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

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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.

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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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Here, our posting is dedicated to the field of geroscience, - the science of aging which has so many common denominators with infertility practice. Don’t miss either one of these two CHR offerings and – whether you love or hate the materials (and, of course, also if you are right in the middle of these two extremes), write to us and let us know what you think. And, also, - just as a reminder, you not only can at any point write a commentary to a paper or express your opinion in any other way. Any communication is welcome and will be considered for publication!

And, yes, you can also apply for a subscriptions to both publications and both are free. So don’t be shy!

The CHR’s Editorial Staff

The Importance of the Aging Ovary for the Study of Aging

There, of course, is no better example for the science of aging to study than ovarian aging because the ovary is not only the most obviously aging organ in humans but likely also the most important organ to enter almost complete senescence so long before other organs (see Figure 1 below).

This, of course also means that it is the only major organ that almost completely enters senescence before death. But, interestingly, that was not always the case: As Figure 2 below demonstrates, life expectancies for females and males have been steadily increasing. Through roughly 1940, they indeed were quite similar, - though mildly favored females.

But after ca. 1940 something happened and women’s life expectancy significantly started exceeding that of males. Though that, in itself, is a fascinating observation that still lacks a good explanation, it is not the subject of this commentary today. The point we are trying to make here is that until the 20^th century, U.S. life expectancy in women barely exceeded age 51, the current average age of menopause.

Unfortunately the historical data on average age at menopause are quite scarce. But available data suggest that – at least in more recent decades – that age has mildly increased and, with it, the reproductive life span of women.² As Figure 2, however, also demonstrates, as recently as at the beginning of the 20^th century, female life expectancy gave them – at best – only approximately 10 years of remaining life after onset of menopause. Until the 18^th century most women, indeed, died even before reaching menopause.

With female life expectancy in the U.S. now in the 80s, that has changed radically and – even with slightly later menopause than centuries ago - women now experience a lifespan of over 30 years postmenopausal. That, of course, has highly significant societal consequences and - suffice to say – has also considerable connotations for fertility practice At the same time, all of these observations, however, also reemphasized the importance of ovarian aging as a study subject not only for the infertility field, - but for geroscience in general and, of course, the opposite: Everything we learn in geroscience pretty automatically also may relate to ovarian aging. And if, until now, you did not understand why we often address geroscience in our literature reviews, - now you know!

REFERENCES

1. Chan et al., BMC Womens Health 2020;19(2):74

2. Appiah et al., JAMA 2021;325(13):1328-1330

Can Mesenchymal Stem Cell Therapy “Rejuvenate” and Slow Down Aging?

The most recent answer to this question is based on a very interesting paper by Chinese investigators in Cell. As the authors noted, aging is characterized by a deterioration of stem cell function. Even-though now already widely offered in many “rejuvenation clinics” in the U.S. and elsewhere, whether (and how) replacing such “aged” stem cells would counteract aging remains unclear. Their study, therefore, tried to establish some clarity regarding the subject.

They started the project by developing senescence (seno)-resistant human mesenchymal progenitor cells (SRCs), genetically fortified to enhance cellular resilience and then, In a 44-week trial, treated aged macaques monkeys intravenously with these SRCs. The result was a systemic reduction in aging indicators, such as cellular senescence, chronic inflammation, and tissue degeneration, without any detected adverse effects (see below the Graphic Abstract of the paper).

Notably, SRC treatment enhanced brain architecture and cognitive function and alleviated the reproductive system decline, with restorative effects of SRCs partly attributable to their exosomes, which combat cellular senescence.

In a commentary in the same journal, two U.S investigators concluded that by demonstrating multi-organ rejuvenation in their macaque study, the authors provided proof-of concept that stem cell therapies can, indeed, be used to slow down aging in general (in contrast to just treating one specific disease with stem cells). And with significant relevance to reproduction and potentially infertility, the SRCs boosted cognitive as well as reproductive rejuvenation, with geroprotection delivered through exosomal cargoes of SRCs.²

This excellent, paper therefore, provided strong initial evidence that genetically modified human mesenchymal progenitors can slow primate aging, highlighting the therapeutic potential of regenerative approaches in combating age-related health decline. And such treatments can – at least theoretically – be apparently applied in general across organ systems but also specifically targeted to one organ (like at least theoretically, for example the ovary) or one disease (like for example primary ovarian insufficiency, POI).

Some key questions remain, however, as the Commentary noted: (i) how do these mesenchymal progenitor cells achieve these rejuvenating effects? (ii) What is the exosome content that promotes the observed rejuvenation? And (iii) how do these cells and the involved exosomes interact with the patient’s immune system?

And then there are, of course, also practical translational questions to be resolved, such as GMP grade manufacturing of SRCs, where to get the stem cell from (which organ), and optimization of process (dosage, mode of delivery, etc.).

But a future of systemic rejuvenation is upon us, - it appears!

REFERENCES

1. Lei et al., Cell 2025;188(18):P5039-5061

2. Gorbunova V, Seluanov A. Cell 2025; 188(23):P6391-P6392

Is longer life really inheritable?

The answer to this question is, of course, intriguing and - so it appears at least according to another recent paper by other Chinese scientists - this time in Science. An Editor’s Summary introducing the paper¹ explained this study perfectly when noting that in some model organisms starvation induces epigenetic changes that extend the lifespan of the progeny of those hungry parents (in itself, of course a fascinating observation demonstrating once more the infinitive wisdom of evolution). The study the paper then reported attempted to determine the mechanism of how this happened in the roundworm and implicated an enzyme – lysosomal lipase-like 4 (LIPL-4) in the process.

Increased activity of LIPL-4 in turn activated signaling in intestinal lysosomes (aren’t the guts involved in everything?) which led to increased transcription and production of variant histones H3.3 which then could be transferred to the germline, where it was modified by a methyltransferase and transmitted to progeny, where it extended lifespan. A commentary here, too, in the same journal further explained the process, making the point that, - though the original paper from China very well documented how lysosome activity can influence the epigenome (and with it transgenerational longevity), the process can also revert, - with signals from the epigenome going to the lysosomes.

REFERENCES

1. Zhang et al., Science 2025;389:1353-1365

2. Bohnert KA. Science 2925;389(6767):1295-129

How Important is Education for Memory Decline and Brain Aging?

Historically, better education has been associated with better memory and healthier brain structure at older ages. But now a study in Nature Medicine involving 400,000 memory scores and 15,000 MRI scans came to very different conclusions, suggesting that the previously observed association was likely due to other early life factors.¹

More education was associated with better memory, larger intracranial volume and slightly larger volume of memory-sensitive brain regions. However, education did not protect against age-related decline or weakened effects of brain decline on cognition. One potential explanation for these findings is that they denote selection of individuals with certain traits to pursue more education. Although education has numerous benefits, the notion that it provides protection against cognitive, or brain decline was not supported by the study.

REFERENCE

1. Fjell et al., Nat Med 2025;31(9):2967-2976

More Evidence that Shingles Vaccine Protects from Dementia Along Its Entire Clinical Course

The world is by now over the surprise that the shingles vaccine protects against dementia, - even though why that is the case is still not clear. But a new paper in Cell actually demonstrated that this protective effect goes even further than was originally assumed.

Using natural experiments (for further detail see below), these authors previously reported that live-attenuated herpes zoster (HZ) vaccination appears to have prevented or delayed dementia diagnoses in both Wales and Australia. Here, they add to these findings that shingles vaccination also reduces mild cognitive impairment diagnoses and, among patients living with dementia, deaths due to dementia. These effects, moreover, were not dependent on one or more specific dementia types.¹

Their research strategy took advantage of natural circumstances in how the vaccine had historically been administered: The researchers took advantage of the fact that individuals who had their 80^th birthday just after the start date of the vaccination program in Wales were eligible for the vaccine for 1 year, whereas those who had their 80^th birthday just before were ineligible and remained ineligible for life.

Their research strategy took advantage of natural circumstances in how the vaccine had historically been administered: The researchers took advantage of the fact that individuals who had their 80^th birthday just after the start date of the vaccination program in Wales were eligible for the vaccine for 1 year, whereas those who had their 80^th birthday just before were ineligible and remained ineligible for life.

The key strength of their natural experiments therefore was, that these comparison groups should be similar in all characteristics except for a minute difference in age. Yet their findings suggested that live-attenuated vaccination prevented or delayed mild cognitive impairment and dementia and slowed the disease course among those already living with dementia.

Their research strategy took advantage of natural circumstances in how the vaccine had historically been administered: The researchers also took advantage of the fact that individuals who had their 80^th birthday just after the start date of the vaccination program in Wales were eligible for the vaccine for 1 year, whereas those who had their 80^th birthday just before were ineligible and remained ineligible for life.

REFERENCE

1. Xie et a., Cell 2025;188:1-16

The CHR’s Editorial Staff

WE ARE ALL MOSAIC – The Huge Genetic Diversity in Cells of At Least Older Individuals

In what Heidi Ledford in a News article in Nature magazine described as a “technical tour de force,” a preprint on bioRxiv reported that researchers sequenced the whole genome of more than 100 individual cells from one 74-year-old male.² What they found was – as she put it - pure chaos: extra chromosome arms, chromosome deletions, smaller snippets of DNA altered, deleted or duplicated. Several cells had no Y chromosome left. In short, - nothing new – it’s is not great getting old.

As the article noted, this is the beginning of a new pilot project for a $140-million project of a consortium of investigators who aim to catalogue mutations in cells from 19 sites in the body using cells from 150 donors.

REFERENCES

1. Ledford H. Nature 2025;648:18

2. Luquette et al., Preprint at bioRxiv. 2025. https://doi.org/10.1101/225.10.31.685648

Sex Differences in the Genetics of Depression

We would say – unsurprisingly – a recent comprehensive genome analysis suggested that women have more genetic risk variants for major depression than do men, and they appear strongly linked to metabolic traits.¹ These findings were unsurprising for us because major depressive disorder (MDD) affects almost twice as many women as men. The biological reasons for this disparity are, however, unknown. Are they, for example, genetic or environmental (or both)?

Above noted study was a meta-analysis of genome-wide association studies (GWASs) — an approach for finding links between genetic variations and observable traits — that included almost 200,000 men and women with MDD. And here is just a little of what they found: Roughly 13,200 causal variants linked to MMD in women and only ca. 7,100 in men, with the latter all shared with women. This suggests that ca. 6,100 variants are exclusively linked to women. In addition the investigation also found three genomic regions with significant effects on MDD in women only, strongly suggesting sex-specific effects.

When the authors then examined genetic correlations – how genetic effects on one trait also relate to another trait, they discovered the much closer association of women than men with metabolic traits (i.e. BMI and metabolic syndrome), which fits with women having metabolic symptoms more frequently than men.

The study revealed several other interesting differences, but further details would exceed our allotted space here. The study is in detail explained in an article in the mothership of Nature journals, Nature by Na Cai, PhD from the Department of Biosystems and Engineering at ETH Zürich in Basel, Switzerland.²

REFERENCES

1. Thomas et al., Nat Commun.2025;16:7960

2. Cai N. nature 2025;647:600-601

We Soon Will Be Able to Transfer Chromosomes In and Out of Cells

This is a promising story because making human genomes has very obviously the potential to transform biology and – with it – human medicine. Now a group of investigators from all over Europe took a first important step in realizing this pipedream of building synthetic human chromosomes.¹

They developed a method to transfer a human chromosome into specialized “assembly” cells which allowed them to safely manipulate the chromosome. The so engineered chromosome then can be used with minimal genetic damage to replace a corresponding human chromosome in targeted human cells. True Science Fiction!

REFERENCE

1. Petris et al., Science 2025;390(6777):1038-1043

A New Dominantly Inherited Mutation Causing Female Infertility Because of Embryo Arrest at Preimplantation Stages

Embryo arrest at preimplantation stages is a quite common cause of female infertility and is frequently experienced in IVF cycles. Though various mutations have been implicated in causing arrest, most of its genetic basis is still unknown.

Geminin, encoded by the GMNN gene, plays an important role in preventing DNA re-replication by inhibiting CDT1. Here, using whole-exome sequencing and Sanger sequencing, the authors identified three rare missense mutations of the GMNN gene in females with preimplantation arrest. The mutation follows a dominant inheritance pattern.

RNA sequencing data from mouse zygotes and a patient’s one-cell embryo demonstrated altered cell cycle processes. The investigators then found that these mutations decreased the binding with CDT1 and resulted in activation of CHK1 as well as DNA damage, resulting in cell cycle disturbances.

As the authors summarized their paper, their findings uncovered a mechanistic explanation for some cases of human preimplantation-stage embryo arrest, which acts by impairing the correct cell cycle and DNA re-replication procedure. This discovery potentially offers a new molecular target for the diagnosis and treatment of some infertile women.

REFERENCE

1. Zhang et al., Sci China Life Sci 2025 68(8):2420-2430

INFECTIOUS DISEASES AND IMMUNOLOGY FOR REPRODUCTION

All Kind of Progress in the Treatment of Autoimmune Diseases

No other disease group has as close a physiological relationship with pregnancy as autoimmune diseases. A revolution is underway in the treatment of several autoimmune diseases with hope of curing the disease rather than just temporarily suppressing it. These new treatments were several years ago successfully introduced into cancer therapy and involve manipulations of the patient’s immune system via so-called CAR-T cells which, in the case of autoimmune diseases, have the ability to attack and eliminate autoreactive lymphocytes responsible for autoimmunity.

We here want to present two recent papers which demonstrated these new applications of CAR-T cell therapy in autoimmune diseases: Both are products of multicenter studies in China, both were accepted for publication within weeks from each other, published together in sequence in the same issue of Nature Medicine, and both reported on treatments with CAR-T cells in treatment refractory systemic lupus erythematosus (SLE).^1,2

PAPER 1 -- The first paper was a phase 1 trial using allogeneic CD-19-targeting T cells for treatment, while in the second paper autologous CD-19- and BCMA were targeted. Let’s start with the first paper by Wang et al.:¹

et al. In this paper the authors remind readers that CAR-T cell treatments (i.e., to spell it out, - commercial autologous anti-CD19 chimeric antigen receptor-T cell therapies) have been demonstrated to be effective in B cell malignancies several years before being used (and shown effective) in autoimmune diseases. The use of these calls is, however, still limited by the requirement for individualized personalized manufacturing at high costs and potential risks from random chimeric antigen receptor insertion into the genome.

To overcome these challenges, the authors of this study developed YTS109, a hypo immune allogeneic T cell product engineered using CRISPR–Cas9 to knock out TRAC, PD1, HLA-A, HLA-B and CIITA, with a CD19-targeting synthetic TCR and antigen receptor (STAR) precisely integrated into the TRAC locus to enable physiological, TCR-like signaling.

The article then reported on five patients with severe, refractory SLE complicated by lupus nephritis, who received lymphodepletion followed by YTS109 at 3 × 10⁶ STAR⁺ T cells per kg body weight. Primary endpoints were safety and SLE responder index 4 at month 3. Secondary endpoints included clinical remission and quality-of-life outcomes through to month 6.

YTS109 was well tolerated, causing only mild cytokine release syndrome but no graft-versus-host disease. All five patients achieved SLE responder index 4 responses by month 3, - sustained through to month 6. 4/5 patients showed rapid reduction in disease activity score (mean 31.30–5.35 by month 6), while one patient showed a mild refractory flare-up at month 6. Renal biopsies confirmed resolution of inflammation and tissue restoration, - unquestionably very promising results.

PAPER 2 – The second paper showed in a similar group of refractory SLE patients that peripheral CD19^⁺ B cells and bone marrow CD19⁻ B cell maturation antigen (BCMA)⁺ long-lived plasma cells are dominant sources of pathogenic autoantibodies, offering – in contrast to the 1^st paper -a strong rational for dual CD19 as well as BCMA targeting.²

The authors of this paper then report results from 15 patients (14 female, one male) in an ongoing phase 1 dose-escalation trial of co-infused autologous anti-CD19 and anti-BCMA CAR T cells after fludarabine/ cyclophosphamide lymphodepletion.

Primary endpoints of these studies were dose-limiting toxicities (DLTs) within 28 days and adverse events within 12 weeks; key secondary endpoints comprised attainment of Lupus Low Disease Activity State (LLDAS) and DORIS remission within 12 weeks and in vivo CAR-T persistence within 24 weeks. Exploratory endpoints were the duration of post-infusion B cell depletion and time to recovery, the kinetics of immune reconstitution and longitudinal changes in autoantibody titers and serum immunoglobulin concentrations after CAR-T cell therapy.

Over a median 712-day follow-up (range, 613–1,134), no DLTs occurred. Grade 1 cytokine release syndrome developed in 86.7% of patients, with no neurotoxicity or treatment-related deaths. The most common grade 3 or higher adverse events were neutropenia (100%), thrombocytopenia (40%) and anemia (13.3%), all of which were reversible with supportive care.

By week 12, 12 of 15 patients (80%) fulfilled both the LLDAS and DORIS remission criteria. Multiomic analyses confirmed elimination of autoreactive CD19⁺BCMA⁺ clones, reconstitution of naive IgM/IgD B cells and durable downregulation of interferon-stimulated and BAFF-dependent signatures, indicating improved immune homeostasis.

Longitudinal monitoring of three patients for 1 year demonstrated sustained eradication of pathogenic clones, suggesting potential cure. Dual anti-CD19/anti-BCMA CAR-T cell therapy, thus, demonstrates good safety and promising clinical efficacy in treatment-refractory SLE and, therefore, supports the further development of this treatment approach.

With publication of these two papers, the two groups of Chinese investigators, moreover, repeated the pioneering involvement in the early days of CAR-T cell therapy in primarily liquid cancers. Truly remarkable work which, - as noted earlier – offers hope for the cure of autoimmune diseases like SLE, - but also offers a clearly better understanding of how abnormal immune system antibody responses may be corrected and/or even prevented, which may have relevance not only for the treatments of abnormalities in self-tolerance but mal- sometimes in the future – also be applicable to the treatment of abnormal tolerance toward the fetal-placental semi- or complete allograft.

VAGUS NERVE STIMULATION -- Completely unrelated to CAR-T cell therapies, another new treatment approach for autoimmune diseases has recently made headlines, - vagus nerve stimulation (VNS). Yes, and if you don’t believe us, the FDA just approved VNS as treatment in rheumatoid arthritis (RA), - in a recent Healio article described as yet another “paradigm shift” in autoimmunity, especially in cases of rheumatoid arthritis.³ Before approval for RA, vagal nerve stimulation was already FDA-approved for the treatment of epilepsy, treatment-resistant depression, and during stroke rehabilitation.

The driving force behind the approval for RA was Kevin J. Tracey, MD, president and CEO of the Northwell Health’s Feinstein Institute for Medical Research (we, indeed, were privy to hear about vagal stimulation at a GrandRounds lecture at the CHR over two years ago).

According to a recent Healio article studies of vagus nerve stimulation are currently considered for multiple sclerosis, inflammatory bowel disease, psoriasis, and spondyloarthritis.

FDA approval was apparently based on a double-blind, placebo-controlled study in which patients over 12 weeks daily underwent 60 seconds of vagus nerve stimulation which produced significantly improved ACR response outcomes over placebo treatments (P=0.0209). The difference was even more pronounced in patients with one prior treatment episode with either a biological or a traditional anti-rheumatic drug (P= 0.0054). The article quoted an Arizona-based rheumatologist as noting that “it would seem that almost any of our diseases where inflammation is driving the condition could benefit from these techniques.”

But who needs implanted devices? There supposedly is no better vagal stimulation than an ice plunge!

REFERENCES

1. Wang et al., Nat Med 2025; 31:3713-3724.

2. Feng et al., Nat Med 2025;31:3725-3736

3. Healio. November 14, 2025. https://www.healio.com/news/rheumatology/20251113/approval-of-vagus-nerve-stimulator-may-herald-pivot-point-for-rheumatology

Important News from the World of Infectious Diseases

SEVERE FLU SEASON – It’s a pretty bad flu season this year and not only for the older population. The yearly vaccine missed the currently dominant strain when the vaccine was designed because the strain wasn’t around then (or at least wasn’t recognized to be around). From that follows that this year’s flu vaccine is not very effective in preventing disease; but it, still, is quite effective in preventing severe disease, including the need for hospitalization.

The CHR, therefore, strongly recommended that infertile women in treatment and/or already pregnant women get vaccinated. Remember, like COVID-19 was more severe in pregnant women, so is the flu! This also corresponds to recommendations from various professional societies, including ACOG.²

Here is a quick summary of the CDC’s weekly U.S. Influenza Surveillance Report Update for week 52 which ended on December 27, 2025, and was published on January 5, 2026.¹ Outpatient Illness

8.2% (Trend ↑ )
of visits to a health care provider this week
were for respiratory illness
(above baseline).

28.1 cumulative hospitalization rate per
100,000 population

31.3 (Trend ↑ ) weekly hospitalization rate
per 100,000 residents

33,301 (Trend ↑) patients admitted to hospitals
with influenza this week.

0.9% (Trend ↑) of deaths attributed to
influenza this week

A first influenza-associated death occurring
during the 2025-26 season was reported.³

The CDC estimated that by January 5, 2026, there have been at least 11,000,000 illnesses, 120,000 hospitalizations, and 5,000 deaths from the flu so far this season.

REFERENCES

1. CDC, Flu View., January 5, 2026. https://www.cdc.gov/fluview/surveillance/2025-week-52.html

2. ACOG Digest, December 3, 2025. Accessed December 5, 2025

3. Taylor L. BMJ. November 24, 2025; 391. Doi: https://doi.org/10.1136/bmjr2480

COVID-19 and the Flu May Reawaken Dormant cancer cells

A Medical News article in JAMA Medical News recently discussed a new finding that respiratory viral infections can trigger the proliferation of dormant breast cancer cells in the lungs.¹ That cancer-mortality had increased during COVID-19 has been known for quite some time; but the explanation widely accepted for this finding – that the pandemic interfered with timely diagnosis and treatments – was apparently wrong or at least partially incorrect.

The person who suspected that the SARS-CoV-2 virus may play a role was a professor of intensive care medicine at the University College London, who’s sister – after being declared breast cancer free – she while on holidays was likely infected with COVID-19. Because of symptoms, she had a chest x-ray that revealed what proved to be metastatic spread form her supposedly cured breast cancer. She died five months later.

Deciding to investigate the issue with some colleagues, the research started in a mouse model and with a closer look at epidemiological data and here is what the investigators found as reported in Nature: They demonstrated, in mice, that influenza and SARS-CoV-2 infections lead to loss of the pro-dormancy phenotype in breast DCCs in the lung, causing dormant disseminated cancer cell (DCC) proliferation within days of infection and expanding carcinoma cells massively within two weeks into metastatic lesions.

These phenotypic transitions and expansions are, moreover, IL-6 dependent. These DCCs also impaired lung T cell activation. CD4⁺ T cells sustained the pulmonary metastatic burden after the influenza infection by inhibiting CD8⁺ T cell activation and cytotoxicity.

These experimental findings then also aligned with the originally suspected human observational data (including in the physician’s sister): An analyses of cancer survivors from the UK Biobank (all kinds of cancers) and Flatiron Health (breast cancer only) databases revealed that SARS-CoV-2 infection substantially increases the risk of cancer-related mortality and lung metastases compared with uninfected cancer survivors. These discoveries underscore the huge impact of respiratory viral infections on metastatic cancer resurgence and – as the authors noted – offer new insights into the connection between infectious diseases and cancers.

REFERENCE

1. Anderer S. JAMA Medical News 2025;334(12):1047-1048

Long COVID, - the Problem That Does Not Go Away

This condition can affect the wellbeing of individuals post-COVID for months or even years and no satisfactory treatment has yet been discovered. The condition, therefore, is in symptomatology similar to other chronic post-infection syndromes.

A recent paper in Nature Immunology by Boston investigators now shed some new light on the condition. Performing immunological, virological, transcriptomic and proteomic analyses from a cohort of 142 individuals between 2020 and 2021, including uninfected controls (n = 35), acutely infected individuals (n = 54), convalescent controls (n = 24) and patients with long COVID (LC, n = 28).

What they found was that the LC group was characterized by persistent immune activation and proinflammatory responses for more than 180 days after initial infection compared with convalescent controls, including upregulation of JAK-STAT, interleukin-6, complement, metabolism and T cell exhaustion pathways. Similar findings were observed in a second cohort enrolled between 2023 and 2024, including convalescent controls (n = 20) and patients with LC (n = 18).

The authors correctly concluded that these data may suggest that LC is characterized by persistent activation of chronic inflammatory pathways, which can suggest new therapeutic targets and potential biomarkers for this diagnosis.

REFERENCE

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

Epstein-Barr Virus – Often Accused but Only Rarely Convicted

As the Editor’s Summary for this article of Westcoast investigators in Science Translational Medicine appropriately summarized, - the Epstein-Barr virus (EBV) has been accused of many crimes, including the accusation that it is a candidate driver of autoimmune diseases like multiple sclerosis and of long post-viral diseases like long COVID.¹

What makes this study so interesting is some evidence this study offers that where there is smoke, there may also be fire because the authors demonstrate a link between EBV infection and later disease development. By identifying EBV-infected cells by RNA sequencing, they were able to demonstrate distinct differences between infected and uninfected B cells.

EBV-infected B cells develop antigen-presenting ability and were capable of activating autoreactive helper T cells which could activate other B cells and that included uninfected B cells (confirmed by in vitro studies). At least in association with systemic lupus erythematosus (SLE), it appears that the EBV can infect and reprogram autoreactive B cells which then , in turn, can drive a systemic autoimmune response in SLE.

Now the question is which other autoimmune diseases can be initiated by the EBV (or similarly functioning viruses)?

REFERENCE

1. Younis et al., Sci Transl Med 2025. DOI. 10.1126/scitranslmed.ady0210

A CITIZEN’S TRULY HEART-FELT BELIEVE ABOUT THE COUNTRY’S HEALTH INSURANCE BUSINESS

When Illness Outlives the Patient

This brief article reflects the feelings of Jolanta Tapper, the CHR’s Chief Operating Officer who lost her son to cancer.

In the United States, laws such as the Affordable Care Act were designed to protect individuals from discrimination based on medical history. These protections aim to ensure that families facing serious illnesses are not denied coverage or treated unfairly simply because they needed care. Yet, real-world insurance practices can still produce outcomes that feel at odds with that promise.

Consider a family whose child spent years battling cancer while covered under a parent’s employer-sponsored group health plan. During that time, the family and their employer did what the system expects: they relied on insurance to cover necessary, life-saving treatments. Tragically, the child passed away in January 2022, leaving the family to cope with profound loss.

Years later, the story takes an unexpected turn. The employer—like many businesses—shops for more affordable coverage during a renewal period. Despite the passage of time and the absence of ongoing high-cost claims, insurers – as it turns out - still view the group as higher risk due to the child’s past cancer treatment. The case, though rare and no longer generating expenses, remains part of the group’s claims history.

As a result, the company now faces significantly increased insurance costs for all employees. In some cases, access to more competitive or lower-cost plans may even be limited. What was once a necessary effort to save a child’s life continues to influence financial outcomes years later—not just for the family, but for an entire workforce.

This situation highlights a lesser-known aspect of the insurance system. While individual protections under federal law prevent denial of coverage due to pre-existing conditions, employer-sponsored group plans—especially those that are experience-rated—can still be influenced by past claims. High-cost cases, even when resolved and no longer active, may affect how insurers assess risk and price coverage.

For the affected family, the emotional weight is obvious. But there is also a broader impact: colleagues and employers, removed from the original tragedy, now share in its financial ripple effects. This can create tension, confusion, and a sense that the system is assigning long-term consequences to events that are both rare and beyond anyone’s control.

At its core, this raises an important question about fairness. Insurance is designed to spread risk, not concentrate it indefinitely on specific individuals or groups based on past hardship. When a single, resolved medical event continues to shape costs years later, it challenges whether that balance is being upheld.

Families who fought to save a child should not remain defined by that fight. And employers who provided coverage during a time of crisis should not face prolonged penalties for doing so.

If the impact of a child’s illness can persist long after both the treatment and the life it sought to save have ended, it forces a difficult but necessary question: is the system truly functioning as a safety net—or has it allowed past tragedy to become an ongoing liability?

You tell us!

One of the never disappointing subjects we have been covering over and over here in the Reproductive Times as well as in the _THEVOICE is the introduction of new treatments and diagnostics into IVF practice based on scant or often even completely absent validations. That, of course, does not mean that this always happens on purpose or even consciously by proponents of these new remedies, - but it is also undeniable that financial incentives and profit motives of companies very often lead to exaggerated claims.

We today address a very recent claim made in a paper published in one of the highest ranked medical journals in the world and – because of hos sensational it was – of course making headlines in many newspapers and other media outlets. The claim made was that embryologists in IVF clinics in over half of all cases fail to identify oocytes in follicular fluids obtained in IVF cycles at time of egg retrievals when following the over 40 years-old routine of manually searching under a microscope for oocytes. Utilizing instead a microfluid chip developed by the company that financed the study, the publication claimed significant added recovery of otherwise overlooked oocytes.

If true, this, of course, would be a highly significant finding because it would suggest that inadequate embryology “loses” eggs and, therefore, reduces the cumulative pregnancy chances of patients in IVF cycles. This claim was moreover further enhanced in its credibility by publication in a very prestigious medical journal.

But, as our today’s posting will make clear, - we are very skeptical about the claims made in this publication. Let us know what you think!

The CHR’s Editorial Staff

During oocyte retrieval eggs are aspirated transvaginal from ovarian follicles under ultrasound control. This aspirate is then handed over to an embryologist who pours the so obtained follicular fluid (FF) into a flat dish and - with a microscope - carefully searches the FF for eggs. Since FF from more than one follicle may be in a single aspirate, at times several oocytes may be in one aspirate.

Now a group of investigators from Boston – using a so-called FIND-Chip (already available for purchase for research purposes) claimed that running FFs though this microfluid chip “rescued” in over half of 582 patients by embryologists overlooked oocytes. In other words, the study claimed that embryologist in routine retrievals overlooked and, therefore, “lost” considerable numbers of oocytes, - obviously reducing the cumulative pregnancy chance for so-affected patients.¹

The FIND-chip (what an original name!) was designed to process in a multistep process unscreened FF, - producing isolated and denuded oocytes, ready for fertilization and/or cryopreservation. To validate the FIND-Chip process, bovine cumulus-oocyte complexes (bCOCs) mixed into discarded human FF were used and optimized to achieve high isolation and denudation efficiency.

In conducting validation studies, the authors, however, unexpectedly noted that the FIND-Chip apparently repeatedly recovered extra human oocytes from the FF samples beyond the number of oocytes used to spike the FF samples for the validation study. In an initial experiment (n=13 patients), they recovered 19 extra oocytes in addition to 39 donated oocytes originally spiked into the FF. In follow-up studies involving a handful of test cases, they had the same experience: follicular fluids after use of the Find-Chip repeatedly “revealed” more oocytes in the fluid than had been used for spiking the samples.

Unsurprisingly, the lay media found this report of considerable interest, leading to a good number of articles with at times rather provocative headlines. The New York Time, for example, described the situation as “A New Fertility Device Retrieving Hidden Eggs”² (hidden??). The media’s enthusiasm about this publication was further fostered by the fact that this paper appeared in one of the highest ranked medical journals, - Nature Medicine, with ca. half of its authors – among those the two senior authors responsible for conduct of the study – from Boston IVF, one of the nation’s most prominent IVF clinics.¹

Here is a brief summary of what the paper claimed: A newly developed microfluidic device (FIND-Chip) allowed automated isolation and denudation of oocytes from FF aspirates with apparently more accuracy than manual human embryology could achieve after over 40 years of such routine practice. The system was initially tested with cow oocytes but – after that – tested the apparatus in a clinical study involving 582 patients from four IVF clinics. Based on this study, the authors claimed that in more than 50% of cases functional and mature oocytes under current clinical practice went undiscovered by embryologists, - therefore, would, of course, be inadvertently discarded., - ultimately resulting in a loss of cumulative pregnancy and live birth rates for so-affected patients.

But the in the paper made claims must be interpreted with great caution: As the authors also noted, – the FIND-Chip increased the number of embryos available for embryo transfer in only two patients and only one of them achieved a live birth, - a rather small sample size we would argue.

According to the New York Times article, the study was conducted by a company (AutoIVF of Natick, Massachusetts) which, of course, developed the technology. It was allegedly supported by a grant from the National Institute of Child Health and Human Development, part of the National Institutes of Health, which is interesting because Congress in principle prohibits support of IVF-related studies.

Ravi Kapur, PhD, MSc, the CEO of AutoIVF (also an author of the study), was quoted saying that the device, called OvaReady, was originally intended to increase efficiency and standardization of a key step in the fertility process, - namely the finding and isolating of eggs, - so they can be fertilized by sperm. He had expected that the device might find “some eggs being left behind,” perhaps in 10 percent of cases, but “not the 50 percent consistently across multiple very high-end clinics in this country.”

According to the article the four clinics that provided most of the samples were in the eastern U.S. and part of “larger networks,” though confidentiality agreements prevented him from disclosing who they were. One of them was, of course, Boston IVF, as six authors of the paper were Boston IVF staff, though also listed as employees of the company AutoIVF, among those the two authors responsible for conduct of the reported study. As employees of the company (and likely shareholders) they, of course, must be considered to be potentially conflicted. That all authors listed on the paper therefore apparently are potentially conflicted, - this fact warrants consideration.

According to Kapur, AutoIVF is in discussions with the FDA and will seek approval to use the device in clinical practice. In the meantime, clinics can already offer it as part of research efforts. What this in practical terms means is, that Kapur’s company already offers the equipment for sale.

We are for several reasons skeptical, but the principal reason is the almost anecdotal presentation of reported data in the paper, - also a major reason for our surprise about acceptance of this paper by Nature Medicine (one wonders who the peer reviewers were). Here are just a few unanswered questions that should have been asked and answered before acceptance of the paper and should have been included in the manuscript: What were the characteristics of studied patients and their IVF cycles? What were the characteristics of IVF clinics that contributed FF samples for the study? What were the qualifications of the embryologists in those clinics? What were the differences between clinics and individual embryologists in “overlooking” existing oocytes? After all, maybe only a small minority of poorly qualified embryologists were responsible for most missed oocytes. Were all embryologists aware that they participated in the study and knew what the purpose of the study was or were only Boston IVF embryologists aware of that fact?

It is also important to note that the current shortage of qualified embryologists may be especially consequential in the large clinic networks (which all four major contributing clinics apparently belonged to) because embryologists who have to deal with large daily retrieval numbers may – with this, of course, being only one among several hypotheses - overlook more oocytes in FF aspirates than embryologists in clinics with smaller patient volumes. Where was, therefore, the internal quality control, comparing efficiency between individual embryologists involved in cycles from which aspirates were later used for spiking?

And here are some additional more technical unanswered questions: How were FF aspirates handled between original follicle aspiration and subsequent FF screening by FIND-Chip? What was the time interval? Who did what? Who made sure that the specimen were not manipulated by interested parties? What were the controls in handling all FF specimens and the spiking process? One commenting expert in the Times article correctly noted that – based on reported results – the “overlooked” oocytes were apparently not “shriveled” as one might expect oocytes to be which do not receive appropriate maintenance. How is that explained?

To say it, therefore, bluntly: As of this point we have a hard time in believing the data presented in this paper. Nobody can argue with the fact that, even best embryologists, may on rare occasions overlook oocytes with currently prevailing manual embryology; but it would really astonish us if well-trained embryologists carrying reasonable patient burdens in over half of all cases would overlook oocytes. This claim, indeed, reminds us of exaggerated claims made (by economically-interested parties) in initial publications introducing closed incubation systems with continuous embryo image monitoring. Initial reports for example claimed significant declines in required embryologist-time spent per patient. Reality – after IVF clinics felt obliged to purchase the equipment – actually demonstrated exactly the opposite, - the time embryologists spent on each patient, indeed, increased.

And then there is the also the already note issue that overlooked oocytes apparently were not “shriveled” and, indeed, seemed to have looked “perfect.” If that were, indeed, the case, embryology for more than 40 years has apparently been overly cautious in handling freshly retrieved oocytes. We very much would like to know what the time delay was in “finding” the overlooked oocytes that then, still, seemingly performed normally.

Or didn’t they? How well did they really perform?

Oocytes were supposedly fluorescent-color-coded to differentiate them from spiked oocytes; but were the allegedly missed oocytes mature MII, mild immature MI or even very immature GV oocytes? What was the time range between follicle aspiration, negative egg search, and subsequent egg discovery. At what temperature and for how long in what kind of gas mixture were these fluids maintained? And the claim is not only that oocytes were missed by embryologists on a first go-around, - but the paper also suggests that missed oocytes uniformly also had substantial potential of producing good quality embryos with good pregnancy chances.

But the paper, indeed, demonstrates nothing like that (i.e., one delivery only!). Combining all of these open questions, one can the presented message, indeed, only consider as anecdotal.

Already thinking about purchasing an OvaReady system (obviously another brilliant name choice!), - Good Luck!

REFERENCES

1. Mutlu et al., Nat Med 2026; https://doi.org/10.1038/s41591-026-04207-x

2. Belluk P. The New York Times. February 24, 2026. pD3. https://www.nytimes.com/2026/02/12/health/ivf-hidden-eggs-device-ovaready.html

It is certainly no longer a secret that we, here at the CHR, are not very friendly imposed toward preimplantation genetic testing for aneuploidy (PGT-A) and we believe for good reasons: The test in general does not improve IVF cycle outcomes and, indeed, in certain sub-groups of IVF patients actually reduces their pregnancy chances and adds significant cost to an already excruciatingly expensive IVF cycle.

The CHR has held this position since 2006 (hard-to-believe, we are celebrating our 20^th anniversary this year!) after reanalyzing two early prospectively randomized studies of Belgian colleagues of what - then – was called preimplantation genetic screening (PGS). Both studies had not found promised IVF cycle outcome improvement PGS-proponents had widely touted and the CHR’s reanalysis of their data actually suggested that PGS may reduce IVF pregnancy chances in older women.

We, of course, were not the only ones who – ever since – against significant resistance from the “PGT-A industry,” had to prove that by the PGT-A industry promised improved IVF cycle outcomes really never materialized. We in the process defined PGT-A as a “test (or procedure) in search of an application” because not only was the PGT-A industry unable to demonstrate promised outcome benefits but had to change the alleged benefits over and over again, as older alleged benefits by a small cadre of PGT-A opponents were slowly but surely and case by case disproven. This in itself was, of course remarkable because shouldn’t evidence be produced by proponents of an intervention? Instead, the opponents of an unvalidated intervention were forced to produce evidence that the intervention didn’t work.

In today’s posting we are discussing recent PGT-A related publications, some valuable, - others not so. We are, however, especially pleased to have the opportunity to present a publication that has mostly remained under the radar of general attention because it was not published in an infertility journal or a highly ranked general medical journal but in a rather peripheral general OB/GYN journal (the limited attention may, indeed, have been a purpose!).

It is a truly amazing study because it presented an acknowledgment of “defeat” by some of the most prominent proponents of PGT-A in the world, for the first time basically openly acknowledging the futility of PGT-A in association with IVF. We could not have asked for a better acknowledgment at our 20-year anniversary from having been making this point. Sometimes good things take time!

The CHR’s Editorial Staff

INTERESTING RECENT NEWS REGARDING CHROMOSOMAL TESTING OF EMBRYOS IN IVF

Any discussion of IVF between patient and physician these days – as over half of all IVF cycles in the U.S. currently utilize this test - should, of course, address the highly controversial issue of preimplantation genetic testing for aneuploidy (PGT-A), the formal name for the testing of embryos for chromosomal abnormalities prior to embryo transfer. We to this day are, however, steadily surprised how many patients reach the CHR still claiming never to have been informed about existing controversies surrounding PGT-A. The issue usually comes up when they present for an initial second opinion consultation to the CHR after often having undergone many IVF cycles with PGT-A with only few – if any – “transferrable” embryos to show for. This is, of course truly astonishing because – if correct – very obviously - at minimum - represents inadequate informed consent. The CHR, therefore strives to fill this information vacuum by steadily reporting on news regarding PGT-A and today there are, indeed, very substantial news to report.

Does PGT-A “Rescue” Poor Quality Oocytes, - Thereby Increasing the Availability of Embryos for Embryo Transfers?

This is at least what a paper of British investigators even in its headings recently suggested and – boy – does this paper not make sense!¹

What the paper suggested on first impression might seem logical: Some not too great-looking blastocysts can still be euploid (of course true and not unexpected). But then the paper becomes silly because it – first – incorrectly suggested that PGT-A – by transferring only euploid embryos – lowers miscarriage rates (according to the 2024 ASRM opinion on PGT-A an incorrect statement²) and then – second – suggests that this especially will be the case in PGT-A tested blasts which, of course, is nonsense.

The need for blastocyst culture and the need for cryopreservation to do PGT-A alone, will indeed significantly reduce pregnancy chances of these embryos (especially if they look “ugly”). Add to this the high false-positive rate of PGT-A and, therefore, the decline in cumulative pregnancy chance from not transferring at least some potentially fine embryos with good pregnancy and live birth chances which erroneously have been tagged with an “aneuploidy” diagnosis (most clinics still do not transfer such embryos), and the paper’s argument of improving potential pregnancy and delivery chances makes absolutely no sense.

There is, however, another reason why we are addressing this paper her: We not too long ago in a prior posting here in quite some detail presented several arguments why editors should not publish their own papers in journals they edit. This paper is another good example for this argument because its senior author is one of the two senior editors of the journal where this paper appeared. And we know this editor well: he is a very good scientist (and editor) who has published large numbers of excellent papers. Why he really needs his name associated with this paper, therefore, also makes absolutely no sense. The connection to the next reviewed paper will also immediately become obvious.

Even Italian Colleagues Can Be Sensible About PGT-A

From its earliest days - even before being given the name PGT-A - Italian colleagues, in contrast to many other Europeans, have been among the most aggressive supporters of PGT-A.

A paper addressing PGT-A that does not push its clinical utilization is, therefore, always a pleasant surprise. Such a paper appeared recently in JARG, making the really not surprising point that – besides chromosomes – other things matter as well in human embryos.

The authors reached this conclusion after learning that, especially embryo morphology (over maternal age and developmental timing of blastocysts by imaging) wins out. And even maternal age exerts its negative effects by adversely affecting embryo competence beyond just increasing aneuploidy. In other words, they reached the correct conclusion that there must be other age-related factors in embryo physiology beyond rising aneuploidy that are the guilty parties why getting pregnant with increasingly older eggs becomes less and less successful.³

Difference in Embryo Ploidy Between Primary and Secondary Repeat Aborters -- The authors of this paper – also in JARG – addressed an interesting question,- do primary repeat aborters (women who from 1^st pregnancy on miscarry) differ in ploidy (chromosomal abnormalities) of their products of conception from secondary aborters (women who had 1 or more children before starting with repeated miscarriages).

This question once again relates to reproductive immunology because – at least when it comes to immune-causes for pregnancy loss – it is well established that a first pregnancy can sensitize a mother’s immune system like a first exposure to an allergen may lead only to a mild rash, while a second exposure can lead to anaphylaxis. Here, too, the mother may have had only mild preeclampsia in her first pregnancy (or may have shown no abnormality at all) but in a second pregnancy may, suddenly, become highly symptomatic.

Such a danger may be especially profound if the first pregnancy was a male (male epitopes elicit more immune responses from mothers than female epitopes).

How Human Embryos Self-Correct

A so-called Mini Review in Human Reproduction by two British authors recently addressed the concept of self-correction in embryos downstream from blastocyst stage when trophectoderm biopsy nowadays are performed.⁴ And we are recommending this paper for readers interested in PGT-A not because the authors referenced four papers from the CHR but because – despite considerable evidence in support – some proponents of PGT-A are still claiming that embryos never self-correct.

Though the authors of the review are not yet ready to commit fully to the concept of embryo self-correction, they acknowledge that embryo mosaicism is well documented in at least over 80% of preimplantation-stage embryos. And this number is likely an underestimate because without testing (almost) every cell in a blastocyst-stage embryo, - only one thing is certain: the only limited biopsy at blastocyst stage that will be 100% accurate is a biopsy that reveals mosaicism. A limited biopsy demonstrating full aneuploidy – unless meiotic in origin – (most aneuploidies, however, are mitotic) in a majority of cases still may be mosaic, - just like a fully euploid PGT-A result much more likely in reality reflects a mosaic embryo.

Moreover, with now consensus reached that aneuploid islands of cells can be found in most term placentas, segregation between euploidy and aneuploidy happens, of course, only in the embryonic cell lineage, while PGT-A biopsies are taken from the trophectoderm, - a product of the extraembryonic cell lineage. Mosaicism, therefore, represent a normal feature of preimplantation stage embryos and, indeed, may be used by embryos to avoid rejection by the maternal immune system during early stages of implantation. But that is a subject for another time!

This review should leave little doubt that those arguing against self-correction still have some reading to do!

IS THIS THE PAPER THAT FINALLY SETTELS THE PGT-A DEBATE?

And then there was another paper, - astonishingly including some of the most vocal proponents of PGT-A over the last 20 years, from Dagan Wells, PhD, to Richard Scott, MD, Juan Antonio Garcia Velasco, MD, Antonio Pellicer, MD, Chaim Jalas, and Antonio Capalbo, PhD, who published - out of all journals - in the American Journal of Obstetrics and Gynecology an international multicenter study involving thousands of patients under the bombshell title:

“Preimplantation genetic testing for aneuploidy mosaicism reporting lacks clinical predictive value for live birth in a multisite, double-blinded study with independent validation” ⁵

And we are quoting here verbatim: The purpose of the study was to determine whether reporting putative mosaicism based on intermediate copy number improves the prediction of reproductive outcomes and should influence embryo selection in clinical practice. And the answer was that the presence of high-level intermediate copy numbers in the trophectoderm biopsy was associated with a modest reduction in live birth rate. Because of its low incidence and limited effect size, mosaic reporting, however, did not contribute to a meaningful improvement in clinical outcomes. In our clinical and laboratory setting, reporting putative mosaicism provides no clinical benefit and should not guide embryo selection in routine IVF practice.

We already noted above in discussing the preceding paper that – considering how small every trophectoderm biopsy is for PGT-A and baring a meiotic aneuploidy (which represents only as small percentage of all aneuploidies in embryos at blastocyst stage), – only a “mosaic” diagnosis by diagnosis of intermediate copy numbers can with certainty be viewed as correct. In contrast diagnoses with either seemingly “euploid” or “aneuploid” copy numbers have a high probability to actually - overall for the embryo rather than only the small 5-10-cell trophectoderm biopsy – in reality to reflect “mosaic” (i.e. intermediate copy number) embryos.

In other words, what this paper finally acknowledges is that a vast majority of PGT-A diagnoses – far beyond what currently is described as “mosaic” - lacks clinical predictive value for live births, provides no clinical benefit and should not guide embryo selection in routine IVF practice. Consequently, one has to ask the question, why are over half of all IVF cycles in the U.S. still using PGT-A?

And obviously less important but nevertheless a very important question, - one also must ask why this important paper was not published in Fertility and Sterility or Human Reproduction? Who wanted it less visible?

At the same time we, however, want to express the CHR’s appreciation to all of authors of this publication. And we do this not because this paper, of course, finally confirmed what the CHR has been trying to communicate to the infertility world for almost two decades, - but because it takes guts to acknowledge having been wrong, and this is exactly what all of this paper’s 24 authors (yes, we counted!) openly and graciously did. Thank you all!

PGT-A In Cases of Severe Male Factor?

When it rains it pours; and we, frankly, don’t know any longer whether to laugh or cry because Chinese investigators recently also published a somewhat strange paper in the quite often strange BMJ involving PGT-A which demonstrated no outcome benefits for PGT-A.⁶

And we – frankly – have absolutely no explanation why our Chinese colleagues chose to investigate PGT-A specifically in couples with severe male factor. At least to us, the study seems to make little sense because what does male factor potentially have to do with PGT-A? Why would or – indeed - should PGT-A affect male factor infertility?

But the Chinese colleagues, nevertheless, investigated the effects of PGT-A in severe male infertility cases by randomizing 450 couples with severe male factor infertility to ICSI with or without PGT-A. For the CHR unsurprising, PGT-A utilization did nothing regarding pregnancy and live birth rates. But – somewhat strangely and unexpected, male infertility couples who used PGT-A had lower clinical miscarriages (13/225, 5.8% vs. 43/225, 19.1%; P<0.001) as well as chemical pregnancies (7/225 vs. 3.1% vs. 19/225, 8.4%; P=0.02), - on first impression suggesting that PGT-A may have IVF outcome effects after all.

But thinking this through, positive effects on miscarriages make little sense physiologically as well as mathematically because if a statistically significant number reduction in miscarriages occurred, how come there was no concomitant increase in live births. The article presumed that PGT-A eliminated embryos prone to miscarriages but why then no increase in pregnancy, cumulative pregnancies and live births?

We smell a statistical rat somewhere in the bushes!

Severe male infertility patients demonstrated an aneuploid rate of 42.6% and - in opinion of the authors – warrants PGT-A because of these numbers. We are, frankly, not sure of that. So much more effort and cost to prevent a still questionable alleged increase in chemical pregnancies (marginal) and clinical miscarriages (statistically significant).?

SUMMARY AND CONCLUSIONS – PGT-A does not improve IVF outcomes in general populations.² In good prognosis patients it may, however, shorten time to pregnancy and may also reduce miscarriage risk. Good prognosis patients, however, even without PGT-A have very high pregnancy and live birth rates. Routine utilization of PGT-A in good prognosis patients may, therefore, not be cost-effective.

The one still unresolved issue in PGT-A are adverse IVF effects from PGT-A utilization. More specifically, which are the subgroups of patients who not only will not benefit from PGT-A, but will actually be harmed by PGT-A. Our analysis of available data suggests that the risk for adverse outcomes is inversely related to functional ovarian reserve of patients and, therefore, to their number of available oocytes and embryos for transfer: The smaller the number, the more likely will PGT-A be harmful because the smaller the available number of embryos for transfer, the more consequential is non-use of a false-positive embryo.

REFERENCES

1. Al Hashimi et al., RBMOnline 2026;52(1):105208.

2. ASRM/SART. Fertil Steril 2024;122(3):421-433

3. Listorti et al., J Assist Reprod Genet 2026;43:143-153

4. Mantzouratou A, Mania A. Hum Reprod 2026;41(3):319-331

5. Gill et al, Am J Obstet Gynecol 2026;234(4):1015-1041

6. Lin et al., BMJ 2025;391:e084050

Trying to alternate for the weekend, we offer in our posting today again commentary in two distinctively different areas of clinical medicine linked to infertility: - male factor infertility in comparison to female infertility has always been the stepchild of the infertility field and, likely, will remain so, even though - as worldwide sperm counts have been declining – male factor infertility represents a growing proportion of infertility cases, with some studies suggesting that female and male infertility factors have equalized. We have, of course been as guilty as everybody else in this discrimination and, therefore, are starting today’s posting with two interesting recent publications raising some very basic questions regarding male fertility and infertility. And we then switch to pregnancy, - of course the happy outcome of every fertility treatment. Within this context, it is, however, important to remember that the ultimate goal of fertility treatments is not pregnancy but a healthy live birth. Making maximal efforts to prevent pregnancy complications before pregnancy occurs is, therefore, an integral part of infertility care and has been a very basic principle at the CHR since its establishment. Tell us what you think!

The CHR’s Editorial Staff

A Provocative Questions – Are Current Semen Analyses Still Worth It?

This is basically the question Italian investigators recently asked in a Review/Opinion article in Endocrinology¹ and – maybe somewhat surprising - the answer was, - maybe not!

Here are some of the more interesting conclusions: (i) Based on WHO recommendations making semen analyses over the years more and mor complicated did not improve the ability to interpret results and to better understand “what is going on in the testes.” (ii) In association with IVF, the male partner is (within reasonable parameters), still, merely considered as a relatively unimportant “sperm provider.” (iii) Consequently, there is a general believe that there really is no need for better semen analysis tools (we very much plead guilty of holding this opinion!). (iv) Some recent investigations have suggested that sexual arousal may produce better semen samples than masturbation, - the usual way specimens are produced in fertility practice. (v) Semen analyses have been shown to differ significantly between laboratories. (vi) Some newly developed tests may have additive diagnostic value (though we are not sure of that at all!). And (vii) because of all the preceding points, the authors recommend to “move away” from the centrality of the semen analysis in evaluating men.

What this review really informed about is that the CHR’s current understanding of what a semen analysis really offers diagnostically is basically correct; As long as an infertile couple is already committed to IVF, ICSI is available, “reasonable” semen parameters regarding count, motility, and morphology, render further details in semen analyses irrelevant.

Andrologists and urologists, - please don’t hate us!

REFERENCE

1. Furini et al., Endocrine 2025.90:1067-1078

The Pendulum Continues Swinging When It Comes to Male Testosterone Supplementation

That androgen supplementation is not only controversial in women but may be even more controversial in men may surprise many of our readers and the principal reason is that indications are so much more variable than in the female.

Testosterone supplementation in men trying to impregnate their partners is, of course, contraindicated because it will shut down sperm production in testes. But otherwise, an FDA panel of experts recently published new recommendations for testosterone supplementation in men which significantly loosened prior restrictions.¹

Comprised of urologists and health officials (but no fertility specialists), the panel recommended for men the loosening of restrictions beyond only low testosterone (T: i.e., hypogonadism), calling for expanded FDA-approved uses beyond disease-induced low T to include age-related declines. In addition, the FDA removed T’s controlled substance status. The change in recommendations was based on prior changes in guidelines from major medical societies and the observation that prior stricter rules led to more unregulated and unsupervised T utilization.¹

As a panel recommendation, these changes are only “advisory” and the FDA leadership must now make final decisions, though the expectation is that this final decision will follow panel recommendations

REFERENCE

1. FDA. December 2025. FDA panel on testosterone replacement therapy for men. https://www.google.com/searchq=FDA+panel+on+testosterone+replacement+therapy+for+men&rlz=1C5CHFA_enUS1083US1083&oq=FDA+panel+on+testosterone+replacement+therapy+for+men&gs_lcrp=EgZjaHJvbWUyBggAEEUYOdIBCjI1NjgxajBqMTWoAgiwAgE&sourceid=chrome&ie=UTF-8

OBSTETRICAL PRACTICE AND PREGNANCY COMPLICATIONS

Most Recent U.S. Stillbirth Rates and Total Fetal Mortality

STILLBIRTHS -- The definition of a stillbirth is the death of a fetus at or after 20 weeks’ gestation. It occurs annually in over 20 000 pregnancies in the U.S. alone, representing a rate of 5.74 per 1000 US births (10.34 per 1000 births among non-Hispanic Black individuals. Approximately half of at least stillbirths at term are believed to be preventable, - yet little progress has been made in reducing stillbirth rates. In 2023, the Department of Health and Human Services, therefore, established a Stillbirth Working Group.

Harvard investigators now reported in JAMA on singleton births between 2016 and 2022 on unadjusted prospective fetal mortality rates overall and in a subgroups of third-trimester births among health insurance claims. Among 2,792,699 total births, 18, 893 (6.8/1,000 births) were recorded. Mortality rates were ca. 0.7/1,000 at 20 weeks, steadily declined to a nadir of 0.13/1,000 at 29 weeks, only to rise back up to similar numbers as at 20 weeks by 38 weeks, - and then quickly rising further to an all-time peak of 2.29/1,000 above 41 weeks.

Interestingly, these numbers were higher than 2021 rates reported by the CDC. In addition no risk factors were identified in 27% of all stillbirths, and in 40.5% of stillbirths even above 41 weeks gestational age, which led the investigators to suggest that we must get better in risk stratifying.

And obviously related, the CDC reported fetal mortality in the U.S. with final numbers for 2022-2023 and provisional numbers for 2024.² Comparisons showed differences between 2022 and 2023.

FETAL MORTALITY -- From 2023 to 2024, the overall fetal mortality rate declined 2%, from 5.53 to 5.41 fetal deaths at 20 weeks of gestation or more per 1,000 live births and fetal deaths. During this time, the early fetal mortality rate (20–27 weeks of gestation) was essentially unchanged (2.88 in 2024), while the late fetal mortality rate (28 weeks of gestation or more) declined 4% (2.55 in 2024, see Figure below).

No significant changes in fetal mortality rates between 2023 and 2024 were observed among the race and Hispanic-origin groups. Fetal mortality rates decreased in 3 states, increased in 1 state, and were not significantly different in 46 states and the District of Columbia from 2023 to 2024. In comparison, from 2022 to 2023, the fetal mortality rate increased for early fetal deaths, for Asian non-Hispanic women, and in five states, and declined in one state (see Figure below).

This analysis of provisional 2024 fetal mortality data found that the total and late fetal mortality rates declined by 2% and 4%, respectively, compared with 2023 rates, while the early fetal mortality rate was essentially unchanged. From 2023 to 2024, no significant changes were observed in the fetal mortality rates for any of the race and Hispanic-origin groups. In comparison, from 2022 to 2023, the fetal mortality rate increased for early fetal deaths, for Asian women.

REFERENCES

1. Sullivan et al. JAMA 2025;334(22):2033-2035

2. Gregory et al., CDC. NCHS, National Vital Statistics System. December 2025. Report No 41. https://www.ncbi.nlm.nih.gov/books/NBK619812/

Pregnancy As an Accelerated Aging Event for Women

That pregnancy can accelerate female aging has over the last year been a subject that attracted considerable attention in the medical literature. We, therefore, previously addressed the subject in these pages but - as Obstetrics & Gynecology recently once more contributed two articles to the discussion - we felt that another round of comments was indicated.

In the first paper colleagues from Stanford University investigated whether longitudinal epigenetic maternal aging in pregnancy was associated with adverse pregnancy outcomes.¹ These data were obtained with 11 epigenetic clocks from Illumina EPIC 2 arrays, - one of them being GrimAge2. Based on earlier reports, what they found was not unexpected: Pregnancy, indeed, accelerated epigenetic aging within a nulliparous woman by up to 5.3 years.,

Older first trimester epigenetic age by GrimAge2 (but not chronologic age) was marginally (p=0.04) associated with a composite of pregnancy complications which – interestingly – were mostly immune system-related, considering the CHR’s longstanding interest in immunology of course a very interesting finding for the CHR’s investigators. Considering that older women currently represent the only remaining age group with still increasing pregnancy numbers, the authors offered the very astute conclusion that

epigenetic clocks should be used in such patients to investigate their risks for pregnancy complications in the first trimester of pregnancy. In the CHR’s opinion, such investigations in older women, could= and should -, indeed, already start during infertility care.

Two colleagues from Columbia University, among them Zev Williams, MD, PhD, Chief of REI at Columbia then contributed a commentary and editorial to the same issue of Obstetrics & Gynecology, correctly noting that – if confirmed – these findings may require a “reconceptualization” of what defines “advanced maternal age.”² They also pointed out that these findings are supportive of the longstanding concept of pregnancy as a “stress test” for practically all organs and bodily systems of a woman. Both papers are important contributions.

REFERENCES

1. Panelli et al., Obstet Gyecol 2025;146(6):783792

2. Williams Z, Suh Y. Obstet Gynecol 2025;146(6):781-782

The T Cell That Likely Helps in Maintaining a Healthy Pregnancy (and also Protects from Autoimmunity)

Here is yet another story regarding reproductive immunology – obviously a topic we, here at the CHR cannot get enough of – that demonstrates how closely intertwined pregnancy-tolerance is with self-tolerance, - i.e., how much in common autoimmune conditions have with certain immunological pregnancy complications.

The subject is the KIR⁺ CD8⁺ T cell, and the story starts with a paper by investigators from the University of Pittsburgh (Li et al¹) in Science Translational Medicine which an editor summarized (this journal smartly starts each paper with an Editor’s Summary).

And this is how she summarized this important paper: In pregnancy the maternal immune system must tolerate the usually semi-allogeneic fetus (in cases of egg donation and in gestational carrier pregnancies the fetus is now fully allogeneic), while still maintaining sufficient immunity to continue reasonably protecting the mother from infections. The investigators in this paper now reported that certain CD8⁺ T cells expressing killer cell immunoglobulin-like receptors (KIRs) – an only relatively recently identified regulatory CD8⁺ T cell population - are in peripheral blood and placental tissue enriched during human pregnancy and express ex-vivo very potent suppressive activity.

As Asher Jones, a science communicator and writer at the University of Pittsburgh noted in a recent communication from the Department of Immunology, KIR⁺ CD8⁺ T cells were higher in pregnant people and increased during the second trimester. ² Moreover, as one, therefore, would expect (because of their Y-antigens), male fetuses produced higher levels of KIR⁺ CD8⁺ T cells than female babies. The researchers, then went into in vitro studies, - taking T cells from mothers and combined them in a dish with umbilical cord cells from their babies. When KIR⁼ CD8⁺ T cells were removed, the mothers’ other T cells reacted much more strongly to the fetal cells, demonstrating their critical role in suppressing maternal immune responses against the fetus.

In pregnant with likely immunologically-induced miscarriages and/or preeclampsia these KIR⁺ CD8⁺ T cells were found further enriched above normal pregnancy levels, suggesting that they may try – unsuccessfully – to control inflammation but were failing. These findings, however, nevertheless suggested that these cells play an important role in maintaining maternal immune balance in normal pregnancy. The authors then also correctly noted that that – due to their functions - they may become candidate biomarkers or even therapeutic targets in pregnancy complications like repeated immune-mediated pregnancy loss and preeclampsia.

As Li et al (then still at Stanford University) already in 2022 reported, these cells have also been demonstrated to be active in autoimmune diseases, such as celiac disease, multiple sclerosis, and systemic lupus erythematosus, as well as with COVID-19,³ of course closing for us here at the CHR the unifying circle between pregnancy tolerance and self-tolerance we referred to at the beginning of this commentary.

REFERENCES

1. Li et al., Science Tranlat Med 2025;17(810). DOI: 10.1126/scitranslmed.adm7697

2. Jones A. Department of Immunology. University of Pittsburgh. October 13. 2025. https://www.immunology.pitt.edu/news/meet-t-cells-help-maintain-healthy-pregnancy

3. Li et al., Science 2022;376(6590):eabi9591

New Information About the Development of the Fetal Immune System

In a quite remarkable paper in Cell, Chinese investigators recently offered new information about the developing fetal immune system, especially during the second trimester of pregnancy, a pivotal stage in human immune system development (and a time when maternal tolerance toward the fetal semi-allograft is at its peak). Here is some detail: Utilizing single-cell RNA sequencing and T cell receptor sequencing, the authors profiled 2,868,420 immune cells from 321 samples across 23 fetal organs, using adult tissues for comparison, identifying an extrathymic CD4⁺ T cell subset mediating TOX2⁺ precursor cells’ transition to mature naive CD4⁺ T cells.

Contrary to the widely held current believe of fetal immune quiescence, they uncovered widespread memory -activated T cells and tissue-resident memory clones shared across organs, indicating systemic immune activity beyond localized barrier defense. Cell-cell communication and functional assays indicated two tolerance mechanisms that suppress fetal T cell activation: ARG1⁺ neutrophils and a PTGES3/PTGER4 signaling pathway. They also found that hematopoietic stem cells (HSCs) disperse across multiple organs and demonstrated that HSCs from non-canonical hematopoietic organs differentiated into diverse immune lineages (see graphic abstract below).

REFERENCE

1. He et al., Cell 2025; 188(25):P7291-7308.E23

Does Hydroxychloroquine (Plaquenil) Treatment in Pregnancy Help in the Anti-phospholipid Syndrome (APS)?

As just noted above, here at the CHR researchers for decades have had exceptional love for the commonalities between pregnancy- and self-tolerance. Yet in parallel, we also developed a clear dislike for what our rheumatology colleagues have originally come to call the anti-phospholipid syndrome (APS). The syndrome, however, not only changed over the years definitions, - but also names. And while there were several reasons for our dislike of what our rheumatology called the APS, the principal one for the CHR has been that we see this alleged diagnosis as “concocted.”

Its history started many decades ago in New Zealand when an internal medicine practitioner in a hospital ward coincidentally noted several women who just had experienced miscarriages, had deep vein thromboses, and were found to be positive for the so-called lupus anticoagulant (LA). Because of the unusual confluence of patients with identical presentation, this practitioner then reported this case series in The Lancet.¹

It turned out to be an important new observation, and the CHR’s Norbert Gleicher, MD, was, indeed, among the first – if not the first - to follow up on it with an article in JAMA, pointing out that the syndrome was not only defined by a positive LA but also by typical autoimmune autoantibodies.²

But then our rheumatology colleagues took over and established the so-called anti-phospholipid antibody syndrome (APAS) as an independent clinical diagnosis, initially defined as a woman with positive LA, a history of thrombosis, and repeated (at least 2) miscarriages. And that never made sense to us here at the CHR because without pregnancies there, of course, are no miscarriages. The diagnosis of APAS, therefore, could not be reached unless a woman experienced at least two miscarriages. What kind of diagnosis is this, when one must wait for at least two miscarriages before being able to fulfill diagnostic criteria of diagnosis. What about women who never got pregnant? And what about men?

Unsurprisingly, names as well as diagnostic phenotypes changed, but never to a degree that here at the CHR made us more comfortable with this diagnosis, - especially as it related to pregnancy. But this, of course, also did not mean that we ignored the topic when it was addressed in the medical literature. To the contrary, like anything autoimmunity-related, we followed the subject with great interest and, therefore, here are presenting a newly published study by mostly Israeli investigators. In a so-called Systematic Review and meta-analysis, they attempted to determine whether hydroxychloroquine use in APS represented effective treatment.³

By way of background, it is generally believed that women with APS have higher pregnancy risks and that roughly 20% of them - despite supposedly appropriate treatment – will still miscarry. Our rheumatology colleagues love the anti-inflammatory hydroxychloroquine (Plaquenil) as a treatment in pregnancy for several autoimmune conditions, including APS, arguing that it offers – especially in regard to miscarriage risk - outcome improvements. Through a Systematic Review and meta-analysis of the literature they now

claimed to have confirmed the positive outcome effects of the medication in pregnancy by increasing live birth rates significantly (i.e., reducing miscarriage risks) and lowering obstetrical risk in general.

To say it mildly, - we were and still are quite skeptical!

While acknowledging our well-known bias against Systematic Reviews with meta-analyses (in most cases basically only confirming the old IBM dictum. - “garbage in, garbage out”), the authors’ circular thinking pattern even further enhanced the dictum in this case and is deserving of further comments: The paper noted in the Introduction section that in APS, - LA, anti-cardiolipin (ACAs) and anti-beta-2-glycoprotein-1 antibodies , previous pregnancy loss, a history of thrombosis, and a history of systemic lupus erythematosus (SLE) are all associated with increased risk for adverse pregnancy outcomes.

In other words – as noted earlier – if you haven’t had pregnancy losses, you don’t qualify, - but if you have SLE you do qualify. But now arises the question, how does one differentiate between SLE and APS causing adverse outcomes? And why is everybody just looking only at ACAs and anti-beta-2-antibodies among anti-phospholipid antibodies (APAs)? The truth is unfortunately not very comforting: they in most laboratories are the only APAs tested.

In other words, studies on ACA basically never have a uniformly defined patient population. As readers of the CHR’s publications by now of course know, - this turns every meta-analysis into a crapshoot!

And since we are already talking about crapshoot, the meta-analysis included only seven retroactive (!) cohort studies and not even a single prospective cohort study (one these days, of course, can only dream about prospectively randomized studies in the fertility field). In short, this study would make a very good case study on how not to do Systematic Reviews with meta-analyses and, therefore, very clearly deserved critique when previously discussed in the _CHRVOIVCE.

This, of course, does not mean that hydroxychloroquine/Plaquenil may not have benefits in the treatment of certain autoimmune diseases; but let’s be honest about what we do and do not know! And to our rheumatology colleagues, - we still don’t like the concept of the APS!

REFERENCES

1. Lubbe et al., Lancet 1983;321(8338):P1361-1363

2. Gleicher N, Friberg J. JAMA 1985;253:3278-3281

3. Berman et al., Rheum Musculoscelet Dis Open 2025;11(3):e005825.

Both of these developments called for a discussion of this subject; but what gave it a degree of urgency was the fact that the Center for Policy and Leadership (CfPL) of the ASRM published a report on the subject which the CHR welcomed but which disappointed in its superficiality. The CHR, therefore, felt once more that, if the ASRM doesn’t do it, why not do it ourselves!

The CHR’s Editorial Staff

This commentary is not what we hoped to write when becoming aware of a new report published by the ASRM’s Center for Policy and Leadership (CfPL) regarding GC-pregnancies (also incorrectly called surrogacy-pregnancies). Considering how much the GC process has been in the news in recent months, we expected a report that would comment on the variety of – unfortunately – not very positive developments in this small, but quickly growing, corner of infertility practice. Instead, what ASRM offered was – as unfortunately only too often – a mostly only abbreviated rehash of previously addressed issues. Though to be fair - in a very short paragraph the report also at least noted the recent discovery that -for still unclear reasons – GC-pregnancies are much more high-risk than previously was assumed. We here, therefore, address some of the other important issues – left untouched - in the ASRM report by the new CfPL. And since this was the first occasion to see a product of the CfPL, we got interested to learn what the CfPL really was all about and – as always – of course have an opinion.

SOME BACKGROUND --The ASRM released on January 27, 2026, in a press release a report of the relatively new Center for Policy and Leadership (CfPL) regarding gestational carrier-pregnancies (GCPs).¹ Considering all the recent news regarding GCPs reported in the literature (most but not all previously discussed in the _CHRVOICE) and many reports on gestational carriers (GCs) in lay media – though seemingly overdue – we were pleased to see the announcement of the new report by the relatively new ASRM center. As further discussed below, - what followed was, however, largely disappointing and, so, we decided to dig a little deeper.

As a first step we, therefore, tried to figure out what the purpose of the CfLP really was and what we found was “somewhat unusual:” A first surprise was a really shockingly primitive animated short video trying to convey that the principal purpose of the CfPL apparently was “to lift a heavy cloud of toxic misinformation which in the U.S. prevents access to reproductive medical care” (to view this really quite unique video, please go to reference²). Founded in 2020, The CfLP on its ASRM website is also described as nonpartisan think tank focusing on reproductive medicine and health policy, practically spoken a Washington-based lobbying entity.

Though think tanks usually have staff, who the “thinkers” in this think tank are, we were unable to identify, except for Rebecca Watson O’Connor, J.D., (She/Her/Hers. – so much for bipartisanship) who is the Director of the ASRM CfPL and – yes - one Associate (see photos below; Source; ASRM). She describes herself as “passionate about advancing reproductive health and social justice with over 20 years of experience in public policy, advocacy, and nonprofit leadership.” And – we assume just to reemphasize her bipartisanship - her bio also notes that she was the recipient of the Social Justice Scholar Award at Vermont Law School, where she earned her J.D. after earning a B.A in Sociology and Anthropology.

As the former Director of Government Affairs and ASRM DEI Task Force Staff Liaison, this new ASRM center, therefore, looks more like a renaming of functions at the ASRM than anything else and, considering O’Connor’s very obvious political leanings, one must wonder about the bipartisanship of the CfPL (and for that matter of the whole ASRM). And in absence of other “thinkers” at this new think tank one wonders who the authors were who put the here discussed document together.

INTRODUCTION -- As the document noted, GC pregnancies in the U.S. make up only a very small percentage of overall IVF births, representing between 2017-2020 only 13.7 per 100,000 deliveries nationwide, - but in those years, nevertheless, increased by ca. 750% from 1,539 (in 2004) to 11,515 (I 2023, the last year of currently available U.S. data). Although it remains a specialized medical intervention, GC use may be the best option for family-building for patients with certain medical indications.

Laws regarding third-party reproduction, as the document notes, however, vary by state and are apt to evolve as policymakers consider GC-related legislative and regulatory proposals amidst intensifying political attention toward assisted reproduction. The document suggests that policy stakeholders should evaluate proposed restrictions on GC treatment cycles tactfully to avoid limiting access to medically indicated care, misaligning with clinical best practice, and exacerbating practical and legal uncertainty for intended parent(s), GCs, and medical providers.

THE REPORT -- Well explained in the document, - in a GC arrangement, an embryo created through in vitro fertilization (IVF), using the gametes of intended parent(s), donors, or both, is transferred to the uterus of the GC who agrees to carry the pregnancy and is not the genetic parent of the child. Consequently, calling this process a surrogacy – as is unfortunately widely the case - – is biologically incorrect since surrogacy involved contribution of the oocyte by the woman who also carries the pregnancy.

This concept of a GC and a GC pregnancy must, therefore, be differentiated from what is called traditional, or genetic surrogacy which, of course, does not involve IVF and instead relies on the carrier’s own oocytes for pregnancy, - usually through an insemination with semen of the future father. In an infertile couple, this kind of true surrogacy, therefore, does not offer the future mother genetic maternity and, therefore, has with the ascent of IVF fallen out of favor as an infertility treatment.

Why this subject has become relevant for presentation here had several reasons: (i) Recent data in the literature for the first time pointed out that GC pregnancies have unexpectedly high complication rates.^3,4

(ii) A newspaper report demonstrated that GCs can be left carrying the costs of medical complications.⁵ And the final issue that made GC pregnancies such a relevant issue of discussion are a large number of media reports pointing out ethical and, possibly, legal abusive use of GCPs by wealthy foreigners^{6 -9} – but more on all that below.

In the U.S., GC arrangements are governed under state-specific statutes, court opinions, and regulatory policies. Many states statutorily permit GC arrangements; others have no statutes or case law specifically permitting or prohibiting GC usage, and some prohibit GC arrangements, making surrogacy contracts void and unenforceable. To date, there exists no overarching federal statute governing the use of GCs. Only one state - New York – has a GC-specific law.

ASRM Practice Committee guidance emphasizes that GCs may be used when clearly documented medical indications make pregnancy impossible or poses a serious risk to intended parent or fetus.

The ASRM Practice Committee indeed identified several examples of such medical indications,¹⁰ including:

· Congenital or acquired absence of the uterus.

· Significant uterine anomalies, such as extensive intrauterine scarring associated with Asherman syndrome or a unicornuate uterus linked to recurrent pregnancy loss.

· Absolute psychological of medical contraindication to pregnancy.

· Serious psychological or medical condition that could be exacerbated by pregnancy or pose significant risk to the intended parent or fetus.

· Familial structures in which gestation by an intended parent is biologically infeasible, including single men and male same-sex couples.

These examples demonstrate that GC usage functions as essential family-building health care for a specific subset of patients with medical indications.

In addition to defining appropriate medical use, ASRM Practice and Ethics Committee opinions recommend procedural safeguards to protect GCs and the intended parent(s). These include independent legal counsel for the GC, comprehensive informed consent practices, and recognition of the carrier’s medical decision-making authority from embryo transfer through the postpartum period. ASRM and SART guidance also strongly recommends single-embryo transfer (SET) as the preferred approach in GC cycles, considering the obstetric risk associated with multiple gestation.

THE PROBLEMS WITH GCPs -- But in our opinion most importantly, this new document of the CfPL acknowledged for the first time the increased clinical risks for GCs by noting that the medical profile of GC pregnancies differs meaningfully from non‑GC pregnancies. A national inpatient sample analysis also – similarly to the earlier noted Canadian study- found higher adjusted risks among specifically U.S. GC pregnancies of multiple gestations, placental abruptions, low‑lying placentas, late‑preterm and peri viable deliveries, and postpartum hemorrhage, but lower cesarean rates in singleton deliveries compared to non‑GC pregnancies.⁴

As the CfPL report correctly concluded, these findings underscore that oversight by qualified fertility specialists on GC arrangements is critical. The data also highlights the importance of avoiding statutory mandates that contradict established, proven clinical practices.

But as already noted above, GCs do not only face increased complication risks while pregnant. As a very poignant article on December 25, 2025, in The Wall Street Journal noted, a GC (not a “surrogate,” as described in the article) by the name Nia Trent-Wilson ended up owing US$ 182,889.63 in medical bills for a bay that wasn’t even hers.⁵ The GC was a veteran with two prior GC pregnancies under her belt when agreeing to a typical GC contract that paid her US$ 70,000 plus fees should extra medical costs arise from any clinical complications in the pregnancy. And that is exactly what happened when complications led to a hysterectomy (removal of uterus) and bilateral salpingectomy (removal of both tubes) after a diagnosis of placenta accreta was made.

When the intended parents of the child defaulted on paying her medical costs, she found herself – as the article noted – “alone.” The parents not only failed to pay for her medical costs but also defaulted US$ 44,800 of her contracted fees for being a GC and allegedly called her a “baby killer” because only one out of two embryo transferred into her uterus implanted (male partner, lawyer, female partner film maker).

The agency through which both parties had met, also refused to assume the medical costs. Consequent, the GC filed a lawsuit against the agency, and a judge awarded her (only) US$ 20,000 after ruling that her contract that capped any liability of the agency at US$ 4,000 was unenforceable since the agency used the GC’s body for a “profit venturing business” and that Wilson’s risks under the contract were out of proportion to the risk of the agency. Wilson is allegedly considering a lawsuit against the couple as well but is concerned that “it may be hard to get them to pay.”

And then there were the billionaires all over the news who supposedly were creating large numbers of children through third-party egg donors and with help of gestational carriers under all kind of strange motivations. A Chinese videogame executive billionaire, Xu Bo, for example, admitted that he never even met some of his over 100 U.S. born children.^6, A judge in California denied his parentage petitions, leaving at least 12 children in legal limbo legal limbo based on a different article in The Wall Street Journal.⁷ The Gadget Review article described it as “not a custody dispute—but the unraveling of an industrial-scale baby commissioning operation that reads like dystopian fiction.”

His company claims that he has only a few over 100 U.S. born GC-children; an ex-girlfriend, however claims that the number is really around 300 if all countries are considered. Al Landes, the author of the Gadget Review article furthermore notes that this behavior seems to be becoming a “business model” among Chinese elites: Wang Huiwu apparently commissioned 10 daughters, using U.S. models as egg donors,- with future strategic marriages being the purpose of creating “unstoppable family dynasties” at ca. US$ 2,00,00 per child.

But it is not only Chinese billionaires who are populating the world, and especially the U.S. with their children. There is also the Russian tech-billionaire Pavel Durov, founder of encrypted messaging app Telegram, who claims to have fathered over 100 children over 15 years as a sperm donor because it is his civic duty to help overcoming the shortage in high quality sperm donors. Supposedly, all of his children will inherit part of his estimated fortune of approximately US$ 17 billion.

Several media outlet took the opportunity of reporting on these crazy cases to have a closer look on the fertility field in general or, as they usually called it, - the fertility industry. And what they came up with was – and who can really be surprised - not always very friendly. Sarah A. Topol, a contributing writer for the New York Times Magazine, even spent a full six months reporting in preparation for an article in The Times on the international surrogacy business and describing young Thai women who “answered an ad for surrogates, and found themselves in a nightmare.”⁹ She in the process interviewed over 100 people “in the industry” and traveled to four countries, - which included Georgia and Thailand.

CONCLUSIONS -- In short, the GC–business appears ripe for a thorough review and reorganization on several different levels, starting with the clinical side, where it seems high time to better understand why obstetrical outcomes in GCs are so much worse than everybody expected. Like egg donors, they indeed should have better outcome based on the fact that these are usually supposedly by agencies carefully selected and tested relatively young women who have already experienced uncomplicated pregnancies.

But the industry that has grown up around GCPs also requires significant reforms at several other levels: GC agencies, - which usually establish the contact between GC and patient must be better regulated. They must be held responsible for poor GC screening and off-the-record misrepresentations to patients.

Especially after the COVID-19 pandemic, which for unknown reasons appears to have increased the demand for GCs, the CHR has noticed a clear decline in the quality of by agencies offered GCs which can only be explained by more lax selection criteria. Patients desiring or needing GCs at the CHR, therefore, are advised not to commit to a GC before we had an opportunity to interview the candidate and do appropriate laboratory testing. Before COVID, the CHR’s recommended rejection rate of candidate was less than 10%. In most recent months, it has exceeded 50%.

At the same time, the increasing demand for GCs has not only significantly raised the costs of GCs (which, of course, includes fees to GCs and the agencies), - but many wealthy patients apparently are willing to pay premium fees for GCs with alleged special qualities and for jumping ahead on waiting lists, and agencies are, of course, more than ready to accept these additional fees.

And then there are, of course, the ethical, economic, and maybe even political abuses of the process already noted above which really almost go beyond comprehension. Which normal man – even if of almost unlimited wealth – would want to be the father of hundreds of children? Or who would want to produce children, - just to be able to later obtain U.S. citizenship? No wonder then that this kind of behavior can unlock crazy conspiracy theories. One example was a recent circulating FOX News story suggesting that China over the last 13 years has been on an industrial scale waging fully planned-out “civilization warfare” against the U.S. through exploitation of birthright citizenship. And they do it by Chinese billionaires using surrogacy (they meant GCs), while other members of their political elite use birth tourism to have their children become U.S. citizens. Who later – as grown-ups – can influence U.S. policies.¹¹

Though seeing the threat from China in this way seems like an exaggeration, - simply because numbers would have to be even much larger than they already are. Moreover , China can and has already achieved this kind of influence in much easier and more traditional ways – together with several other not necessarily friendly countries to the U.S. – by simply making big donations to our elite colleges and universities. Their education alone, then – as we can witness practically almost any day on our streets and in our media - turns the country’s young future leaders into political water carriers for Communist China (and other countries).

In short, they don’t necessarily need GCs for these purposes but – even in absence of this problem – there is more than enough to worry about how much the use of GCs – very much in analog to the use of third-party egg donors – has become a Wild West in need of much better regulation of especially candidate selection but also of financial security of GC and patient.

REFERENCES

1. ASRM. January 27, 2026. https://www.asrm.org/news-and-events/asrm-news/press-releasesbulletins/asrm-center-for-policy-and-leadership-releases-policy-report-on-gestational-carrier-pregnancies/

2. ASRM Center for Policy and Leadership. https://integration.asrm.org/advocacy-and-policy/center-for-policy-and-leadership/about-the-cpl/

3. Velez, et al., Ann Int Med 2024;177(11): https://doi.org/10.7326/M24-0417

4. Masjedi et al., J Assist Reprod Genet 2025;42(1):-211

5. Long K. The Wall Street Journal. December 29, 2025. PA1. https://www.wsj.com/us-news/surrogacy-unregulated-debts-profits-b9fdd987?gaa_at=eafs&gaa_n=AWEtsqe4ucMHcvO3SjfUEV2iw4_pjWEpHoEzISAxJdiX81XzwdO2DCZkqUj7eepmwps%3D&gaa_ts=69b5aac6&gaa_sig=a9t2_2PW4AW20cSrplPKuS7mwc1JRmbx2AUskvl-9VX2dzi7MQE63b _GQyulGoKEsr8Mgei5ffCNL8Y8QiomQg%3D%3D

6. Landes A. Gadget review. December 22, 2025. https://www.yahoo.com/news/articles/chinese-billionaire-admits-never-met-163000920.htmlguccounter=1&guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&guce_referrer_sig=AQAAADCiW9mz9fS3bjwtJEeaS1LE7CN1JZ_eQdTwqAr182xRquX6sWNYN_5BVwhq5k2sUjHuSIOYbw3StmdQJv6Fw2eP-AVTT47ZeIYXvuFt1gRKozCdFhVbpi3Tg1DsOPNhMBFmMkMkNR0Ndg7ELS1YtwrXUtEA0OpwFSNOCYM2-sz9

7. Long K. The Wall Street Journal December 13, 2025. https://www.wsj.com/us-news/chinese-billionaires-surrogacy-pregnancy-7fdfc0c3gaa_at=eafs&gaa_n=AWEtsqcUvSsSJSZq3SdwzFlTPyIjg7guV_zSLu5bQaoivCr6CIF2bKbm2QYQgbTyvxk%3D&gaa_ts=69496701&gaa_sig=C67uCdrwXr_zshHspXAur9LBmnbjeL7LOFCy0YReJzafQPedQo0mv_2peUFJym2TUlLesAsFZzYWxpJoQcfZg%3D%3

8. Biswas S. Times Now. December 25, 2025. https://www.timesnownews.com/business-economy/industry/global-sperm-crisis-telegram-founder-pavel-durov-offers-free-ivf-has-100-children-promises-17-billion-legacy-article-153345488

9. Topol SA. The New York Times Magazine. December 14, 2025. https://www.nytimes.com/2025/12/14/magazine/fertility-surrogates-trafficking.html

10. Practice Committees of ASRM and SART. Fertil Steril 2022;118(1):65-74

11. FOX News. Bacall M. January 21, 2026. https://noticias.foxnews.com/media/china-exploiting-birth-tourism-gain-long-term-political-influence-us-author-warns or video link https://www.foxnews.com/video/6388014110112

The CHR’s Editorial Staff

We are here presenting a potpourri of recently published articles in the medical literature which we feel have a message for patients as well as fertility service providers. They are short commentaries, - hopefully motivating some of our readers interested in a given subject to look up the respective reference. If you have comments to make regarding any of the here presented manuscripts, - we are very much looking forward to receiving them. Among others, the subjects are: Is a conception through IVF predictive of increased endometriosis and adenomyosis risks? Does the new “fashion” of re-biopsying embryos – and, yes, medicine also has its “fashions of the moment” - make sense if a first biopsy failed because of insufficient DNA or the result is questioned for other reasons? Is repeated implantation failure associated with dyslipidemia, and several other interesting mostly clinically-relevant issues. Let us know what you think!

These short commentaries originally appeared in the January issue of the _CHRVOICE but were updated and reedited.

Have Female Children Conceived by IVF Increased Risk of Endometriosis, Adenomyosis, and Related Symptoms?

According to a study by Norwegian investigators, the answer was YES!¹ But this is one of those studies which we usually describe as “self-fulfilling prophecy studies” because everybody, of course, knows that endometriosis is an especially familial condition.

The authors, of course, knew this and claimed to have adjusted the data based on the women’s endometriosis and adenomyosis histories. But we also, of course know how inaccurate patients’ endometriosis and adenomyosis medical histories are. In short, not a very credible and, therefore, valuable study!

REFERENCE

1. Magnus et al., Fertil Steril 2025;. 0015-0282, https://doi.org/10.1016/j.fertnstert.2025.10.002; ahead of print.

Why Would Anybody Re-biopsy an Embryo After PGT-A and Especially After a “Simple” Segmental Deletion?

And here is another paper that basically makes little sense, - this time by Chinese colleagues who concluded in their study that an embryo at PGT-A diagnosed with what the authors called “simple” segmental deletions (in contrast to not so “simple” deletions?) had “low predictive value.”¹

That is, of course, not a surprise because if a first embryo biopsy is considered “inaccurate,” why would anybody believe that a repeat biopsy would -suddenly – be more accurate? Moreover, the literature by now has clearly demonstrated that embryos with segmental “aneuploidies” (the “-“ here have a

purpose!) have similar pregnancy and live birth rates (45.5%) to “euploid” embryos (50.0%). These are even better rates than (low) mosaic embryos (34.3%)² which an increasing number of IVF clinics already have started transferring. One more thing that makes absolutely no sense in PGT-A practice.

REFERENCES

1. Wang et al., Reprod Biol Endocrnol 2025;23:156

2. Spinella et al., Hum Reprod 2025;40(Suppl 1).deaf097.266 (abstract)

Is Dyslipidemia a Risk Factor for Repeated Implantation failure?

This is at least the conclusion that another group of Chinese investigators recently reached (Chinese investigators are slowly dominating submissions to medical and science journals and more on that in the near future in these pages) in a paper in JCEM.¹ Epidemiological observational studies have indicated an association between type 1 diabetes (T1DM) and systemic sclerosis (SSc, also called scleroderma). The reasons have, however, remained unclear.

Here a Mendelian randomization (MR) investigated the bidirectional causal relationship between the two. through a bidirectional two-sample analysis and revealed such a causal link between genetic susceptibility to T1DM and an increased risk of SSc, though not vice versa. This example, therefore, emphasizes the need for validation across diverse populations. Further exploration of underlying mechanisms, moreover, could offer interesting results with relevance beyond just SSc.

REFERENCE

1. Huang et al., J Diabetol & Metab Syndrome2025;17:195

Have You Ever Thought About Transferring Zona-free Blastocysts in an IVF cycle?

If you did and believe colleagues from Charlotte, NC, it does not seem to work very well: pregnancy rates in frozen-thawed cycles were lower and chemical pregnancies and miscarriages were higher in comparison to transfers with intact zonas. But what does that mean?

On first impulse, one could conclude that it is the absence of a zona that is responsible for observed poorer outcomes. But hold on for a moment: Why would 12.6% of the authors’ frozen embryos have been zona-free. Maybe, they were just – for whatever reason - lousy embryos that hatched earl. Or, maybe, they hatched early because they were frozen too late. We basically don’t know why such a large percentage of embryos ended up zona-free; but we know that this is not normal.

This paper, therefore, does not suggest whether absence of a zona - in itself - represents a poor prognostic sign regarding embryo quality and/or chance of implantation. This question can only be answered by prospectively randomized study with embryos randomized to zona removal or not before embryo transfer. So, don’t try it yet (unless, of course, there is no choice)

REFERENCE

1. Ying et al. J Assist Reprod Genet 2025; 42:4301-4307

Is Systemic Sclerosis Associated with Risk of Premature Ovarian Insufficiency (POI) (also called Primary Ovarian Insufficiency)

Using data of 61,569,984 women, - claiming that there was no data in the literature on a possible association between systemic sclerosis (SSc) and occurrence of primary ovarian insufficiency (POI), Chinese investigators explored this question and concluded that SSc was, indeed, associated with a 1.6-times increased risk for POI. But for anybody familiar with the very strong association of autoimmunity with POI, this does not come as a surprise. If anything, we would have expected an even stronger association. Since, except in women with Addison’s disease, when autoimmune oophoritis demonstrates an obvious ovarian epitope for an autoimmune response against the ovary, no other ovarian epitope for an autoimmune response has been identified in decades of research, the important question that remains unanswered is, what associates autoimmunity so strongly with POI?

As we have noted in these pages repeatedly, the most likely explanation is that the autoimmune response causing POI is not directed against an ovarian epitope but against and extraovarian epitope, with the autoimmune response against that epitope demonstrating cross reactivity with a functional ovarian epitope. Our strong suspicion is that it may be an adrenal epitope because ovaries and adrenals share a common embryological primordium.

REFERENCE

1. Dai et al., Rheumatology 2025; keaf479 (abstract)

A new Marker for Recurrent Miscarriage Risk?

Australian investigators recently published an interesting paper in Human Reproduction which was based on observations in a mouse model. The study implicated abnormally low concentrations of nicotinamide adenine dinucleotide (NAD) in repeat miscarriages. More specifically, perturbations of NAD synthesis due to genetic and/or environmental factors causes NAD deficiency, implicated in so-called congenital NAD deficiency disorder (CNDD) which, in turn, is characterized by recurrent pregnancy loss and congenital anomalies.

In CNDD mouse models, fetal anomalies and embryo loss are prevented if NAD levels are raised by - during pregnancy - supplementing the mother’s diet with a NAD precursor, such as vitamin B3,.

The investigators, therefore, executed a prospective pilot cohort study of 88 non-pregnant women between 20 and 40 years of age, 37 with and 51 without a history of recurrent miscarriages, who served as controls. Recurrent miscarriage patients were defined as a history of two or more consecutive spontaneous miscarriages before 20 weeks’ gestation, with the last miscarriage between 6 weeks and 2 years prior to recruitment.

And women with a history of recurrent miscarriage indeed demonstrated higher blood, plasma, and urine concentrations of NAD Salvage Pathway excretion products. Moreover, urinary excretion of nicotinamide (NAM) was also elevated, compared to control women.

So, what is then the meaning of these findings: (i) Elevated excretion of Nam and its derivatives appears linked to differences in NAD synthesis pathways; and (ii) also in some ways appears linked to higher miscarriage risk.

But there also exist other adverse pregnancy outcomes that are associated with effects in NAD metabolism based on the secretion of elevate metabolites, raising the question whether elevation of these markers (the authors identified three specific metabolites) is, indeed, suggestive of miscarriage risk or of a more general poor pregnancy outcome risk. Despite these remaining uncertainties, nevertheless, a potentially important paper!

REFERENCE

1. Cuny et al., Hum Reprod 2025;40(12):2247-2259

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

We in today’s posting return to the subject of whether gender-affirming treatments are appropriate for children and young adults up to age 19 years and we do so because so much has happened surrounding this subject since our Medical Director, Norbert Gleicher, MD, addressed this issue in January here in The Reproductive Times and in the _CHRVOICE .

Our steady readers by now for sure know that for several reasons the CHR strongly feels that irreversible steps toward transition should not be taken in individuals under age 19. Solid data now unquestionably demonstrate that – under the age of 19 – a large percentage of youths who at younger ages considered transition changed their mind and lived relatively happy lives ever after (not different from those among us who never felt like morphing into the other sex). The CHR, therefore, strongly feels that young people under age 19 who consider transition should receive psychotherapy and other help as well as advice but not be exposed to treatments – whether medical or surgical – that become irreversible. Exceptions can, of course, be made with properly obtained consent from parents, - but only in IRB-approved study settings. The CHR, of course, fully supports transition treatments in properly consented adults.

This article, however, also now explores another issue close to the CHR’s heart as an institution and that is the increasingly frequent observed inability of the medical field in its various medical specialty areas to police itself in how clinical practice is pursued. And how medicine pursued gender transition in our U.S. youth until only relatively recently has been truly shameful and, therefore, has become an excellent example for how medicine in general has to learn to better police itself. The main reason is obvious: When and where self-policing fails, the only arising alternatives – government and/or court interventions – can have very negative consequences for patients as well as treating professionals.

When we addressed this issue over a month ago the last time, we received a ton of comments, - with a good number not being very friendly. Whether friendly or not, we love your responses. Don’t, therefore, be shy and let us know what you think!

The CHR’s Editorial Staff

This article in a much shorter format previously was published in the CHR’s Reproductive Times and _CHRVOICE. It was now retitled, updated, reedited, and expanded because of significant new developments.

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 childrens 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-119 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 patients 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 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, however, 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 inexplicitly involves politics. And political considerations, of course, only very seldom concur 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 examples 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 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 life0changing 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 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 addresses 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 euphoria. 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) and severely contaminated by ideological and political biases; but media organizations were at least still attempting to hide those. After Sulzberger’s comments especially the younger generation of journalists, however, suddenly perceived themselves freed from the shackles of objectivity and embraced by 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 not only garnered a substantial following on the left ideologically 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$2million 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

Gender issues have become a polarized and political subject in modern pediatrics and indeed, in broader society. These include the management of infants with disorders of sex development and transgender sports participation, but especially recently regarding the management of gender dysphoria. The European Academy of Paediatrics (EAP) acknowledges that there are deeply held beliefs about this issue based on conscience and social norms. Several European countries, led by the UK, have recently reviewed the management of gender dysphoria in children and young people. Recognizing the need for far more research into treatments such as pubertal suppression and cross-sex hormones in children and young people, we review the current ethical and legal dilemmas facing children with gender dysphoria, their families and the clinical teams caring for them. We suggest an approach that maintains the child’s right to an open future whilst acknowledging that the individual child is the crucial person affected by decisions made and must receive appropriate support in decision-making and care for any associated mental health or psychological issues. Noting that national approaches to this vary and are in flux, the EAP advocates a child-centered individual rights-based analytical approach.

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 lafter 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:

Earlier this week, NYU Langone announced their decision to capitulate to the Trump Administration’s discriminatory anti-trans agenda and discontinue their gender-affirming care program for youth. New York State Senator Kristen Gonzalez (D59), who represents the hospital, led a letter sent to Dean and CEO of NYU Langone Health, Robert L.Grossman, demanding that the hospital reverse this decision, and stand with the trans community. Assemblymember Jessica Gonzalez-Rojas and Councilmembers Tiffany Caban, Chi Osse, and Virginia Maloney circulated the letter in the Assembly and City Council, and 73 legislators across New York have signed on.

The letter states that in addition to the harm the discontinuation of the Youth Gender-Affirming Care Program will have on New York families, it may also be in violation of New York State human rights Laws–a claim supported by New York Attorney General Letitia James’s advocacy on this issue.

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 get, - 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 (see article below). 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 a 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 very 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 likely reaching 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 Elon 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 attorney 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. link

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. link

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/

Today’s topic is dedicated to Restorative Reproductive Medicine (RRM), one more term introduced into the English language for political and ideological reasons that makes absolutely no sense. But this time it is not the extreme political left that plays word games to make a purely political point palatable to the public, - but the once widely admired Heritage Foundation, - very obviously on the political right – and recently no longer the voice of the conservative political right, - but increasingly the voice of the extreme, fringe right, as the defense of Tucker Carlson by Heritage Foundation president, Kevin Roberts, so well demonstrated.

By publishing a White Paper regarding fertility treatment recommendations in place of IVF, the Heritage Foundation not only demonstrated complete ignorance about modern infertility care but ended up promoting outdated treatments pursued decades ago. Medicine and politics just don’t match, whether on the political left or right!

This article originally appeared in the January issue of the CHRVOICE but was updated and reedited.

Everybody at the American Society for Reproductive Medicine (ASRM) appears very concerned, - and so seem also many medical journals, including some not even primarily in the infertility field.1 Who, therefore, can be surprised about all the press releases and articles suddenly talking about Restorative Reproductive Medicine (RRM). ACOG, for example, describes RRM as follows:2

Recently, a non-medical approach called “restorative reproductive medicine” (RRM) has entered fertility. RRM can expose patients to needless, painful surgical interventions; limit their access to the full range of evidence-based fertility care interventions; and delay time to pregnancy, while potentially increasing overall costs.

RRM is built on two major concepts: the incorrect suggestion that endometriosis is the dominant cause of infertility, and the idea that other causes of infertility can be addressed by fertility awareness and lifestyle changes. The RRM movement is, at its roots, tied to the so-called personhood effort, which previously led to a temporary pause on IVF altogether in the state of Alabama, causing pain and confusion for people who were undergoing and planning to undergo IVF treatment in the state. The personhood effort seeks to elevate the legal status of fertilized eggs to that of people, leading to wide implications for access to medications, medical interventions, and management of high-risk pregnancy. Similarly, the RRM movement has been used to discourage patients from accessing evidence-based IVF in order to avoid the creation of fertilized eggs as part of the IVF process. It is important to understand that RRM is not a medical term. Focusing on endometriosis excision as the chief barrier to pregnancy unnecessarily exposes some patients to the potential risk of complications associated with the procedure and may not be necessary to address in order to achieve a pregnancy. Concentrating on fertility awareness and lifestyle changes can add unnecessarily to the timeline; be ineffective and redundant, as most patients have already tried these methods before seeking infertility treatment; and make patients less likely to have a baby by delaying the identification and treatment process until patients are much deeper into—or even past—their fertility window. Although endometriosis excision, fertility awareness, and lifestyle changes may have value for some patients and should be a part of conversations people have with their doctors, they must not be the sole approaches available to people undergoing fertility treatment.

The values, goals, and needs of the patient should determine the appropriate course of treatment for infertility.

The CHR, of course, fully agrees with ACOG on this matter but it appears to us that the emphasis of ACOG, ASRM, and many individuals who have been writing about RRM has overemphasized the socio-political aspects of the RRM movement and completely ignored the fact that physician -surgeons and, among them some very prominent names (see also later), have for many years been making the argument that endometriosis – if not guilty for all of female infertility - was at least guilt for a lot of female infertility. And they, therefore, have furthermore been arguing that practically every infertile woman should, therefore, have a diagnostic laparoscopy. And – if endometriosis is found – every woman should have excisional surgery. And that is, of course, bonkers!

In other words, it is not only the right of center Heritage Foundation – suddenly interested in female infertility – which publishes such surgery centered nonsense; the same arguments have been made for years (if not decades) by selected surgeons, for all practical purposes claiming special skills in rescuing infertile women (even with – and by some surgeons claimed, especially, in mild only stage I endometriosis cases.

It is, of course, true that the Heritage Foundation recently issued one of the organization’s so-called White Papers urging infertile couples to explore (especially surgical) non-IVF options.³ But then,- who can take anything coming from the Heritage Foundation these days too seriously. Even much of the foundation’s own staff no longer takes them seriously and has departed to a competing Conservative thinktank. Who, of course, can take seriously an organization that associates itself these days with Tucker Carlson – by some also lovingly called “Little Hitler,” who – not too surprisingly for those who have listened to his words carefully since he was booted by FOX (after he was booted by CNN) has now come out of the Nazi closet formally, - once the Qatari cash started streaming.

The 3 take aways of the Heritage Foundation’s White Paper by Ema Waters and Natalie Dodson were:

(i) The fertility industry is an under-regulated, multi-billion-dollar global enterprise that profits from the creation and selection of human life.

(ii) Traditional medical practices are typically owned and managed by physicians; the fertility sector is dominated by private equity firms and venture capital investors.

(iii) Modern reproductive healthcare is a narrowly conceived vision of women’s health. Restorative reproductive medicine (RRM) is a more comprehensive approach.

And Marguerite Duane, MD, a family practitioner by training, offers in the document an overview of RRM. Here are a few selected quotes from the document we found at times to be precinct and on other occasions to be quite “wacky:”

Restorative reproductive medicine (RRM) is an approach to health care designed to identify and treat root causes of reproductive or hormonal dysfunction to restore the reproductive system to the way it is designed to function. Although infertility is commonly labeled as a causal diagnosis of reproductive concerns, it is not the root cause but rather a symptom; RRM thus seeks to identify and treat the true underlying causes of infertility to restore health and fertility.

That “infertility” is considered “causal” for infertility is, of course, pure oxymoronish; but the rest of this paragraph could indeed have been written by a CHR staff member. The description of RRM protocols, however, speaks for itself: to characterize this description as anything but “wacky” would be a clear understatement. Looking up what the fancily-named protocols really denote, returns infertility practice over 50 years back to when the infertility “sub-specialty” (note the “ _ “) existed in a pre-science environment and, therefore, in the OB/GYN field was considered “the hocus-pocus subspecialty (among newly established subspecialties in obstetrics & gynecology).

Several comprehensive medical protocols have been developed, including Natural Procreative Technology (NaProTechnology), which is based on the Creighton Model. NaProTechnology aims to identify and treat underlying conditions through medical and surgical management to facilitate natural procreation. Dr. Phil Boyle, who was trained in NaProTechnology, has since developed NeoFertility, which can be used with the ChartNeo app or other FABMs to expand treatment options for infertility. NeoFertility is the newest RRM approach and seeks to address many more of the underlying issues that can contribute to infertility, including hormonal imbalances as well as autoimmune and inflammatory conditions. Fertility Education and Medical Management (FEMM) collaborates closely with the Reproductive Health Research Institute to address a wide range of women’s hormonal health issues using evidence-based medical protocols.

And then the White Paper presents a case report, - just like we used to practice medicine over 50 years ago!

The next section is authored by Patrick Yeung Jr., MD, one among a small number of talented – nowadays mostly laparoscopic and robotic surgeons who, as already noted in the introduction to this commentary, are making a very good living from doing a lot of endometriosis surgeries and, often, do not accept insurance coverage. Such a surgery not infrequently, therefore, exceeds the costs of a complete IVF cycle.

And just to reaffirm our earlier comment that colleagues specialized in endometriosis surgery have, indeed, significantly contributed to the rising popularization of the RRM concept, we here are quoting next from Dr. Yeung’s contribution to the White Paper, as he explains how detail-oriented and time consuming endometriosis surgery is:

But one-and-done surgery takes time. Excising endometriosis completely can take hours, and there’s only one billing code if you are in network. No medical professional can survive in network by excising endometriosis. We, like all centers of endometriosis, provide these services out of network or on a cash-pay basis in order to be able to do a good job. It takes time, expertise, and risk to go after all of the disease. And in some cases, there is a lot of it. For example, I have found endometriosis in the bowel, ovaries, fallopian tubes, and diaphragm, but it has also been found in the lungs, brain, and the back of the eye.

Nobody, of course, argues with the fact that some endometriosis patients will benefit from surgery, - but the patients who often do benefit from surgery are women with severe endometriosis symptoms during menses (dysmenorrhea) and/or pain during intercourse (dyspareunia). Beyond anecdotal data – often case reports - there are no data in the literature whatsoever to suggest that patients with advanced stages of endometriosis will benefit in time to pregnancy from surgery (in comparison to IVF). Very much to the contrary, recovery after such major surgery delays IVF treatment by at least 3-6 months. Moreover, resection of endometriosis often involves the ovaries and women after such surgery present with significantly decreased ovarian reserve, - not infrequently, indeed, in early menopause.

There is a reason why the infertility field has moved away from surgery and toward IVF: Going back 50 years ago, every “fertility specialist” (note “-“) had to be a good surgeon because surgery was the only treatment we had. In the early days of IVF – while pregnancy rates were still very low – surgery survived. But as pregnancy rates with IVF continued to improve, the choice became increasingly obvious. And IVF was the clear winner!

One, therefore, can summarize RRM in one very short sentence: It is an attempt by people who don’t know anything about treating infertility efficiently and cost effectively with treatments that were the routine 50 - or maybe even more - years ago. Would anybody do this in any other field of medicine?

And one more comment on the professional ignorance of the RRM proponents from the Heritage Foundation. Preceding above discussed recent White paper, Emma Waters a year earlier published another Heritage document, with title, “Why the IVF Industry Must Be Regulated.”⁴ This document even more than the recent one very clearly not only documented her substantial lack of knowledge but also demonstrates an astonishing lack of biological understanding. And we again quote:

There are profound issues with the way IVF is practiced in the U.S. (a statement we agree with) in many cases amounting to eugenics. Over 75% of fertility clinical offer preimplantation genetic testing for genetic issues: 73 percent offer testing for sex selection or hair, eye, and skin color.
Children born through IVF have a higher likelihood of cancer, autism, minor cleft palate, or congenital heart defects

She seems clueless about infertility as well as biology! Except for the first sentence, none of the subsequent facts is correct. She simply does not know what she is talking about. Just one more reason to feel sorry for the Heritage Foundation. It was an excellent intellectual source for logical Conservative thought for such a long time until the current leadership took over. What a waste!

REFERENCES

1. Liao et al., JAMA. 2025;.doi: 10.1001/jama.2025. https://jamanetwork.com/journals/jama/article-abstract/2842960

2. ACOG. Restorative Reproductive Medicine. June 2025. https://www.acog.org/advocacy/abortion-is-essential/trending-issues/issue-brief-restorative-reproductive-medicine

3. Waters E., Dodson N. Heritage Foundation. March 24, 2025. https://www.heritage.org/marriage-and-family/report/treating-infertility-the-new-frontier-reproductive-medicine

4. Waters E. Heritage Foundation, March 2024. https://www.heritage.org/life/report/why-the-ivf-industry-must-be-regulated

Today’s postings address two main subject, first reproductive immunology – where amazing things are happening - with special reference to autoimmune diseases. And, secondly, we are re-presenting two issues of considerable clinical as well as medico-ethical relevance, - what should the limits be for gamete donors (eggs or semen) in how many pregnancies they should be allowed to contribute to and – the second issue - the commercial offering by a small number of laboratories and IVF clinics the so-called polygenic risk scoring of embryos (also called PGT-P), which an ASRM opinion just rightly exposed as something that can only be described as a “snake oil offering.” As always, the CHR does not mince words and – this time – we are especially pleased to speak out because it is a pleasure to have the ASRM seemingly on our side.

The CHR’s Editorial Staff

Are We at the Very Exhilarating Moment of Moving from Treating to Curing Autoimmune Diseases?

The Editorial Staff of the CHR

One of today’s main topic is immunology, and especially autoimmunity. Eric Topol in one of his recent Substack postings, GroundTruth, noted that the treatment of autoimmune diseases is at an “exhilarating” turning point, switching away from nonspecific immune system suppression to elimination of disease causes. He in that posting then also reminded us that autoimmune diseases have doubled in prevalence after the COVID-19 pandemic, - implying that curing autoimmune diseases is more urgent than ever. Autoimmune diseases, of course, occupy an unusually close association with reproduction because both are dependent on a normally functioning immune system, able to induce tolerance. In pregnancy this means that the mother’s immune system must develop adequate tolerance toward the paternal allograft (the placental-fetal unit). And – if that does not happen, – we experience pregnancy losses and, possibly, also implantation failure. In autoimmunity a person’s inherent tolerance against “self” has broken down, resulting in that person’s immune system attacking a component of the patient’s own body. This is the reason why autoimmunity is such an important subject in reproductive medicine and why it is so difficult to understand that so many REI - colleagues still consider the maternal immune system to be largely irrelevant for fertility treatments. Here is, therefore, a short update on important new developments in autoimmunity with relevance for reproduction.

Here covered materials were already addressed in the January 2026 issue of the _CHRVOICE but have been updated and reedited.

New Revolutionary Treatments for Autoimmune Diseases

Two recent developments lead Topol to the believe that cures are just around the corner: The first, called “hard reset,” is a new development initially reported by German researcher just approximately four years ago, in which they “stole” a brilliant idea from our oncology colleagues, - the use of engineered T cells, known as chimeric antigen receptor (CAR) cells. This treatment is described as hard reset because it depletes B cells and - once after depletion of “bad” B cell repopulated – they no longer are the self-attacking disease-causing immune cells they were before.

In the initial German experiment that started the hard reset treatments of autoimmunity, a 20-year-old woman with treatment -resistant systemic lupus erythematosus (SLE) received one single infusion of CAR T cells that targeted CD-19 on lymphocytes, and this cured the patients (at least so-far). The patient’s response to the treatment over only six weeks is depicted in the Figure below.

The German investigators have since achieved similar success with systemic sclerosis and idiopathic inflammatory myositis. As other investigators have started to apply this treatment – for several years before that in wide use in oncology especially in so-called liquid cancers (lymphomas, leukemias) - CAR T cell treatments now also is becoming a mainstay in autoimmunity, for the first time making it apparently possible to cure autoimmune diseases.

By now being already able to use allogeneic cells from healthy donors (in early stages of these treatments only autologous cells were used which had to be manufactured at very high cost outside the body) or from a master cell banks, everything now can be accomplished inside the patient’s own the body. Because this in vivo treatment no longer requires lymphocyte depletion (via chemotherapy) the treatment has become much less toxic and can be given on an outpatient basis. Several companies are, indeed, using this new approach, already in in vivo clinical trials for several autoimmune diseases.

In contrast to the hard reset, the so-called “soft reset,” follows a different approach in treating autoimmune diseases, producing inverse vaccines to induce tolerance. This second approach appears to us of special interest for reproductive immunologists and REIs because insufficient induction of anti-paternal tolerance is, of course, a frequent cause of repeated pregnancy loss. And the CHR wouldn’t be surprised if poor tolerance induction also played a role is some cases of so-called “unexplained infertility.”

The goal of a so-called tolerogenic vaccines is exactly the opposite of a traditional, standard vaccines, which have the purpose of strengthening the immune response against a given virus. Tolerogenic vaccines, of course, have the goal of weakening the immune response against “self-epitopes.” Autoimmune diseases already in clinical trials with such tolerogenic vaccines - according to Topol - are celiac disease, multiple sclerosis, and type 1 diabetes as well as rheumatoid arthritis.

Celiac Disease, - the Great Imitator

It is no coincidence that autoimmunity is such an important and frequently featured subject by the CHR because there is likely no other group of diseases which has as close an association with reproduction as autoimmune diseases. The reason is obvious and has been noted in these pages over and over again: The core issue in autoimmunity and pregnancy is the same: It is called immune -tolerance, - in pregnancy tolerance by the mother’s immune system of the fetal-placental unit (in most cases a paternal semi-allograft but increasingly frequently also a full allograft if donor eggs are used of if a gestational carrier carries the pregnancy) and in autoimmunity it is self-tolerance. If tolerance fails in pregnancy, the pregnancy fails. If self-tolerance fails, autoimmunity is the result.

There is so much more to say about this commonality between autoimmunity and pregnancy, first recognized by Professor James S. Scott (1924-2006) in the UK already in the 1960s and 1970s, in his obituary in the Independent correctly described as “having done as much as any obstetrician of his generation to unravel the diseases caused by defects in the immunological relationship between mother and baby.”²

The CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, knew Scott quite well and considered him to be a prophetic mentor on this subject. He always tells the story that he witnessed Scott preaching to rheumatologists to join him in using the pregnancy model to learn to understand SLE (imagine how much Scott would have enjoyed the above discussed Topol Substack!)

A brief Medscape article by Kevin Fernando, MBChB, is meant to remind us that the autoimmune disease, celiac disease (CD), is frequently misdiagnosed and often outright missed as a diagnosis. This is highly relevant to any infertile patient population because CD is not rare. It affects approximately 1.4% of the population, and like most autoimmune diseases shows strong female preponderance (and these numbers very likely significant underestimate the real prevalence). Average age of (often late) diagnosis is 40s through 60s, therefore potentially defining most of the CHR’s patients in diagnostic ages.

CD also shows the additional characteristic of often occurring in combination with other autoimmune diseases. Its, likely, however, most tricky characteristic is its greatly variable symptomatology which makes the differential diagnosis with several other gastro-intestinal conditions difficult. Those can include irritable bowel syndrome (IBS) or even inflammatory bowel diseases. And – considering how frequently we diagnose CD for the first time in the CHR’s patient population - granted a much older population than at other IVF clinics,- it in quite a number of infertile women seems to be an often overlooked diagnosis.

REFERENCES

1. Topol E. Substak-GroundTruth; December 14, 2025. https://erictopol.substack.com/p/the-exhilirating-movement-from-treatment

2. Independent. October 2, 2006. Orbituary.

   https://www.the-independent.com/news/obituaries/professor-james-scott-418521.html Accesses December 25, 2025.

3. Fernando K. Medscape.. December 5, 2025. https://www.medscape.com/viewarticle/1003090

Important Ethical/Clinical Issues for Fertility Practice

The Editorial Staff of the CHR

We are here discussing two important clinical issues with significant ethical relevance, - how many offspring a gamete donor (whether egg or semen donor) should be allowed to have and - second – the concept of embryo biopsy for polygenic risk determination (PGT-P). Both subjects have remained controversial, and we feel that publicizing the CHR’s positions on these two issues is of importance

Here presented articles were already published in the January 2026 issue of the _CHRVOICE but have been updated and reedited.

To How Many Offspring Should a Gamete-donor – Whether Egg- or Sperm-donor – be allowed to contribute to?

That is a question that has “plagued” the infertility field since the inception of gamete donations. And guidelines from professional societies have not made the decisions easier because their cut-offs usually made little sense. Here are some examples: The ASRM suggests under current guidelines published in 2024:¹

Institutions, clinics, and sperm banks should maintain sufficient records to allow a limit to be set for the number of pregnancies for which a given donor is responsible. It is difficult to provide a precise number of times that a given donor can be used because one must take into consideration the population base from which the donor is selected and the geographic area that may be served by a given donor. It has been suggested that in a population of 800,000, limiting a single donor to no more than 25 births would avoid any significant increased risk of inadvertent consanguineous conception. This suggestion may require modification when the population represents an isolated subgroup or when the specimens are distributed over a wide geographic area.

OOCYTE DONORS -- should be limited to six (6) treatment cycles per donor representing a total of ca. 120 eggs and at most 25 births.

The basis for this recommendation is rooted in concern over the cumulative risk for the donor after undergoing more than six ovarian stimulations and oocyte retrieval procedures. When splitting donor embryo batches, the potential risk of siblings in close geographic proximity should be considered.

SEMEN DONATIIONS – Interestingly, there are no specific recommendations for semen donors.

ESHRE in a Position Paper in 2025 published very different guidelines which under the title, “International Limits on the Number of Offspring Per Gamete Donor,”^2. are still under membership review and only considered a draft. ESHRE in this document also recognized that gamete donation these days can often cross borders.

The debate in Europe was recently boosted by the discovery that a very active Europe-wide sperm donor through a European sperm bank (he fathered at least 197 children) turned out to be an unrecognized carrier for a cancer gene (Li - Fraumeni syndrome which carried a 90% lifetime risk of developing various cancers, including several childhood cancers) he passed on to offsprings conceived with his donor sperm,- several of whom developed cancers.³

In its pending policy paper ESHRE proposes an international limit on the number of offspring per donor. In contrast to ASRM guidelines, ESHR also proposes that limits be set in terms of families rather than individual children and proposes now a generous limit of 50 families but, ultimately, supports – after a run-in period – a limit of 15 families. ESHRE, moreover, proposes that gamete banks self-impose those limits immediately until governments and/or EU can legislate the process.

The European document also included a table that listed current maximal limits for gamete donors in many European countries. For oocyte donors the numbers were in countries that allow egg donation between 3 and 10, - and between 3 and 15 for sperm donors.

In short, - gamete third-party donation is in many ways still the Wild West and would – arguably – greatly benefit from a rational worldwide set of rules. That such rules are overdue is also demonstrated by a related phenomenon, - characterized by the sudden desire of some super-wealthy individuals to have huge numbers of children. Recent reports in the lay press, for example, reported on several Chinese billionaires with allegedly each claiming over 100 children, most delivered by surrogate or gestational carriers, while a recent report in The Wall Street Journal reported on Pavel Durov, the Russian founder of Telegram, who now resides in Dubai, and claims to have donated his semen to over 100 births. The girlfriend of one Chinese Billionaire, Xu Bo, alleged that he has worldwide over 300 children (a story we reported before) He claimed that he, one day, wanted his over 20 U.S. children to take over his business.

In comparison, Elon Musk, with his 14 children, has still lots of catch-up to do!

REFERENCES

1. Practice Committees of ASRM and SART. Fertil Steril 2024;122(5):799-813

2. ESHRE Draft document. https://www.eshre.eu/Europe/Position-statements/Stakeholder-review

3. Gallagher J, Truswll N. BBC. December 10, 2025. https://www.bbc.com/news/articles/ckgmy90z991o

We Welcome the Long Overdue Publication of an ASRM Ethics and Practice Committee Report on Polygenic Risk Screening

The CHR in late 2025 published in its two publications a “CHR Opinion” wondering what had happened to a many months earlier among members of ASRM circulating draft of an ASRM & SART policy statement regarding the practice of polygenic risk screening of embryos (PGT-P) in IVF cycles. With this document now finally published in December of 2025, - under only signature of the ASRM Ethics and Practice Committees (why SART dropped out was not announced), we found it important to reprint the ASRM’s formal summary opinion, as originally distributed by the ASRM in a press release.⁴ The full length document was, as always, published in Fertility & Sterility.⁵

PRESS RELEASE

December 8, 2025

Washington, DC—Fertility and Sterility, the flagship publication of the American Society for Reproductive Medicine (ASRM), has published a joint report from the Ethics and Practice Committees evaluating the use of preimplantation genetic testing for polygenic disorders, known as PGT-P. The report concludes that this emerging technology is not ready for clinical practice and should not be offered as a reproductive service at this time, given the predictive uncertainties of the results and the substantial ethical considerations that it raises.

PGT-P aims to estimate an embryo’s potential risk for developing certain multifactorial diseases such as hypertension, heart disease and diabetes, but current predictive models are limited by insufficient data, incomplete understanding of gene and environment interactions, and a lack of diverse genomic representation. These gaps mean that the scores produced may not translate into meaningful clinical guidance for patients or providers. The Committees also note that whether individuals will ultimately develop the conditions for which PGT-P is being offered can be significantly impacted by factors such as diet, lifestyle and future medical treatments, with polygenic risk scoring accounting for only a small percentage of clinical variation.

Key Findings:

· PGT-P is a nascent and unproven technology that should not be used clinically at this time.

· Current evidence does not support the predictive accuracy, safety, or clinical value of polygenic embryo screening.

· The technology risks misleading patients by overstating what polygenic risk scores can reliably determine.

· PGT-P raises significant ethical issues, including concerns about equity, autonomy, disease prioritization, and the potential for biased or incomplete risk assessments.

· Any use of PGT-P should occur only in research settings under Institutional Review Board oversight until scientific, clinical, ethical, and societal concerns are addressed.

·

Together, this analysis provides an ethics-based framework to guide clinicians, policymakers, patients and the public at large as they navigate the emergence of polygenic embryo screening. By outlining the current limitations and risks of PGT-P, the Ethics Committee and Practice Committee underscore the critical importance of rigorous research, transparent communication, and careful scientific review before this technology is considered for clinical use.

AND HOW THE CHR SEES IT -- The CHR fully agrees with the summary of the ASRM guideline as published. The ASRM is, indeed, to be congratulated on publishing this document which – we are convinced – faced strong opposition from the genetic testing industry which has started offering PGT-P already through several laboratories and IVF clinics. To publish this opinion was morally and ethically the correct decision.

It must be said loud and clear: It is bad enough that daily thousands of normal embryos are either not transferred and/or discarded for no good reason because of preimplantation genetic testing for aneuploidy (PGT-A), thereby adversely affecting cumulative pregnancy and live birth chances for thousands of infertile couples seeking out fertility treatments. It is simply incredible that the genetic testing industry (i.e., PGT laboratories and selected IVF clinics) now further enlarge the pool of unused embryos in IVF with still good pregnancy chances that are not used or disposed by offering to their patients PGT-P in addition to PGT-A. One can only hope that, for all the reasons so well summarized in the ASRM document here re-presented, these offerings will now, based on this ASRM publication, stop.

But ASRM opinions have not much mattered when it comes to PGT-A and we, therefore, are doubtful that this recent document will make much of a difference. The only opinion the genetic testing industry apparently does take seriously is that of plaintiff lawyers. Too bad!

REFERENCES

1. Practice Committees of ASRM and SART. Fertil Steril 2024;122(5):799-813

2. ESHRE Draft document. https://www.eshre.eu/Europe/Position-statements/Stakeholder-review

3. Gallagher J, Truswll N. BBC. December 10, 2025. https://www.bbc.com/news/articles/ckgmy90z991o

4. ASRM. Press relase. December 8, 2025. https://www.asrm.org/news-and-events/asrm-news/press-releasesbulletins/asrm-ethics-and-practice-committees-release-new-report-concluding-polygenic-embryo-screening-is-not-ready-for-clinical-use/

5. Ethics and Practice Committees of the ASRM. Fertil Steril 2025; 10.1016/j.fertnstert.2025.10.023; ahead of print.