t think so!

So here is the context: We all by now know about the (in)famous opening section of every issue of Fertility and Sterility (F&S), the mother-journal of the ASRM, where one or more editors of the journal are assigned a theme and then go out to recruit other authors to provide articles, - usually covering different aspects of the targeted subject. The so-selected editors are, of course, chosen for the project based on being perceived as “experts” on the selected subject. And as such they, of course, have opinions which in one way or the other can be assumed to be - rightly or wrongly – biased. In selecting other authors to contribute. One can further assume that there, consequently, will be at least some selection bias at work in favor of opinions that are close to those of the editors.

Responsible editors will be aware of these concerns and will, hopefully, try to avoid them as much as possible. One of the best ways of avoiding such conflicts would be, of course, not to invite collaborators and not to invite yourself to contribute an article (nobody of course will be more biased toward the editors’ opinion than the editors themselves).

So what did these two editors do under the theme “rethinking embryology dogma.” They, first, - as is customary - wrote a brief introductory article as co-authors in which they made the point that in order to achieve progress in embryology, it was essential to learn lessons from the past (we of course fully agree!). But they then went on arguing that this makes opinions from experts in the field “indispensable” to transition from tradition-based technologies or dogma to new, evidence-based approaches and, here, we strongly disagree!.

But this is not yet the end of the story: They then went out and solicited only one article. From whom? From themselves, of course, - with one being the first and the other being the last author. Between the two senior authors, they then added three of the most prominent – if not the most prominent male embryologists, all known to have significantly contributed to embryology:² Jacques Cohen, PhD, can be viewed as father of the concept of embryo selection and many other things, including PGT-A, David K. Gardner, D. Phil, is unquestionably the father of extended embryo culture to blastocyst-stage and an active proponent of many other things including elective single embryos transfer, and PGT-A, and Denny Sakkas, PhD, with 168 references in PubMed just under IVF is certainly also not missing contributions to the IVF field and is in addition a career-long proponent of embryo selection, PGT-A, etc. Nor can anybody doubt that they are really “experts” in embryology.

And if we sat the expectation that we will now here destroy their paper, we will disappoint because we actually liked their review, - especially their discussion of laboratory automation was insightful. But why we liked the paper most of all was because it confirmed our opinions about “expert bias:” Of course not a word about the questions that have arisen about current routine IVF practice (and since we are talking here about dogma), such as routine ovulation triggers at all ages at same follicle sizes, embryo selection beyond morphology, about routine culture to blastocyst-stage, about elective single embryo transfer and, of course – how could we stay away from it – how about PGT-A, - all clearly dogmas in so many IVF clinics, including the authors’. Shouldn’t all of these issues be addressed first before venturing out into hypothetical future automation chambers?

Just a thought!

REFERENCES

1. Rienzi L, Racowsky C. Fertil Steril 2026;125(1):1

2. Rakowsy et al., Fertil Steril 2026;125(1):2-12

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 editorial office of The Reproductive Times or the _CHRVOICE or directly at either ngleicher(at)thechr.com or ngleicher(at)rockefeller.edu

In today’s posting, we are returning to a subject we repeatedly previously addressed. But, interestingly, while still on the forefront in European countries, it – after a short burst of attention following two court decisions - in the U.S. has again disappeared from the medias’ attention. The subject is youth gender medicine.

But ignoring a problem does not solve it and we, therefore, here publish an updated report on the subject from the CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD.

No other subject garnered as many responses on prior occasions from our readers and we are fully aware of the fact that some of you do not agree with the CHR on this issue. But we see this as just another reason to present the facts as we see them. Helping patients in completing their families does not only mean helping them having babies. It also means making their lives more complete and more fulfilled and that also means helping them in being parents. And having children – as this subject so well demonstrates – is not always easy.

We in our next posting will again return to covering more clinical issues directly related to infertility and in the meantime are looking forward to your responses to this article.

The CHR’s Editorial Staff

Several major developments in recent weeks have in the U.S. thrown into complete chaos the practice of gender medicine in children and adolescents with transgender euphoria. First, the American Medical Association (AMA) - until recently a strong supporter of such treatments - “discovered” (oh, - what a surprise!!!) that such treatments really lacked sufficient supportive medical evidence. One, therefore, is of course left wondering what the AMA’s prior support for these treatments was based on, - except, of course, for ideology and progressive politicking? In parallel, a large national surgical society came to similar conclusions, raising the question how come our surgeon-colleagues for several long years found nothing wrong with performing life-changing surgeries on gender-euphoric children who, of course – if left alone or with psychiatric/ psychological support alone – often fully normalize. And then one is left wondering about all the other related medical and non-medical professional societies which found nothing unusual about treating juveniles (at time against the will of their parents) with life changing medical treatments.

It moreover is also important to point out that – rather than self-policing the practice of gender transition in juveniles - medicine has turned this responsibility over to the courts. A first important decision came recently from the U.S. Supreme Court which – unsurprisingly at least for the CHR - found unlawful the in California (amazingly) legal practice of keeping children’s in school expressed desires to gender-transition secret from their parents. A second recent legal event may, however, ultimately turn out to have been even more impactful, - as it defined surgical reassignment surgeries at young ages as potential malpractice and, therefore, involves cold cash: A court – for the first but likely not t last time – awarded an at the time 16-year-old female who underwent bilateral mastectomies as part of her gender transition treatment the significant malpractice award of US$2 million.

Finally, we here address the most recent government interventions regarding the subject which, whether state – or federal government-driven, - almost never make much sense.

Though we in detail covered the subject of medical gender transition of juveniles already in the January 2026 issue of the _CHRVOICE and in a January posting of The Reproductive Times, we – because of the importance the CHR attaches to this subject couldn’t resist here, once more, to update the subject, - considering how many important new events have happened over the last few weeks. Moreover, this subject also offers an excellent example for the lack of self-awareness and, therefore, the failure of self-policing by the medical profession in general, which ultimately can only lead to outside policing by either government or the courts. This is, of course, another prominent subject the CHR feels strongly about (just consider PGT-A in association with IVF, where – similarly after a failure in self-policing medical practice – a series of class action suits have turned over the responsibility to the courts). The CHR is awaiting your responses.

A little bit of history

It occurred suddenly, was explosive, and long overdue, - but it did finally happen: Among several other organizations, two major professional medical societies in the U.S. – after for several years having been outspoken leaders in supporting gender-affirming treatments in children and teens - offered revised public policy statements, now recommending delays to adulthood in so-called gender-reaffirming treatments which – whether medical or surgical - often have lifelong consequences. Though this reflects progress for common sense, the wording – or more correctly what was not said – is still astonishing but not surprising (and was not noted by most media outlets), - considering the societies’ prior public stance in fully supporting such treatments. Their change of mind can, however, not be considered sufficient.

Here – as quoted verbatim by The New York Times,¹ the statement of the AMA:

The American Medical Association (AMA) strongly supports evidence-based, gender-affirming care for youth and opposes government interference in these medical decisions. The AMA emphasizes individualized care, typically deferring surgical procedures for minors to adulthood, while supporting access to care that improves mental health and well-being.

How shameful!

In the first sentence of this statement, the AMA basically fully reaffirmed its longstanding position of opposing all government interventions into medical practice (an opinion the CHR in principle shares, - though, of course, with exceptions: Doesn’t government through the FDA already control some aspects of medical practice? Pharma companies, for example cannot bring to market a pharmaceutical that has not previously undergone a very detailed (and often much too slow) review process by the FDA. But such restrictions do not only apply to pharmaceuticals. Organ transplantation programs in hospitals and, for example gamete donations in IVF clinics (eggs as well as semen) are closely regulated and supervised by the FDA.

But it is the second sentence of the AMA statement that makes it such a shameful document because – in it - the AMA basically pretended always to have advocated deferral of such treatments to adulthood. And that is – blatantly spoken – a lie!

In the past, the AMA to our best knowledge not even once has made the argument that juveniles should not be offered irreversible treatments to transition. One can, indeed, argue that the society aggressively supported the right of unrestricted gender transition at all ages without excluding treatments of minors suffering from gender euphoria.

The CHR, of course, fully supports the rights of adults to undergo gender transition after appropriate counseling, - but we find it reprehensible that, despite a very active visible debate (though mostly in Europe), neither the AMA nor any other major professional organization found it necessary to carve out juveniles from their support of such treatments. If considered “indicated’ by health care providers, the AMA, other professional organizations, and many major academic medical institutions, on many occasions, indeed, defended such highly consequential medical treatments and surgeries exactly under the pretext of the first sentence, - that the AMA opposes government interference into medical practice.

But what should government do when relevant medical societies, like the AMA, The American Society of Plastic Surgeons, The American College of Surgeons (ACS), The American College of Obstetricians and Gynecologists ACOG), the American Society for Reproductive Medicine (ASRM), etc., go rouge or remain silent in the face of unethical medical practices and, indeed, often support such obviously unethical and insanely illogical medical practices in their realms of alleged medical expertise?

Alleged Motivations

As already - in a Piece of My Mind article – in the January issue of the _CHRVOICE suggested, the behavior of organized medicine regarding gender reaffirming medical care of minors has brought shame on all of U.S. practice of medicine. That above quoted statement – even as of this point - is all the AMA is willing to offer is, indeed, quite astonishing. Where is the loud and clear “mea culpa, - we are sorry it took so long” – and only further demonstrates the reckless politization and resulting moral as well as ethical bankruptcy of much of organized medicine in the U.S. How gender transition in juveniles has been handled by organized medicine was, very obviously, not accidental and/or unique. How the COVID pandemic was handled is likely the most obvious general medical example; but the infertility field is not lacking examples either. Just consider how organized medicine has been handling preimplantation genetic testing for aneuploidy (PGT-A) over more than two decades (more on that later).

According to REUTERS,² the American Society of Plastic Surgeons in its statement – like the AMA – now suddenly also concluded that surgeons should in gender-euphoric youths delay gender-related breast or chest, genital, and facial surgeries until a patient is at least 19 years old. The cited reason, - once again of course “lack of evidence supporting the procedure’s benefits.” But if there is lack of evidence now, there was evidence lacking from the beginning. Where has this society of surgeons, therefore, been over so many years during which thousands of children were irreversibly medically and surgically damaged by so many of this society’s members?

And once again, of course no “mea culpa,” no regret!

Nothing, therefore, has very obviously been learned from this ethical as well as clinical disaster, which just resulted in a first million-dollar legal judgment against a psychologist and a plastic surgeon for driving a 16 year-old girl toward a bilateral mastectomy while undergoing gender transition and – as THE FREE PRESS reported - “leaving her disfigured for life.”³ If one does not recognizes one’s errors, one is predestined to repeat them (after a quote from the Spanish-American philosopher George Santayana in his book The Life of Reason, published in 1905).⁴ It seems high time to recognize our errors in this matter, acknowledge them, and change practice!

Many more such trials are on the way and even much bigger pay-outs can be expected, likely also including major medical institutions (often affiliated with famous medical schools and/or universities) that often not only tolerated such practices but even encouraged them. And the motivation(s)? Besides an obvious need for political correctness, these institutions (and the involved clinical psychologists as well as physicians), of course, had unlocked a significant new revenue source, and established yet another new “medical specialty” in which they could present themselves as “experts.”

In a posting on January 31, 2026, on X, Elon Musk – in our opinion correctly - predicted that “there will be thousands of court cases of children who were mutilated by evil doctors, modern day Mengele” (the infamous physician at Auschwitz who experimented on the bodies of Jewish prisoners). While the analogy to Mengele is obviously an inappropriate exaggeration that minimizes Mengele’s human deprivation, it is telling that such an alleged associations can even see the light of day.

Since its existence the CHR has warned about too much government intervention into medical practice; but we have also for decades argued that - whenever medicine fails in policing itself - government not only will, but must, intervene. As the COVID-19 pandemic (among many other valid examples) again so well demonstrated, government is unfortunately not very good at intervening. While there, of course, are many good reasons why medical practice should not allow to be dictated by government, - a main reason is that every decision then quite automatically involves politics. And political considerations, of course, only very seldom concur primarily only based on biological facts. Yet, as the public discussion about gender transforming care in juveniles has evolved, politics have clearly gotten out of hand, and the last few weeks have been especially telling.

The Increasing Impact of Ideology and Politics on Medicine

Here is the paradox: Though everybody in organized medicine claims to oppose government interventions into medicine, political ideology has never before been as influential in medicine as it is now and that impact – if anything – is still growing. To a degree this is not surprising because force always elicits a counterforce. Following a quite radical progressive Biden administration, the current conservative Trump administration is now determined to counteract perceived ideologically and politically motivated interventions into the U.S. health care system by the Biden administration. And the end result is a swinging pendulum that goes from one extreme to the other.

Though by no means the only political and/or ideologically-driven medical treatment discourse medicine currently faces, gender-bending medical care of children has – nevertheless – become the likely, most visible and – for that reason - also most telling example, - demonstrating the dangers of ideology and politics becoming the basis for medical decision-making. In opinion polls a so-called “80:20 issue” (80% against, 20% for gender-bending treatments of juveniles ) – it being at the center of such a volatile political dispute between political right and left - does not really make much political sense. And for states, like California, passing laws prohibiting teachers from informing parents when their children in school are transforming from Michael to Michaela (or vice versa) seems like pure insanity, as most recently fortunately reaffirmed by the Supreme Court (more on that below).

The sad thing, however, is that we physicians allowed this insanity to enter medical practice. That

life-changing and irreversible treatments for gender euphoric children would ever be considered acceptable by medical practice, professional societies, hospitals, and academic institutions is, therefore, deeply disturbing (equally disturbing is, of course, that teachers’ unions have been aggressively supporting above-noted California law that until a recent Supreme Court decision supported the notion that teachers should keep secret from parents their children’s gender transition efforts in school). One, indeed, does not even have to be an educated medical service provider, psychologist or ethicist to understand how illogical – and purely stupid – it is to ask children for informed consent to receive puberty blockers and have major surgeries like mastectomies and/or other irreversible surgeries or other medical treatments.

Similarly, it seems almost incomprehensible that – as now widely revealed - parents were literally forced into giving consent on behalf of their children for such totally unsupported treatments under false pretexts. Many were falsely told that their children otherwise would commit suicide and/or were threatened to be accused of child abuse if they refused such life-changing treatments for their children (more on that below).

Medicine (and with it the AMA and other medical societies) over the last 40 years has transitioned from a politically very conservative field into a politically highly-progressive profession and, in the process, has abandoned objectivity under the influence of ideology. This is very obviously a generational shift, seen not only in medicine (journalism is another very good example). What makes this shift in medicine, however, so peculiar is the fact that medicine during these decades has increasingly argued in favor of so-called evidence-based (i.e., data-driven) ethical medical practice. Only the break-out of a pandemic of ideologic reconsiderations, therefore, can explain previously noted “sudden” recognition by AMA and the Society of Plastic Surgery that gender-bending treatments of children have no evidence to support them.

And just to be unbiased and complete, where have our other professional societies been hiding when it comes to this subject? Where are ACOG, ASRM/SART, and where is ESHRE?

Organized medicine thus does not want a conservative government to insert itself into medical decision making, - but with open arms welcomes so-called progressive ideas into medical practice, - gender bending medical care of juveniles, of course, being a prime example. As a consequence, a radically progressive social ideology has in most aspects driven gender transition practices, - however lacking even minimally required scientific evidence.

Why Most Legacy- as Well as Social-media Have Been In-cahoots

And then there are, indeed, public media, - without which neither ideology nor politics can exist, but which increasingly have lost their common sense. It, therefore, should not surprise that for the longest time – with incredibly few exceptions – media in general ignored the here addressed subject, - until it basically was no longer ignorable.

Above noted AMA and Society of Plastic Surgery statements about gender transition treatments of juveniles, therefore, were all over old and new media. Both in their superficiality, however, at least initially mostly only address the surgical transgressions of the field, - while completely missing that the statements of AMA and the surgery society basically avoided to address non-surgical gender transition treatments like puberty suppressing drugs which, of course, also can have devastating life-long physical effects on children, - not even to mention their psychological effects.

Those recently were extensively discussed in an excellent review article from Sweden.⁴ Why, for example, has there been almost no discussion in the U.S. about differentiating between children with true gender euphoria and only TikTok-socially-infected children? Where have been the professional societies of clinical psychologists and psychiatrists whose members, as part of “transgender medicine teams.” often offered highly biased psychological and psychiatric counseling.

Calling themselves mental health professionals, - so many among them shamefully reaffirmed children in often TikTok-derived euphories, rather than warning them about premature conclusions regarding their often only momentary artificial social euphories. These professionals (or wouldn’t it be more appropriate to call them pseudo-professionals), therefore, ended up driving many of these gender-euphoric youngsters toward lifechanging treatments they later ended up deeply regretting.

And to remain polite - these pseudo-mental health providers often also treated the children’s parents shamefully when indoctrinating often totally unprepared parents with almost unimaginable falsehoods. As already noted above, the worst according to later appearing repeated public statements by so-affected juveniles, likely was the claim that - if not offered these treatments - their children likely might commit suicide. Hearing this from alleged “experts,” - often “famous professors” at major medical schools - one can easily imagine the impact.

The real shame for these pseudo-professionals, however, lies in the fact that the literature actually suggests exactly the opposite: It suggests that suicides in gender-bending youth is actually rare. A recent Finish study, indeed, reported that clinical gender dysphoria does not appear to be predictive of either all-causes of death or of suicide mortality when psychiatric treatment history is accounted for.⁵

On a relevant side note, - isn’t it interesting that most papers on the subject of treating gender euphoric youths have come from Europe. This, of course, also includes the so-called Cass Review in the UK ,⁶ - frequently before discussed in these pages and, undoubtedly, mostly responsible for the counterrevolution against gender determining treatments of juveniles.

And returning to the media, supposedly interested in society’s wellbeing yet, at least initially, almost unanimous in agreeing that government should not intervene in this matter. In almost all cases, legacy- and/or social-media were, indeed, in full agreement with schoolteachers and their unions, which often encouraged and facilitated gender transition of pupils in schools behind their parents’ back and, of course, in a huge majority supported unrestricted treatments of transitioning youngsters at all ages.

Originally led by who-else but The New York Times, the newspaper’s management in 2020 - after the George Floyd events - formally announced a major change in its longstanding reporting and publication traditions by moving from offering “objectivity” (or “neutrality) in information in the news section of the newspaper to “independence,” “fairness,” and “truth.” A. G. Sulzberger, publisher of the newspaper, has been quoted as saying that “independence” is a better descriptor of the newspaper’s goal than “objectivity,” which The Times now argues can be misunderstood as “both-sideism.” This word alone is, of course, in a way symbolic of The Times’ seemingly steadily increasing arrogance as the nations’ principal change agent (for U.S. history, the 1619 Project; for the ethics of journalism above quote by Sulzberger; and for changes in the English language,” both-sideism”). What a word!

While Sulzberger’s comments on first impression may seem like an unimportant word-salad, they had a major impact not only on The Times, - but on almost all media because, if the world-famous Times (“Everything That’s Fit to Print”) acknowledges that objectivity/neutrality no longer matters, why should it continue to matter at other media outlets?

The media world was at that point, of course, already anything but perfect (which it really never was or even can be) and severely contaminated by ideological and political biases; but media organizations were at least still attempting to hide those biases. After Sulzberger’s comments especially the younger generation of journalists, however, suddenly perceived themselves freed from the shackles of objectivity and embraced the ideology of the neo-Marxists of the Frankfurt School who likely represented a majority of their college faculty and always had taught them that objectivity equaled discrimination, for as long as one did not consider whether it involved the suppressed or the suppressors. And under such a viewpoint (and, of course fully compatible with Sulzberger’s statement), personal biases not only had no longer to be avoided in reporting the news, but were, indeed, the right way to see and report the news.

But the ideas of the Frankfurt School did not only penetrate journalism. They penetrated all relevant studies of higher learning, of course including the study of medicine. In short, the changes we above described to have taken place within the journalism field also affected the medical field. Here too, the conclusion reached was that biases were not only allowable but morally and ethically “the right thing to do.” Personal opinions of right and wrong, reflecting what individuals considered independence, fairness, and truth, therefore, entered the businesses of medicine and journalism roughly in parallel.

And the consequences, of course, also were similar: On the journalism side, CNN and FOX News ended up presenting news as often outright opposing realities of the world. On the medical side, whoever held political power decided what was good medicine (and how poorly that works we by know from many examples, starting with the management of the COVID-pandemic, which demonstrates greatly varying outcomes in countries, - not dependent on overall quality of medical services, - but based on what political etiology was ruling).

While in an objective and balanced environment the absolutely ludicrous idea of unrestricted transgender medical care for minors – at times even behind their parents’ back – would likely not even be seriously considered, in an atmosphere of radical diversion between political left and right, the idea garnered a substantial following on the left ideologically and, indeed, evolved into a core issue.

The one media outlet that broke many news stories on the subject was THE FREE PRESS (as then almost every time reported by the _CHRVOICE since this subject has been closely followed at the CHR for years). On February 1, 2026, however, everything changed when Varian Fox - at time of her mastectomies only 16-year-old - was awarded US$2 million in damages. Suddenly however, many more media outlets – beforehand completely disinterested in the subject – discovered the issue of gender medicine in children and young adults as a subject of interest, - among them, of course, The New York Times.^.7 But the title of an article in THE FREE PRESS once again said it best: “A Legal First That Could Change Gender Medicine.”⁸ And, since this legal judgment for the first time established significant financial risks for practitioners and hospitals, we are convinced that it, indeed, will finally change the practice of gender medicine in juveniles in this country.

The in the Debate Still Missing Professional Societies

As already noted, medical societies in general have so-far mostly either remained absent from the debate or – after initially proactively supporting the practice of treating juveniles – have fallen silent. A good example is the American College of Obstetricians and Gynecologists (ACOG) which historically has supported access to gender-affirming care for transgender and gender-diverse youths and has remained silent on the issue since 2021.⁹ In other words, ACOG has failed to at least update the society’s universal (i.e., unrestricted) support for all evidence-based care of juveniles, even though, for example the AMA – as noted above – has clearly recognized that much of widely practices care juveniles had received was not evidence-based.

Yet, amazingly, by not having updated its 2021 policy statement on the subject, ACOG still basically claims that such care does represent “individualized evidence-based care.” Its 2021 policy statement has still not been recalled and/or replaced and also pointed out similar statements of other professional societies, including mainstream societies like the Endocrine Society, and the Pediatric Endocrine Society, and obviously potentially economically conflicted societies like The World Professional Association for Transgender Health, - all of which like ACOG – have not yet updated their policy statements. We here reprint the section affecting adolescents in the 2021 ACOG policy statement:

Medical care and community support that affirms adolescents’ gender identities improves the health and lives of transgender and gender diverse young people.

• Adolescents must be able to live openly and consistent with their gender identity, without fear of stigma, discrimination, or retaliation from clinicians, support systems, schools, communities, and elected officials and other policymakers.

• Health care professionals can play an important role by creating a welcoming, confidential clinical environment, where adolescents can openly discuss issues and needs, including sexual and reproductive health, disclosure of gender identity to their families and communities, community resources and support, and gender transition care.

• ACOG joins major medical associations in supporting access to evidence-based gender affirming care for transgender youth, free from political interference.

• Medical experts in transgender care, including the World Professional Association for Transgender Health, the Endocrine Society, and the Pediatric Endocrine Society, have published guidelines on how best to care for transgender adolescents, including the provision of gender affirming care.

• There is no uniform transgender experience. Each individual will desire different outcomes, underscoring that as with all care, health care and counseling for transgender youth should be individualized, confidential, evidence-based, and free from discrimination and government interference.

• Health care professionals alone cannot provide the support transgender adolescents need.

And we, of course, are also still missing our principal professional societies in the infertility field in this debate: Neither ASRM nor ESHRE – to the best of our knowledge after literature searches – have ever addressed here discussed issues. One really wonders how that can be!

As the gaps between political left and right have increasingly become more pronounced, this likely reflects a politically understandable strategy for many professional societies but, on an ethical and professional level, seems cowardly since - after all - the first rule of medical practice is, “to do no harm.”

And doesn’t this rule also apply to medical societies?

That so many relevant societies have remained silent on the subject is, therefore, disappointing.

Considering the widening gap between opinions, we found a relatively recent statement by the European Academy of Paediatrics of interest because it succeeded in directing the attention toward inappropriate treatments in adolescents by pointing out that treatments like pubertal suppression and administration of cross-sex hormone in children and teenagers require more research. The society thus basically acknowledged that current evidence was insufficient. Since this opinion – overall – was well written, we below reprint the document’s abstract summary.¹⁰

And the Latest Developments

When – as noted above - the Trump administration, under the threat of cutting Medicare reimbursement to hospitals for non-compliance (including in New York State) published a U.S Department of Health and Human Services order to disallow gender-affirming treatments in children and young adults, New York State Attorney Letitia James, JD, - based on past public pronouncements during her first election campaign and her later legal actions against President Trump personally not a Trump-lover – in return threatened New York state’s hospitals with lawsuits if they complied (we will return to this point below). But, as the media started to better understand that U.S. gender medicine had reached a point where it had to choose between a collapsing consensus within the medical community on pediatric and adolescent transition treatments and children’s’ well-being, - the interference by blunt politics started to get out of hand.¹⁰

Glenna Goldis, JD, reported in THE FREE PRESS her own personal story of how she - a progressive lesbian and specialist prosecutor of consumer fraud in the New York State Attorney’s office – was fired by James because she participated in a public demonstration that had called out gender affirming care in minors (see picture below).⁷ New York’s States Attorney therefore - quite obviously - feels strongly that minors should remain subject to gender-changing treatments.

But – unfortunately quite obviously only based on legal and financial rather than ethical and humanitarian considerations - NYC’s hospital industry apparently did not stand with James on this issue. On February 16, 2026, NYU-Langone Health, one of the city largest hospital network which also includes the city’s currently highest ranked medical school, publicly announced that it had discontinued its gender-affirming medical program for minors.

And this decision did not only include stoppage of debilitating surgeries, - but also meant for patients under age 19 cessation of puberty blocking treatments and other hormonal therapies. According to media reports, this decision was driven by “the current regulatory environment” (no kidding!) and threats of federal funding loss under new executive orders.⁸ But – if we have to guess - it may have been more influenced by – as already noted earlier - a court for the first time awarding US$2 million in malpractice damages to a 16-year old whose breast were removed as part of gender reassignment treatments she received.³

Gender-affirming care for adults, however, continues at NYU, and we see nothing wrong with that. How sad, however, that NYU could not bring itself to simply stating that the hospital was just trying to do the right thing when it comes to the treatments of children and adolescents!

Instead – obviously in view of the political landscape in the city of New York and the state - the institution practically apologized for the decision, - suggesting that it was forced upon NYU by the Trump administration’s executive order. The CHR, of course, wished NYU, instead, had apologized for allowing for so many years this kind of medical care within its walls in the first place.

But you have to give it to the NYU administration, they do know their city and state government because only three days after announcing the closing of the program on February 20, 2026, NYS Senator Kristen Gonzalez shot off a threatening letter to NYU Dean and CEO, Robert L. Grossman, MD, under the heading, - “73 NY Legislators Demand NYU Langone Reverse Discontinuation of Youth Gender-Affirming care Program, in letter led by NYS Senator Kristen Gonzalez.”⁹ And we here quote from the press release announcing the letter:

And it, indeed, did not take very long for New York state’s Attorney General to follow up with her own threatening letter to the NYU-Langone administration, demanding that the hospital resume gender affirming care for minors.⁹ The poor NYU administration now finds itself caught between opposing legal demands (and, therefore, of course financial threats) from federal and state governments.

But NYC and New York state are, of course not alone in opposing the Trump administration on this issue: California also appears to continue supporting the concept of transgender care for children and juveniles because – as just reported by Jill Cowen in The New York Times – California sued the largest health system for children in the state, Rady Children’s Health, to prevent it from ending gender-related treatments for transgender young people. The state’s attorney general, Rob Bonta, JD, (remember his name!) in a lawsuit claimed that the hospital system had violated a legal agreement with the state by unilaterally deciding to stop providing hormone treatment and other gender-related health services to patients under age 19.¹¹

It is remarkable how illogical and inhumane politics can become, - incited by nothing else but political hunger for power. And culpability lies, of course, on both sides of the political spectrum because – as much as the two state attorney generals have no business in telling hospitals how to practice medicine - so doesn’t the Trump administration. Which brings us to a point the CHR has been making and advocating for years, - if not decades: When the medical field fails in self-policing itself, government will - and indeed, must of course – insert itself as a last resort and that then becomes the kind of political mess we are now observing here. Once this point is reached, what is best for medicine - in this case what is best for children - no longer matter because under such circumstances only political ideology rules.

But things, of course don’t need to end this way. Europe in this case offered a much better alternative which started with the British medical community authorizing the so-called Cass Review, a several years-long scientific review of the medical literature led by a prominent academic pediatrician which concluded that – then widely practiced treatments for gender change were not sufficiently evidence supported to continue them.⁶ Though not everybody agreed with this principal conclusion (as is, and should be, the case with practically any scientific publication) medical communities (as well as governments where applicable, - though in most countries those were decisions made by the medical field) agreed that – considering medicine’s first ethical rule of “doing no harm,” these treatments must be stopped. And that is exactly what happened throughout Europe!

Note the difference: no need for interventions by government dictum, and no opportunity for political grandstanding by attorney generals (though Six European Union countries have outlawed “unnecessary” surgeries, including Malta, Germany, Iceland, Greece, Spain, and Portugal). Reflecting the importance of “first do no harm,” it is remarkable that – in contrast to the U.S. – liberal Scandinavian countries were especially proactive in prohibiting gender transition treatments in juveniles. What does this say about our supposedly liberal states, like New York and California which are the strongest supporters of transgender care to juveniles?

A very well written summary by Emily Yoffe, a senior editor at the publication, on the rise and fall of youth gender medicine worldwide, including of course, the U.S., was presented in a recent article in (where else?) THE FREE PRESS, - under exactly that title.¹²

And also related and very timely, Amanda Lock Swarr in Science¹³ reviewed a book by Iain Morland who she calls – arguably – the foremost theorist of critical intersex studies. The title of the book is “Intersex” and Moreland’s key criticism of current clinical practice is that - “… regardless of outcome, intersex is never erased by surgery.” The question then, of course, becomes, why would anybody expect surgery to work in transgender situations (see below)?

After President Trump on January 28, 2025, signed earlier noted executive order under the title “Protecting Children from Chemical and Surgical Mutilation,” which restricted access to gender affirming care to individuals under age 19 – with considerable delay in comparison to most of Europe - at least some sanity appeared to have entered the realm of juvenile gender transition treatments in the U.S. According to several media reports approximately 21 to over 40 hospitals have in the U.S. since paused or ceased gender affirming care to minors, among those – besides NYU-Langone – other well-known academic institutions, like Children’s Wisconsin, Children’s Hospital Los Angeles, and Children ‘s National Hospital in Washington, DC.

A report in The New York Sun claimed that Medicaid spent more than US$100 million over the last five years on gender treatments and surgeries for minors.¹⁴ Other reports by recently more interested media regarding this subject extensively reported on the Supreme Court Decision in early March (Mirabelli vs Bonta/Olson) which blocked a California law that allowed schools to conceal a student’s gender transition in school from her/his parents. Amazingly, California state law supported this and it took this landmark decision on March 2, 2026 by the U.S. Supreme Court to end this outrage:¹⁵ The Court in a 6-3 ruling (what did the 3 judges who voted against this opinion really think?!) held that the state of California cannot keep student “transgender” identities secret from parents, with the argument being that the secretive policies likely violate the First Amendment rights of the children’s parents.

Because Christian teachers and parents were the parties challenging the California law in court, the uber-liberal New York Times –– reported on the Supreme Court’s decision under the headline, “Supreme Court Sides with Religious Parents …”¹⁶, - as if gender transition of juveniles was just a religious issue. It, of course, is not only a religious issue but an in principle ethical and humanitarian issue which, unfortunately, has also become a divisive principally political issue between left (pro) and right (against) that over the years has assumed absurd proportions. In conservative Texas the conservative attorney general (who is also running for the Senate) threatened “consequences” to Texas health professionals – whether physicians or therapists – who facilitate “those radical procedures.”¹⁷

Summary and Conclusions

In short, how children and young adults up to age 19 should be medically treated if they - for whatever reasons - are considering a gender transition is up in the air. The principal reason is that the medical field has allowed political ideology rather than medical evidence to dominate the discussion. If one were to follow the “first, do no harm” principle, there – like in Europe – the matter would have been settled a long time ago because - considering the time this dispute has remained unresolved is evidence enough that currently available evidence levels for almost any treatments besides psychotherapy are insufficient. Consequently, none of these treatments should be offered outside of properly (by parents) consented clinical trials.

Because the medical establishment, due to obvious political interreferences and motivations, cannot agree on this common sense and in medicine basically routine standard of care, the definition of what standard of care should be, - is being farmed out to the court system, with every aspect of the discussion likely destined to reach the Supreme Court. And this is not only deplorable but – frankly – to a significant degree undermines the already very much weakened authority of the medical health care system after the COVID-19 fiasco.

But – whether for the good or bad – while the Supreme Court will ultimately define the relevant legal principles of gender transition treatments in minors, the court system will at much lower court levels affect medical practice in this arena in an also even more important way, - through malpractice suits!

As Ilan Musk correctly noted, following the recently successful first case in which a young female plaintiff who underwent a bilateral mastectomy at age 16, was awarded US$2 million in damages, there will be hundreds, - if not thousands – cases like this filed all over the country which will keep the court system busy and active practitioners in the field and the clinics, hospitals and surgery centers that support these practices on their toes. And we, indeed, predict that these court cases will be more effective than the big Supreme Court cases in stopping irresponsible gender transition treatments in their tracts.

But this is, of course, anything but good news, because does medicine really want to turn over how we practice medicine to the courts? And the here presented circumstances regarding gender transition are, as we in the infertility field have recently learned, not the only example. Just think about the multitude of class action suits filed recently all around the country by attorneys against PGT-A (preimplantation genetic testing for aneuploidy) laboratories.¹⁸ There, too, the CHR for many years has been warning that the IVF field, ultimately, will either face an intervention by government (FDA) of from plaintiff lawyers. And the latter – the worse of the two risks – now already happened, - just because medicine cannot police itself!

REFERENCES

1. The New York Times. February 4, 2026. https://www.nytimes.com/2026/02/04/health/gender-surgery-minors-ama.html

2. Sathosh C. Reuters. February 3, 2026. https://www.reuters.com/business/healthcare-pharmaceuticals/us-plastic-surgeons-group-advises-delaying-gender-surgery-until-age-19-due-2026-02-03/

3. Ryan B. The Free Press, February 1, 2026. https://www.thefp.com/p/a-legal-first-that-could-change-gender

4. Linander I, Lauri J. Social Health Illn 2026;48(2):e70141

5. Ruuska et al., BMJ Ment Health 2024;7(1):e300940

6. The Cass Review. Final Report. Archived June 20, 2022. https://webarchive.nationalarchives.gov.uk/ukgwa/20250310143829/https://cass.independent-review.uk/about-the-review/

7. Goldis G. The FreePress. January 27, 2026. https://www.thefp.com/p/i-was-fired-by-new-yorks-attorney-gender-affirming-care

8. Jacobs A. The New York Times. February 3, 2026. https://www.nytimes.com/2026/02/03/health/gender-surgery-malpractice-varian.html

9. Press release, Kisrten Gozalez. February 20, 2026. https://www.nysenate.gov/newsroom/press-releases/2026/kristen-gonzalez/73-ny-legislators-demand-nyu-langone-reverse. Accessed March 7, 2026

10. Offenhartz J. AP. March 3, 2026. https://apnews.com/article/nyu-hospital-letitia-james-trans-3d6b918fd7b084642698cb8246bec0d2

11. Cowan J. The New York Times. February 8, 2026;p14. https://www.nytimes.com/2026/02/06/us/california-children-hospital-transgender-care.html

12. Yoffe E. The Free Press. February 5, 2026; https://www.thefp.com/p/the-rise-and-fall-of-youth-gender?utm_source=substack&publication_id=260347&post_id=187025125&utm_medium=email&utm_content=share&utm_campaign=email-share&triggerShare=true&isFreemail=false&r=5dj1m5&triedRedirect=true

13. Lock Swarr A. Science 2026;391(6780):p31

14. Ryan B. The New York Sun. Updated February 26, 2026. https://www.nysun.com/article/medicaid-spent-over-100-million-in-five-years-on-gender-treatments-and-surgeries-for-minors-government-investigator-finds

15. Clancy K. Liberty Justic center. March 3, 2026. https://libertyjusticecenter.org/newsroom/u-s-supreme-court-delivers-historic-groundbreaking-victory-for-parental-rights-dismantles-californias-secret-gender-transition-regime/

16. Marimow AE. The New York Times. March 2, 2026. https://www.nytimes.com/2026/03/02/us/politics/supreme-court-california-trans-students.html

17. Cortright B. The New York Sun. March 3, 2026. https://www.nysun.com/article/texas-mental-health-professionals-prohibited-from-providing-radical-gender-transition-treatment-to-minors

18. Duchame J. Time. March 6, 2026. https://time.com/7264271/ivf-pgta-test-lawsuit/

And what we, therefore, today are posting are brief summaries of the subjects the A.I. world directed us toward with special emphasis on issues where the CHR disagrees with what you may be hearing elsewhere.

By doing so, the CHR, of course, does not want to imply that the CHR is always right and others are always wrong (even though - at least in most such cases - that is, of course, the case), but we want to reemphasize that there are difference of opinion within the infertility field and the CHR feels that patients are frequently not advised of these controversies.

So, for example, we are still almost daily reminded by patients that many fertility clinics to this day fail to inform their patients about the controversies surrounding preimplantation genetic testing for aneuploidy (PGT-A), all-freeze cycles, etc. Franky, - we consider this not only surprising, - but shameful because it denies patients self-determination.

We hope you will enjoy today’s posting, and we promise to address the direct needs of our non-medical readership more often. What today’s posting, however, also reveals is that we read your comments and take them seriously. So continue sending them!

The CHR’s Editorial Staff

Like hopefully most providers of fertility services, the CHR is always interested in improving its institutional understanding of how the public views various fertility services routinely provided by most fertility clinics in importance complexity levels, accessibility, etc. We, therefore, recently asked several A.I. platforms which infertility diagnoses the public perceives as most difficult to treat. And – though there were small discrepancies between various platforms, there was surprisingly considerable unanimity and we, therefore, decided to summarize these subjects for this issue of The Reproductive Times.

It seems that everybody agrees that a single universally agreed upon “hardest” infertility problem does not exist, but in clinical reproductive medicine a few conditions consistently stand out as the most difficult to treat and least responsive to current therapies. The answer also depends on how “difficult” is defined. It ultimately depends on whether “hardest” means biologically untreatable, low success rates, or limited available interventions. Here are the main contenders:

Diminished Ovarian Reserve (DOR) / Ovarian Aging, at the CHR Called Low Functional Reserved (LFOR)

Because the CHR’s worldwide reputation as a leading fertility center of last resort evolved over the years to a large degree from the center’s innovative treatment of what in the infertility literature is usually called diminished ovarian reserve (DOR) – though the CHR prefers the term low functional ovarian reserve (LFOR) – we were very pleased to learn that most platforms considered DOR/LFOR the most fundamentally limiting problem in infertility care.

Here is why the CHR prefers the term LFOR: Everybody agrees that the total ovarian reserve is made up of two components, - with the first being the so-called pool of resting (or primordial) follicles – and the second pool being so-called growing follicles (i.e., the follicles that have been recruited out of resting stage and over three or more months either grown and mature toward ovulation or die and get absorbed).

When a patient’s ovarian reserve is evaluated with either FSH and/or AMH measurements (or even antral follicle count) we are, however, only evaluating the growing (i.e., functional) follicle pool. We have really no way to assess the resting follicle pool size, except for the fact that resting and growing follicle pools maintain a correlation in their respective numbers: A small growing follicle pool, for example, also means a small resting follicle pool and, of course, vice versa. Figure 1 below demonstrates the decline in growing follicles with advancing female age and the in parallel increase in poor quality oocytes produced by those remaining follicles in ovaries with advancing female age.

Since follicles produce the AMH hormone, its levels reflect the FOR. Approximately 10% of all women -independent of race, ethnic background or any other patient characteristic will end up with a diagnosis of premature ovarian aging (POA) which, of course, can be mild, moderate or severe. Approximately 1% of those 10% (i.e., 1 in 100) will demonstrate primary ovarian insufficiency (POI) defined by amenorrhea, FSH above 40.0 mIU /mL, undetectable AMH, - all reached before age 40.

So why is treating DOR/LFOR so relatively difficult?

• The ovary contains a finite, non-renewable pool of follicles.

• Both quantity and quality (aneuploidy rates) decline with age.

• Pregnancy chances are strongly tied to egg biology, which currently can still not be reversed.

Clinical reality is that:

• Even with in vitro fertilization (IVF), success rates drop sharply with age.

• No therapy reliably improves egg quality in everybody, though some therapies are effective in selected patient groups.

• Egg donation is, therefore, often the only highly effective option, which – unfortunately – leas many, if not most, IVF clinics to conclude that all women above age 42-43 should be advanced into egg-donation cycle.

• Increasing numbers of fertility clinics leave patients, indeed, no choice.

• This is, however, not the CHR’s practice: At the CHR, patients are not told how to live their lives. They instead are – with full transparency – told their chances with all available treatment options, - and then it is the patients’ choice which treatment they wish to receive.

• It is, likely, the strong desire of most patients (husbands often even more so than their wives to – first of all - work with their own eggs, - even if that means lower pregnancy chances than with donor eggs.

• Donor eggs can be and are nowadays frequently used into the mid-50s (and sometimes beyond); they, therefore, remain an option for quite some time, while a woman’s own eggs, of course, vanish.

Poor Oocyte and - Consequently - Embryo Quality Due to Various Causes Including Aneuploidy

Oocyte and, therefore, embryo quality are obviously linked to aging; but they, nevertheless, can be conceptually distinct in what the cause is for poorer quality. The best way to illustrate this fact is to point out that there are young women with older behaving ovaries and older women with young behaving ovaries, - just as there are young women who look older than they are and older women who look younger.

Which brings us to what makes and oocyte be of poor quality? And the answer is that advanced age, can, of course, be responsible; but, even if poor quality is age-related, it can have several different causes. It may at random be a “bad” cycle; the patient may have received inappropriate gonadotropin stimulation; the timing of her egg retrieval may have been off; the embryology laboratory may not be great, and once egg quality is bad, embryo quality will be bad as well.

And then there is, of course, aneuploidy (an abnormal set of chromosomes), - with the likelihood of aneuploidy in oocytes and embryos increasing with age. Figure 2 below schematically demonstrates how a blastocyst-stage embryo is diagnosed in what is called preimplantation genetic testing for aneuploidy (PGT-A) resulting in either a “normal’ (i.e., euploid) test result, in “aneuploidy” (all cells presumed to be aneuploid), and in a “mosaic” result (the embryo is presumed to have a mix of normal and abnormal cells.

Because miscarriages in over half of all cases were demonstrated to show abnormal karyotypes (abnormal chromosome numbers), the hypothesis arose over 20 years ago that IVF pregnancy and live birth rates (per embryo transfer) could be improved by testing an embryo’s chromosomal complement before transfer, - and transferring then, therefore, only “euploid’ embryos. This testing, initially given the name preimplantation genetic screening (PGS) or preimplantation genetic diagnosis (PGD) was later renamed PGT-A.

Investigators at the CHR – after reanalyzing published data form Belgian investigators, - however already in 2005/2006 developed serious concerns about the hypothesis of testing embryos in this way and not only concluded that this kind of testing very likely did not improve IVF cycle outcomes but – especially in older women, indeed, reduced pregnancy chances. Almost 20 years later, even the American Society for Reproductive Medicine (ASRM) finally concluded in September of 2024 in a formal “Opinion” that PGT-A to this day has not demonstrated any outcome benefits for IVF, - but to this day has still not made a final statement concluding – as the CHR’s investigators and a small group of other scientists by now have well established – that PGT-A utilization for several subpopulations of IVF patients, especially women who produce small embryo numbers and/or who are older – may, indeed, reduce pregnancy and live birth chances.

There are many reasons for this and here is not the place to go into further detail (see our Reading List for that purpose below) but it is now really already appropriate to say that PGT-A is simply a “lousy” test which for several reasons never can offer a reasonably accurate embryo diagnosis about its ploidy status to make the crucially important decision whether an embryo deserves to be excluded from transfer. Since most errors in diagnosis are so-called “false-positive” diagnoses, this means that such a diagnosis automatically reduces a patient’s cumulative pregnancy and live birth chance which this falsely deselected embryo usually would have offered the patient.

The genetic testing laboratory industry in 2016 only further confused the issue by introducing the diagnosis of “mosaicism” to PGT-A (before that date embryos were diagnosed only binary, as either “euploid” or “aneuploid.” Even though simple logic would already suggest that taking at random from a ca. 250 cell blastocyst-stage embryo a biopsy of only on average 5-6 cells mathematically cannot reflect the complete embryo, the introduction of “mosaicism,” of course only further complicated, therefore, the interpretation of results. Figure 3 below schematically demonstrates the concept.

In contrast to most other IVF clinics in the U.S. and really the rest of the world, the CHR, therefore, does not recommend the routine utilization of PGT-A in IVF cycles, though, of course offers the test if patients so desire. The test is unfortunately too often described as “accurate” in diagnosis, though “unfortunately unable to correct those embryos.” This is a categorically incorrect description of the test. The principal shortcoming of PGT-A does not lie in its inability to “correct” chromosomal abnormal embryos but in the test’s very high false-positive diagnosis rate which leads to disposal or other non-use of many embryos with good pregnancy and delivery chances for chromosomal-normal offspring.

This was also proven for the first time by the CHR where investigators (in collaboration with two at that time still existing other IVF clinics) in 2014 started transferring selected by testing as “aneuploid” diagnosed and reported embryos. In the fall of 2015 the CHR reported the first 4 chromosomal-normal pregnancies after transfer of such “abnormal” embryos. The CHR has continued this practice and established a case registry for such transfers, which every few years is published, demonstrating a steadily growing number of healthy children born from those transfers.

Since the CHR, as noted above, does not recommend PGT-A to its own patients, most of the “abnormal” embryos the center transfers are moved in from other IVF clinics which – to this day – refuse such transfers.

Severe Endometriosis

The emphasis here is on the word “severe” because – frankly speaking – nobody even knows with certainty what the prevalence of mild endometriosis really is. After all, a significant portion of mild endometriosis is microscopic. Even laparoscopy, therefore, can miss endometriosis. We, therefore, here do not offer a general discussion of endometriosis in regard to infertility but will try to make a few important points which are not often well understood by infertility patients and the public in general.

• Not every woman with endometriosis is automatically infertile. Indeed, many women with endometriosis are normally fertile and may not even know that they have endometriosis.

• Mild endometriosis can be very symptomatic, while even very severe endometriosis may be so asymptomatic that patients don’t even suspect that they have the disease.

• Once a decision has been reached that a patient requires IVF, whether she does or does not have endometriosis no longer matters because presence vs. absence of endometriosis does not change IVF protocols.

• Therefore a diagnostic laparoscopy after one or more failed IVF cycles “to find out whether a patient has endometriosis – as we frequently see in the history of patients – makes absolutely no sense.

• All of this also means that so-called restorative reproductive medicine (RRM), proposed by some right wing political pundits in a Republican think tank, supposedly meant to treat “root causes” of infertility like endometriosis (through surgery) rather than IVF, is pure nonsense.

•. There are good reasons why IVF has replaced surgery in most cases of endometriosis when the goal is fertility. Surgery may, however, still be the best treatment choice when the primary problem is not infertility but pain.

•. And a final word about the use of surgery in endometriosis: It can be very difficult to say “no” to cutting away once one is in surgery and sees pathology. Especially in the older days it was not uncommon to see women going into endometriosis surgery with good ovarian reserve and coming out of surgery in menopause.

From Intrauterine Adhesions to Full Blown Asherman’s Syndrome

That this subject would rank among the most difficult to treat fertility related conditions came somewhat as a surprise, - not because a true Asherman’s syndrome (see Figure 5) obliterating part or all of an endometrial cavity is not, indeed, an extremely difficult to treat condition but because true Asherman’s are fortunately rare. In contrast, endometrial adhesions here and there are quite frequent, - but in most cases do not represent a major treatment problem.

Some very recent reports from Spanish investigators suggested that bone marrow-derived stem cells may turn out to improve standard treatments of Asherman’s syndrome which traditionally only involved dissection of the scar tissue during hysteroscopy with insertion of a ballon into the endometrial cavity to prevent re-adhesion of anterior and posterior uterine walls and accompanied by high-dose estrogen treatments.

Severe Uterine Factor Infertility

Once again the emphasis is on the word “severe” because minor uterine pathologies are usually not too difficult to overcome. Figure 6 offers schematic drawings of congenital – so-called Müllerian uterine abnormalities. Most of these abnormalities are best left alone but the literature suggests that so-called septate uteri may benefit from septum resections. One has, however, to be careful in differentiating between septate and arcuate uteri, because the latter does not benefit from resection and risks uterine perforation.

Uterine reconstructions for bicornuate or even diadelphy uteri, in contrast, are usually major surgeries, requiring special surgical skills. The same applies to reconstruction of uteri after major myomectomies because myomas (fibroids) – especially if protruding into the endometrial cavity can interfere with implantation and/or increase miscarriage risk if embryos implant on such a protruding fibroid.

“Unexplained” Infertility also Called Idiopathic Infertility

This is a frustrating diagnosis for patients as well as physicians because it basically states that the treating physician has no idea what a patient’s (infertility) diagnosis is. For many really good reasons, the CHR has, indeed, very “strong” (negative) feelings about this diagnosis, which in many textbooks is still considered a valid infertility diagnosis. Indeed, some colleagues claim that it may involve up to approximately one-third of all infertility cases.

We don’t think so and, indeed, consider this diagnosis an outright oxymoron. And here is why: Like in any attempt in life to discover something, the success of the efforts will depend on how deep one digs. Infertility is not different: An attempt at finding one or more causes for a couple’s infertility can be more or less superficial (or should we say more and less in depth). Several years ago, the CHR’s investigators, indeed, published several papers on the subject, arguing that – if the investigation is only deep enough – this diagnosis basically does not exist.

This is also a very basic reason why obtaining a very detailed patient history and then performing – based on this past medical history – a very detailed and directed diagnostic work-up is at the CHR considered of major importance. In short, we do not believe in “unexplained” infertility!

Repeated Implantation Failure (RIF)

This is yet another widely applied diagnosis in the fertility field, the CHR has significant problems with. And once again, here is why: The medical literature in general considers a patient to qualify for the diagnosis of RIF after two unsuccessful attempts at embryo transfers in IVF with good quality embryos. And this definition – to say it mildly – is absurd because even at peak fertility (ca. at age 25) only 1 in 3 good quality embryos will lead to pregnancy.

How do we know this? Because it takes a couple at peak fertility on average ca.3.4 months to conceive. And since every normal couple at that age can be expected to produce on average one embryos every month, the math is simple and straight forward. As women get older, their oocytes (eggs) become progressively less efficient in producing good quality embryos and, therefore, pregnancy chances decline. Though numbers are more discrepant by age 45 than age 25, it is reasonable to assume that by that female age the 1:3 ratio of embryos leading to pregnancy reaches a ratio of 1:15 to 1:20.

To consider two failed embryo transfers with good quality embryos as qualifying for a RIF diagnosis, therefore, not only is not sensical for a couple at peak fertility around age 25, - but makes even progressively less sense as women advance in age. In other words, to reach a RIF diagnosis independent of considering a patient’s age is – as noted above - simply absurd and is just another example for how often too much of currently widely accepted infertility practice makes absolutely no sense!

Suffice it to say, the CHR never makes a RIF diagnosis without adjusting expectations to female age which in practical terms means that even in the CHR’s highly adversely selected patient population - which frequently involves women who failed many IVF cycles even before coming to CHR – we hardly ever end up considering a patient a RIF patient.

And why is this important? Figure 7 below offers the answer: The figure not only depicts graphically possible ways to real IF but also the possible obstetrical and neonatal consequences one has to consider from such a diagnosis. In other words, a false-positive diagnosis of RIF will lead to a considerable number of unnecessary and costly treatments and, in the end, may indeed negatively affect outcomes.

Immunological Infertility Including Repeated Immunological Pregnancy Loss

Because the CHR, since its founding, has been one of only very few fertility clinics not only practicing reproductive immunology but conduction an ongoing research program in reproductive immunology, this has been a subject of repeated and constant discussion in these pages. We, therefore, will not go into much detail but, still, want to reiterate a few key points where the CHR – once more – disagrees with what likely represents a significant majority of colleagues in the field:

• Because pregnancy under normal circumstance is a semi-allograft (50% genetically “foreign” transplant from the male partner) and a full (100%) allogeneic transplant in cases of egg donation, gestational carrier pregnancy or embryo donation, the CHR considers pregnancy in principle to be primarily an immune system-driven condition, - as tolerance induction in the maternal immune system must predate any other maternal influence on the pregnancy, - including endocrine effects.
• Most colleagues disagree with this conclusion and, therefore, still view pregnancy primarily as an endocrine condition.
• Considering this divergence of opinion, it cannot surprise that the CHR considers immunology as an essential component of infertility practice, - while a majority of colleagues consider immunology at best as a minor influence and, often, as completely irrelevant.
• In some contradiction, even immune-skeptic colleagues, however, usually acknowledge that immunology plays a role in implantation and in some pregnancy losses.
• The CHR believes that involvement of the maternal immune system in (a still unknown percentage of) miscarriages must be considered as established, with this kind of pregnancy loss being called immunological pregnancy loss.
• Because the ultimate role of the maternal immune system in the implantation process is still only incompletely understood, many aspects of this immune response (normal or abnormal) are becoming increasingly clear, - among those that establishment of tolerance likely is not a one-step process that either functions normally or not. It instead likely involves several steps over time, starting with local immune tolerance followed by systemic tolerance, - likely fully completed only by the beginning of the second trimester of pregnancy.
• How the maternal immune system, ultimately, tolerates the logarhythmically growing “tumor of pregnancy” is still not well understood (organ transplantation demonstrates how difficult adequate tolerance development is even if the transplant – except for liver transplants – usually does not increase in size). Some evidence, however, suggests that this may be a so-far undefined function of the to the fetus extracorporeal placenta and its maintained aneuploidy environment.

Consequently, patients with reproductive immune problems can expect at the CHR a very different treatment approach than at most other IVF clinics.

READING LIST
Gleicher N, Weghofer A, Barad D. Defining ovarian reserve to better understand ovarian aging. Reprod Biol Endocrinol 2011; 9:23
Cohen J, Chabbert-Buffet N, Darai E. Diminished ovarian reserve, premature ovarian failure, poor ovarian responder – a plea for universal definitions. J Assist Reprod Genet 2015;32:1709-1712
Gleicher N, Barad DH, Patrizio P, Orvieto R. We have reached a ded end for preimplantation genetic testing for aneuploidy. Hum Reprod 2022;37(12):2730-2734
Orvieto R. Preimplantaton genetic screening – the required RCT that has not yet been carried out. Reprod Biol Endocrinol 2016;14:35
Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020;382:1244-1256
Santamaria X, Pardo- Figuerez, Gonzalez-Fernandez , Querol S, Rodruguez L, Valcarcel D, et al., Autologous cell therapy with CD133+ bone marrow derived stem cells for Asherman Syndrome a phase 1&2 trial. Nat Commun 2026;17:1093
Santamaria X, Rosen B, Perez-Moraga R, Verkatesan N, Pardo-Figuerez M, et al., Nat Commun 2023;5890:14
Gleicher N, Barad D. Unexplained infertility: Does it really exist? Hum Reprod 2006;21(8):1951-1955
Kricinska AM, Maksym RB, Szewcyk G. Immunological causes of Infertility: Diagnostic Perspectives. Biomolecules 2025;16(1);39

NEWLY APPROVED AND REGISTERED CLINICAL TRIALS AT THE CHR, - READY FOR ENROLLMENT

Please call our registration desk at (212) 994 4400 if you or a friend is interested in further information.

In today’s posting we present a broad overview about recent literature on the Polycystic Ovary Syndrome (PCOS). It seems like the subject is finally gaining some new and urgently needed traction and we hope to contribute by disseminating the new knowledge.

Please let us know what you think and – just as a reminder – we always welcome your comments and ideas and we – still – offer subscriptions to this publication for free.

The CHR’s Editorial Staff

MORE GENOMIC STUDIES ON PCOS SUBGROUPS/PHENOTYPES - That PCOS is likely not one single condition has been known for decades, even though agreement was never reached how many “phenotypes” the syndrome indeed represented. The most widely accepted classification (called Rotterdam criteria) defined PCOS by four phenotypes (A, B, C, and D), with especially some leading members of the Androgen Society having argued for the longest time that the D-phenotype should really be separated from the other three phenotypes.

More recently – using varying approaches and new research technologies the understanding of PCOS has shifted. Using clinical observations and genomic analyses, a new understanding of PCOS evolved: Over a decade ago PCOS – more or less accidentally - became a major research area at the CHR after we in preparation for a minor planned aging study of PCOS patients pulled all of the CHR’s PCOS patients out of the center’s electronic medical record data base and - to our surprise and really shock - discovered that the CHR almost exclusively had serviced only phenotype-D PCOS patients, - widely considered the smallest group of PCOS patients. Initially convinced that this must have been a coding error, we repeated the search, - only to confirm the results.

It then dawned on us that – as a last-resort fertility center (over 95% of CHR patients received and failed fertility treatments, usually IVF cycles, before reaching out to the CHR) – the A, B, and C – phenotype PCOS patients must be conceiving before reaching CHR, while something in the D-phenotypes must prevents these patients from conceiving even with IVF, which is why these women end up reaching the CHR in otherwise unheard proportions. Unsurprisingly, this conclusion activated our curiosity, and the rest is by now history.

Based exclusively on clinical observations in these patients the CHR’s investigators concluded that PCOS was basically a condition likely made up of only two phenotypes, a first representing mostly what under Rotterdam criteria was called phenotypes A, B, and C and – more-less in analogy of earlier suggestions by the Androgen Society – and a second group representing what had been the D-phenotype, also called the “lean” PCOS phenotype in contrast to all the others which are characterized by truncal obesity.

The CHR’s investigators – based only on clinical observations - were, therefore, the first to publish that PCOS likely represented only two distinctively different patient sub-groups with different relevance for fertility but also for their long-term well-being (there, of course, also exist overlapping cases).^1,-3

In parallel the very prominent medical endocrinology group at Mount Sinai lead by Andrea E. Dunaif, MD, came to similar conclusions using genomic studies, with clustering studies also defining two PCOs phenotypes (i.e., clusters) and a third one representing a group that overlapped between those two, - forming a third cluster.⁴ They described these two groups as “reproductive” and “metabolic.” The former was characterized by high luteinizing hormone (LH), high sex hormone binding globulin (SHBG), and relatively low BMI as well as insulin levels, while the latter was characterized by high BMI, glucose and insulin levels and lower LH and SHBG.

In 2024 a group of Chinese investigators through genomic clustering also concluded that PCOS represented this kind of 2+1 distribution of phenotypes.⁵ Patients in this study underwent their first cycle of IVF and unsupervised cluster analysis was performed. Controlled ovarian stimulation parameters and reproductive outcomes were then compared between the different clusters of PCOS which they called “reproductive”, “metabolic”, and “balanced” clusters based on nine traits: The reproductive group was characterized by high levels of testosterone (T), SHBG, follicular stimulation hormone (FSH), LH, and anti-Müllerian hormone (AMH). The metabolic group was characterized by high BMI, fasting insulin, and fasting glucose. The balanced group was characterized by low levels of the aforementioned reproductive and metabolic parameters, except for SHBG.

Compared with reproductive and balanced clusters, those in metabolic cluster had lower rates of good quality day 3 embryo and blastocyst formation. Moreover, PCOS patients in the reproductive cluster had greater fresh embryo transfer (ET) cancelation rate and clinical pregnancy rate after fresh ET than metabolic cluster. And compared with PCOS of metabolic cluster, PCOS of balanced cluster also had higher chances for fresh ET cancelation.

And yet another most recent Chinese study in Nature Medicine suggested the presence of four “subtypes” which they validated across diverse populations ⁵ (as the CHR has done as well).⁵ Those four were: (i) Hyperandrogenism; (ii) Obesity; (iii) High SHBG; (iv) High LH as well as high AMH, - defined by unsupervised clustering of 9 clinical variables in 11,908 affected women (based on Rotterdam criteria) in a multicenter study validated across five international cohorts.

Despite some shortcomings (which we will return to below), this study offered unique insights because it included a 6.5 year follow up of patients and IVF treatments. Consequently distinct reproductive and metabolic trajectories could be observed. Those included the following: (i) Hyperandrogenic PCOS was associated with the highest prevalence of second trimester pregnancy loss and dyslipidemia; (ii) PCOS with obesity exhibited the most severe metabolic complications, lowest live birth rates and highest PCOS remission rates; (iii) PCOS with high SHBG demonstrated favorable reproductive outcomes and the lowest incidence of diabetes and hypertension; PCOS with high LH as well as AMH had the greatest risk of ovarian hyperstimulation syndrome (OHSS) and the lowest PCOS remission rates. Additional comments to the paper were offered in an accompanying Research Briefing by two of the authors in the same issue of Nature Medicine:⁷

A mild criticism considering an, otherwise, excellent stud is in place because by selecting their study population based on Rotterdam criteria, the researchers basically preempted the possibility of a “new” definition of PCOS. This study, therefore, just further defined the PCOS we all have known since establishment of the Rotterdam criteria in 2003. Characteristics of evolving patient subgroups are, however, quite amazingly similar between all the varying studies referred to here.

All here mentioned studies – despite obviously expected variability - have basically agreed on which clinical phenotypes represent characteristic presentations for the definition of PCOS subtypes/ phenotypes, - BMI defining obese vs, lean; androgen levels defining hyo- and hyperandrogenism; SHBG, physiologically going the opposite way of androgens; and beyond reproduction, defining long-term risk for metabolic syndrome (diabetes, hypertension, and heart disease, - Rotterdam phenotypes A, B, and C) and a hyperactive immune system as reported by the CHR (defined by autoimmunity, inflammation, and allergies, and Rotterdam phenotyp-D).

Most importantly for the infertility field, all of these publications moreover concur that some PCOS patients are affected in their reproductive success but not uniformly: The CHR believes that the clinical studies of the CHR defined these risks so-far the best when it comes to infertility, including IVF resistance, and with increased miscarriage risk by defining PCOS in two phenotypes (and an overlapping phenotype) along the following principles:

• All PCOS patients are characterized by abnormally high functional ovarian reserve (FOR) reflected by abnormally high AMH levels, antral follicle counts (AFCs) for age,and hyperandrogenism and, because of the latter’s effect on SHBG by normal or even low SHBG levels. This observation contradicts the Rotterdam criteria, which describe the D-phenotype as non-hyperandrogenic (an error we will explain next).

• The D-phenotype under Rotterdam criteria is hyperandrogenic, - but only short-term after menarche and – due to insufficiency of adrenal androgen production – starts a steady decline which, approximately by age 25 results in these women entering normal androgen range, where they remain for approximately a decade, only to reach hypo- androgenic levels by approximately age 35. Because over 90% of all PCOS diagnoses are made between ages 25 and 35, this is the reason why this phenotype by Rotterdam was described as normo-androgenic. All other PCOS patients remain hyperandrogenic into advanced ages.

• The D-phenotypes is correctly described by Rotterdam criteria as “lean” and usually ovulatory. These women, therefore, also are ovulatory (most of the other phenotypes are not) and therefore have regular menstrual patterns (other PCOS patients are usually obese and oligo-amenorrheic). The D-phenotype also does not present with hirsutism, acne and metabolic abnormalities (all stigmata routinely associated with PCOS. Consequently phenotype-D patients in a large majority of cases go undiagnosed or report a medical history of ones as teens having been told that they may be PCOS patients but later were told that this has been an erroneous diagnosis.

• This incorrect correction of their original diagnosis often moreover appears confirmed by the fact that these women – while in normal androgen range – are fertile and often normally conceive and deliver. They, however, often demonstrate a repeat miscarriage pattern, explained in a moment below.

• By approximately age 35 – after becoming hypo-androgenic – they suddenly become infertile. This is a major reason why women diagnosed as repeat (immune) aborters before that age demonstrate a natural history of becoming infertile. They, therefore, usually become infertility patients only after age 35 and, therefore, quickly enter IVF treatments, characterized by large egg numbers but, because of poor egg quality, few good quality embryos.

• This egg to embryo discrepance in numbers is a typical sign in the IVF history of these patients, is a consequence of their hypo-androgenism, and is the principal cause for their IVF resistance (there, of course, are also others). Because their hypo- androgenism is adrenal in nature (demonstrated by significantly lower DHEA-S than DHEA) and, therefore, correctable with androgen supplementation. Since hypo-androgenism is usually associated with elevated SHBG, successful androgen supplementation will reduce SHBG levels in parallel with increases in total testosterone (TT).

• Finally, PCOS is usually associated with risk for the metabolic syndrome. Women with D-phenotype usually do not experience this risk. They, however in ca. 85% of cases demonstrate a history and/or have laboratory evidence of a hyperactive immune system which can manifest as either autoimmune findings, inflammatory markers, and/or as significant allergies. They also in ca. 45% demonstrate evidence of autoimmune thyroid disease.

• Since hyperactive immune systems – whatever the cause – significantly predispose to immunological pregnancy loss, these women are at significantly increased miscarriage risk once they do conceive and must receive appropriate prophylactic treatments to prevent pregnancy loss. They also are at significantly increased risk for other pregnancy complications during a second high risk period in the third trimester of pregnancy, which mimic typical autoimmune risks, including premature labor and delivery, small for gestational age infants, preeclampsia and autoimmune exacerbation in the postpartum period.

The CHR has been publishing these facts now for over 10 years in medical journals^1-3 and in our in-house publications, - the _CHRVOICE and the Reproductive Times. We, therefore, are still always surprised how many undiagnosed patients with this presentation still present to the CHR as a practically daily event. Because these women go from being hyper- to being hypo-androgenic as a key diagnostic feature (the other one being laboratory evidence of a hyperactive immune system), we have described this PCOS phenotype/ subgroup as hyper/hype-PCOS (HH-PCOS).

Here cited publications of genomic studies by the Mount Sinai group in NYC – just a few blocks uptown from the CHR on Madison Avenue and, since then, from two Chinese groups – while not 100% overlapping with our clinical observations – are nevertheless strongly supportive of the CHR’s understanding of how PCOS affect fertility and reproductive success in general and represents one of the most important breakthroughs the CHR achieved in its over 40 years-long research history, marked by several major breakthroughs.

It is also an excellent example for two additional observations worthwhile mentioning: First, even in days of amazing genomic capabilities, clinical observations are, still, at the core of medical practice. And one can never predict where an unexpected finding will lead to. In this case, indeed, two totally unexpected findings lead to the discoveries here described: The unexpected discovery that practically all of the CHR’s PCOS patients were phenotype D patients, we already mentioned. A second one – not less important, - however, also deserves recognition: Preceding everything we here presented, the CHR only once in its decade-long history submitted a paper to a prestigious medical journal in which its investigators could not explain the outcome of the reported study.

And we said so in the paper, even though we were concerned that the journal for that reason would not accept the paper for publication. The editor-in-chief of the journal at the time was, however, pleasantly surprised us and (wisely!) accepted the paper.⁸

That paper reported on the CHR’s IVF cycle outcomes based on how FSH and AMH levels in their relationship affected pregnancy chances. Both of these hormones are supposedly assessing FOR. They, therefore, should run in parallel, - that is, of course, in opposite directions - as FSH should go up and AMH should go down as FOR declines. But we observed was that this not always was the case. To our surprise, we found that a HIGH/HIGH pattern gave us by far the best pregnancy rates and we had no idea why?

That is, - until we started to get interested in above described PCOS research. It suddenly dawned on us why the HIGH/HIGH pattern had done so well: Those women were practically all women with PCOS (high AMH). And they were HH-PCOS patients because we did not see any other PCOS patients at the CHR.

By that time (2012), we had already for a good number of years been supplementing hypo-androgenic women with DHEA, which very frequently improves egg quality and pregnancy chances because ovaries need good androgen levels to make good eggs (another IVF break through made at the CHR⁹). And since we now understand what our 2013 paper in the Journal of Clinical Endocrinology and Metabolism (JCEM) really meant, we now had another diagnostic hint when a new patient presented with elevate FSH (which happens quite often in PCOS patients) but also has higher AMH than one would expect with an elevated FSH.

And this also needs to be said: The CHR is incredibly lucky for having the most unique patient population of any IVF clinic in the U.S., and likely in the world. If it were not for this unique quality of the CHR’s patients, our investigators could never have made all of the breakthroughs in fertility treatments the CHR has achieved and is continuing to make. A big Thank You, therefore, goes to all of our past and future patients and to our physicians and other scientists for always going with open eyes through the day.

ANOTHER PAPER WITH CONSIDERABLE RELEVANCE TO THE PRECEDING – And since we have been already talking about PCOS phenotypes, the Mount Sinai Endocrinology group, and the JCEM, here is some information about another article in JCEM by the Mount Sinai group in which they report the ontogeny of distinct reproductive phenotypes in girls at risk for PCOS during the postmenarchal transition.¹⁰

Daughters of women with PCOS and girls with overweight/obesity can have hyperandrogenemia beginning in childhood. Other features of their early reproductive phenotypes, however, can differ, suggesting the existence of mechanisms conferring upon them increased risk for PCOC. Unfortunately investigating only a too small a number of children (PCOS 15, overweight 12, and 17 lean controls) between 0.2 to 1.2 years of menarche the number of patients was really too small to be able to come to definite conclusions. The data, however, were, nevertheless, interesting.

As one would expect, SHBG levels were lower in PCOS and overweight girls than in lean controls. Free testosterone levels were higher in overweight girls, while DHEA-S levels were marginally higher in PCOS vs. controls and trended higher in overweight girls. Morning LH levels were higher in PCOS vs overweight girls and LH and FSH responses to GnRH analog were also increased in PCOS vs overweight girls. The prevalence of hyperandrogenemia was similarly increased with PCOS and overweight, - and the prevalence of ovulatory dysfunction was also increased in both groups.

The authors concluded that PCOS and overweight girls had persistent hyperandrogenemia during the early postmenarchal transition. However, ovulatory dysfunction, neuroendocrine abnormalities, and elevated basal and stimulated LH responses to GnRH analog were observed only with PCOS and suggested that these findings support the existence of distinct developmental trajectories leading to polycystic ovary syndrome, with early neuroendocrine dysregulation in PCOS and with overweight to peripheral, likely adiposity-related, androgen excess .

This was neither a very exiting paper in content nor in recognition of preceding publications. For example, a 2016 paper by NIH investigators from what then was the Stratakis laboratory, reported on a subset of young women with PCOS with a pattern of glucocorticoid secretion that mimicked that of patients with micronodular adrenocortical hyperplasia.¹¹

This meant that they had smaller adrenal volumes and higher steroid hormone secretion after dexamethasone compared to a group of PCOS patients with appropriate response to dexamethasone. This possibly also meant that micronodular adrenocortical hyperplasia could be a precursor condition to above -discussed PCOS phenotype D.

AND A MINI-REVIEW ON THE INTIMATE RELATIONSHIP OF ADIPOSITY TO PCOS BY TWO GIANTS IN PCOS RESEARCH – Worldwide, there are very few other people around with the credibility of Robert L. Rosenfield, MD, and Daniel A. Dumesic, MD., the first a pediatric endocrinologist in San Francisco and the second a REI in Los Angeles. Any Review article for which these two powerhouses get together, therefore, is worth the read.

And the recent Mini Review in the JCEM on adiposity in association with PCOS is certainly no exception.¹² It is, however, important to point out that the authors – wisely – restricted their review to “the relationship of increased adiposity to hyperandrogenic oligo-anovulatory PCOS.”

Why is this important? Because most papers in the literature, unfortunately, do not distinguish between PCOS phenotypes in selecting patient populations for studies or in discussing PCOS. By concentrating their review only on hyperandrogenic PCOS, they for all practical purposes did not include above extensively discussed D-phenotype under Rotterdam criteria (even though – as also noted above – this phenotype for a short period between menarche and ca. age 25 is also hyperandrogenic) and this kind of distinction between PCOS subgroups/phenotypes is, of course, what must finally happen, - if highly overdue progress is to be made in better understanding PCOS.

The authors, indeed, implicitly endorse the so-called two “reproductive” and “metabolic” subtypes of PCOS as described by the Mount Sinai group⁴ when noting that PCOS demonstrates functionally two forms, a “functional typical” form characterized by ovarian hyperandrogenism characterized by a unique pattern of ovarian steroidogenic hyperresponsiveness to gonadotropin stimulation explainable by gene variants that cause overexpression of an activating variant of DENND1A and of a “functional atypical” form (roughly one-third of PCOS cases) lacking this excessive ovarian response.

While the authors claim that their “typical” and “atypical” forms of PCOS share clinical traits with the respective “reproductive” and “metabolic” subtypes described by the Mount Sinai group, we would argue that this alleged overlap is much less pronounced than the overlap in clinical features between the two Sinai group phenotypes and the two by the CHR reported phenotypes. We would further argue that the difference in overlaps in those two comparisons is, likely due to inclusion of patients in studies which, individually, showed overlaps in clinical presentation between the two principal sub-groups/phenotypes, thereby establishing, for practical purposes a third “mixed” group.

Returning to the main subject of the Mini Review (we reemphasize here that the authors specifically only addressed hyperandrogenic PCOS), the authors suggested preferential, often subclinical abdominal fat accumulation represents a central feature of PCOS that also affects metabolic functions.

Here is, however, an important additional point that this paper – and really practically all PCOS research – still is overlooking: For infertility practice (we are here not addressing long-term health effects of PCOS) the “classical” hyperandrogenic, obese, anovulatory PCOS patient is – as the CHR’s patient experience so well demonstrates - a solved problem. These women conceive with standard fertility treatments, whether ovulation induction alone or IVF. The remaining problem are the PCOS patients who do not conceive, and that is the HH-PCOS patient!

A WORD ON THE IMMUNE SYSTEM IN PCOS – That PCOS can be associated with immune system abnormalities has been known for decades. A detailed understanding has, however, over all this time been prevented because PCOS was never investigated sub-group/phenotype -specific. To the best of our knowledge, this was for the first time done when the CHR’s investigators noted the approximately 85% association of the HH-PCOS phenotype with a hyperactive immune system in general and with thyroid autoimmunity in ca. 45%.^1-3

Now a group of investigators from the U.S. closely associated with the Androgen Society (though in this paper not speaking for the society) offered some additional information in a paper in JCEM.¹³ Importantly, this retrospective cross-sectional study used blood samples from the Androgen Excess Biorepository, according to the British Society for Endocrinology a specialized collection of biological samples such as blood, serum, and tissues, —paired with clinical data, dedicated to researching conditions where androgenic steroids are elevated, primarily PCOS. These repositories, therefor, primarily are geared toward the study of hyperandrogenism which, of course, automatically biases every PCOS study since it almost completely excludes normo- and hypo-androgenic PCOS patients (i.e., the HH-PCOS phenotype above age 35). Because the study population involved women between ages 18 and 45 years, between ages 25 and 35, a small group of still hyper-androgenic young women may have been included. However, their long-term disease profile would, however, have separated them from prolonged hyperandrogenic PCOS patients.

Because these two groups of patients were not separately analyzed, in this paper presented data must be viewed with caution. It is, indeed, reasonable to assume that – given what the CHR reported the high prevalence of hyperactive immune systems to be in HH-PCOS patients, the in the study obtained results would probably have looked differently, - had HH-PCOS patients been removed from consideration before analysis or had been analyzed separately.

The study results, however, suggested the following: What the authors described as a significantly lower level of circulating immune markers (CRP, 96 markers including IL-6, TNF-alpha, IL-18, interferon-gamma) was really only a marginal result (p<0.05). Growth factors, proinflammatory cytokines, and chemokines were – independent of race – reduced. The authors concluded from these findings that what they considered to be a prevailing notion to be, - namely that PCOS is a chronic low-grade inflammation -was incorrect. Instead, they are now considering PCOS a condition of immune suppression and impaired angiogenesis.

Studying this paper, one, indeed, does not know where to begin the criticism because everything – from patient selection and description to data interpretation and conclusions – is (trying to remain polite) insufficient. This paper therefore is, indeed, a very good example for why PCOS has remained such a confusing diagnostic entity and why reproductive immunology has gotten such a bad reputation in reproductive medicine.

MYOINOSITOL (MI) IN THE CLINICAL MANAGEMENT OF PCOS – A recent Commentary by Italian colleagues in RBM Online confirmed our suspicion that MI has slowly been gaining widespread use in the management of infertility in PCOS patients.¹⁴ And once again, one has to wonder why and based on what studies?

As the authors state in their article, there exist claims that inositols improve insulin sensitivity and ovarian function. But where is the evidence?

The authors, therefore, correctly conclude that myoinositol (and for that matter also other inositols) should not be recommended as routine treatment in PCOS patients. We, of course, fully concur but want to make an additional point we have repeatedly made in the past in these pages: Myoinositol should definitely not be used in normo- and hypo-androgenic PCOS patients because it lowers androgen levels even further.

VITAMIN D IN IVF CYCLES OF WOMEN WITH PCOS – Yet another Chinese multicenter study – this time in the BMJ – which investigated whether vitamin D supplementation would improve IVF outcomes in PCOS patients.¹⁵ And to be blunt, not only did vitamin D supplementation not show any effects on IVF cycle outcomes in PCOS patients, - but the paper really did not even offer a hypothesis why vitamin D should be effective.

Moreover, the study design can only be described as pathetic (yes, even though the paper appeared in the BMJ, at least by some in the medical field still consider a respectable medical journal): (i) PCOS phenotypes, of course, were not separated. They, indeed, were not even noted. (ii) Out of 1,272 patients screened, only 31 were found to be ineligible but 365 declined participation (one wonders why and how much their refusal further biased the study). (iii) That left 876 alleged PCOS patients (per Rotterdam Criteria and, therefore, including phenotype-D patients, - i.e., HH-PCOS patients, - though in untold distribution) which means 36.5 patients only per participating center (24 clinics participated). Imagine how different IVF cycle management protocols must have been between these centers.

In other words, just one more of these completely useless studies that appear to continue to increase in numbers and are giving medical and scientific research a bad name at a time, when especially some Chinese research laboratories have really started to produce worldclass work.

REFERENCES

1. Kushnir et al., J Ov Res 2015;8:45. Doi. 10.1186/s13048-015-0175-x.

2. Gleicher et al., Endocrine 2018;59(3):661-676

3. Gleicher et al., Biomedicines 2022;10(7);1505

4. Dapas et al., PLoS Med 2020;17.e1003132

5. Chen et al., Chin Med J. 2024;137(5):604-612

6. Gao et al., Nat Med 2025;31:4214-4224

7. Zhao S, Zhao H. Nat Med 2025;31:4002

8. Gleicher et al., J Clin Endocrinol Metab 2013;2136-2145

9. Gleicher N, Barad DH. Hum Reprod 2008;23(12):2868-2870

10. Torchen et al., J Clin Endocrinol Metab 2026;111:553-560

11. Gourgari et al., J Clin Endocrinol 2016; 101(9):3353-3360

12. Rosenfield RL, Dumesic DA. J Clin Endocrinol Metab 111(1):11-23

13. Pacheco-Sanchez et al., J Clin Endocrinol Metab 2026;111:656-664.

14. Palomba et al., RBMOnline 2026;52(2):105269

15. Hu et al., BMJ 2026392:e087438.

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Today’s postings reflect this fact, as they address the growing number of embryo implantation models being developed in laboratories and offering important new information about what still is the most widely used animal model – the mouse – by comparing mouse and human ovaries along advancing ages in both species.

We hope you will enjoy the discussions of both subjects and – as always – want to encourage you to become an active participant by either commenting on our postings or even proposing an article. We also want to take this opportunity to remind you to sign up for a free subscription to the Reproductive Times [HERE] and register at greatly discounted early bird rates for this year’s annual Foundation for Reproductive Medicine Conference (FRMC) in NYC on December 4-6 which the CHR as always co-sponsors [HERE].

Finally, we want to bring to our reader’s attention several new clinical trials which recently were approved by the CHR’s IRB, have been formally registered, and are ready for enrollment. If you or somebody you know may be interested in enrolling, please call the CHR’s registration desk at (212) 994 4400.

The CHR’s Editorial Staff

One of the most basic issues the CHR has been pursuing almost since its establishment in 1981 in Chicago, is the information deficit between clinical practice of infertility and the research bench. What we mean by that is the ignorance of clinical fertility practice about relevant basic research that is going on in research laboratories and the ignorance of research scientists in reproductive biology and other related research areas about how their research could contribute to improvements of clinical practice when it comes to female and male infertility. This has also been the principal reason why the CHR in collaboration with The Foundation for Reproductive Medicine (FRM) established the annual December FRM Conference (FRMC) which – as its principal goal – brings leading basic scientists and clinicians together in one room for three days, so that they can learn what their mutual needs for collaboration are.

As part of this effort, we today – based on several recent publications - are discussing two important basic research areas with significant potential relevance for clinical infertility.

Will Newly Developed Models of Embryo Implantation Finally Allow a Better Understanding of Implantation?

Several laboratories have recently reported workable models for human implantation, raising expectations for a better understanding of the process. One – by Chinese investigators – is still at preprint stage at eLife.¹ A second one by European investigators was just published in its full beauty in Cell.²

The first paper claims to have established an endometrial organoid culture system that mimics the window of implantation. Considering that nobody really exactly knows when this alleged implantation window starts and ends in a cycle, it seems to us that the claim of having an endometrial organoid system mimicking the window of implantation may be a little exaggerated. The second paper by a European collaborative established a 3D in vitro model that supposedly “supports” human implantation and development. With what defines a “receptive” endometrium still somewhat controversial, the authors of this paper attempt to define it molecularly.

Implantation of a human embryo into the endometrium is, of course, likely the most crucial event in pregnancy. It, after all, marks the very beginning of a pregnancy. It is also – for a variety of known and probably even more unknown reasons – is prone to high failure rates. Even at peak fertility in the early 20s, only 1/3 embryos will implant. By age 45, this ratio is probably around 1/20.

The European model is alleged to recapitulate the luminal, glandular, and stromal compartments of the superficial layer of receptive human endometrium. Human embryos as well as blastoids allegedly implanted into this endometrial model, achieving post-implantation hallmarks including advanced trophoblast structures that underlie early events in placental development.

Single-cell RNA sequencing of the embryo-endometrial interface at day 14 uncovered predicted molecular interactions between conceptus and endometrium. Disrupting signaling interactions between extravillous trophoblast and endometrial stromal cells caused defects in trophoblast outgrowth, demonstrating the importance of crosstalk processes to sustain embryogenesis (see the Graphic Abstract below). This study does offer potentially important insights into our understanding of implantation!

But there is a “but” - and this “but” relates to a subject that on several occasions before has been addressed in these pages , - the question whether pregnancy should primarily be viewed as an endocrine event (i.e., dependent on a hormonal “window of implantation”) or an immune event – first and foremost – dependent on the development of appropriate maternal tolerance toward the fetal semi-allograft (and increasingly full allograft if egg donation or a gestational carrier are involved).

We here, of course, will not rekindle this discussion; but – while not ignoring the relevance of hormones for the establishment of successful implantation and pregnancy, the CHR sees pregnancy, for biological reasons, as primary an immune- rather than endocrine- mediated condition. And this opinion, of course, also translates into clinical practice, which – for decades – has given close attention to our patients’ immune systems.

We, therefore, strongly believe that all the modelling of implantation will remain unsatisfactory until and unless models also receive an “immune system.”

REFERENCES

1. Zhang et al., eLife 2025. https://doi.org/10.7554/eLife.90729.3

2. Molè et al., Cell 2026;189:1-19

Comparing human and mouse ovaries across advancing ages

Though mouse models have been used in ovarian research for decades, - neither women nor men are mice.” We here at the CHR learned this a long-time ago, even-though it was mouse work by colleagues which, finally, explained to us ( and whoever was interested in knowing) why androgen supplementation (in our case with DHEA) in hypo-androgenic women often improves outcomes in IVF cycles.¹ Considering how especially difficult in vivo human research can be in the fertility field, without obtaining these mouse data we still might not understand why androgen supplementation (including with DHEA) is so successfully in treating hypo-androgenic infertile women with androgen supplementation in preparation for IVF.

But because neither women nor men are mice, not everything observed in mice will also end up applying to the human experience. We, therefore, were intrigued when colleagues from UCSF recently published a paper in Science comparing mouse and human ovaries over advancing ages² (the Graphic Abstract is below).

Specifically, the authors compared ovaries between the two species by using three-dimensional imaging, single-cell transcriptomics, and functional studies. In mice, they recorded declining follicle numbers and oocyte competence during aging. In human ovaries they studied demonstrated cortical follicle pockets and decreases in density.

Without going into detail, this study revealed probably more similarity between mouse and humans than expected in form of conserved cellular specialization. That included sympathetic nerves and glia and species-specific dynamics of follicle depletion with age, oocyte maturation, and stromal remodeling. This is important information, validating mouse models for many more future studies.

REFERENCES

1. Sen A, Hammes SR. Mol Endocrinol 2010;24(7):1393-1403

2. Gaylord et al., Science 2025;390(6778): DOI: 10.1126/science.adx0659

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