NEWS ABOUT GYNECOLOGY AND GYNECOLOGICAL PRACTICE
Important considerations about the polycystic ovary syndrome (PCOS)
THE EVOLVING GENOMICS OF PCOS PHENOTYPES - Though there is disagreement about how many phenotypes exist within the condition generally called PCOS, investigators only relatively recently attempted to define phenotypes genomically as well. We previously noted in this context the work of the medical endocrinology group at New York’s Mount Sinai, which from such genomic studies concluded that PCOS basically represented two distinct entities (1). Their genomic findings, to a considerable degree, also mirrored what investigators from New York’s Center for Human Reproduction (CHR) concluded based on clinical observations (2).
Recently, based on the hypothesis that genetic risk loci could influence measurable PCOS phenotype traits, U.S. investigators elsewhere investigated 404 PCOS patients (diagnosed not by Rotterdam but by NIH criteria) and 408 normo-androgenic controls with regular menses and identified several associations: In a combined analysis of cases and controls, two variants in loci containing the genes PRSS23 and FSHB were associated with gonadotropin levels. Two variants in loci containing NEIL2/GATA4 and CYP3 were associated with androgen levels. Three variants in loci containing SHBG, ZBTB16, and CYP3 were associated with ovarian morphology. One variant in the locus containing FTO was associated with hip circumference and was influenced by body mass index.<sup>3</sup>
Unsurprisingly and correctly, the investigators concluded that these results demonstrated that genetic risk variants associated with PCOS may influence hormones, ovarian morphology, and risk for obesity, all classical findings in a majority of women currently considered to be PCOS patients.
But, sadly, the study also made the only too frequent patient selection error—unfortunately characterizing basically almost every recent PCOS study—by incorrectly assuming that every PCOS patient into advanced ages is hyperandrogenic and that, therefore, no normo-androgenic woman in reproductive years can be a PCOS patient (and, therefore, theoretically could qualify for a control patient group).
Most PCOS patients are, indeed, hyperandrogenic into older ages. A likely greatly undercounted group of PCOS patients—under Rotterdam criteria defined as phenotype D (in the literature also frequently called the “lean” or—erroneously—the non-hyperandrogenic phenotype)—in this study—like in almost all PCOS studies published in recent years—was, however, in this paper basically excluded from the PCOS study population (and possibly included among control patients) because these women, after being hyperandrogenic after menarche in their late teens (because of declining adrenal androgen production, possibly an autoimmune phenomenon), start dropping their abnormally high androgen levels. By ca. age 25, their androgens are usually in normal range. But ages 25 to 35 is the time when most PCOS cases are diagnosed—therefore, the very obvious reason why this phenotype erroneously under Rotterdam criteria is still widely considered to be non-hyperandrogenic. Because of continuously declining adrenal androgen production, these women then, after approximately age 35, become hypo-androgenic, which can lead to infertility and treatment resistance even with in vitro fertilization (IVF) (3).
By either purposefully excluding these PCOS patients or, alternatively, by unknowingly including them with hyperandrogenic PCOS women among controls, patient selection—either way—automatically has to be considered “contaminated.” That this study, nevertheless, was still able to demonstrate above-noted associations, therefore, suggests that the observed associations in this study very likely must be statistically quite pronounced and, therefore, urgently deserve further exploration.
ASSOCIATION BETWEEN BMI AND PCOS - Related to the preceding, a recent study by Chinese investigators in the JCEM demonstrated in a bidirectional 2-sample Mendelian randomization study a causal association between elevated BMI and the risk of PCOS (4). The study also demonstrated that the severity of PCOS may contribute to elevated BMI levels.
Though all of these findings linking phenotypical features of PCOS to specific genotypes do so far not contribute much to our clinical appreciation of PCOS, they help in establishing a new direction for research in PCOS (hopefully with proper patient selection for study and control groups).
References
1. Dapas M, Dunaif A. Endocr. Rev 2022;43(6):927-965
2. Gleicher et al., Biomedicines 2022;10(7):1505
3. TIDWELL ET AL., J Endocr Soc 2024;9(1):bvae219
4. Fang et al., J Clin Endocrinol Metab 2025
Some news about endometriosis
PREGNANCY OUTCOMES IN ENDOMETRIOSIS PATIENTS - The literature on how endometriosis patients fare in their pregnancies once they conceive is, indeed, surprisingly sparse. A paper by French investigators on the subject in Fertility and Sterility, therefore, attracted our attention (1).
Unsurprisingly, the endometriosis group reported infertility more often before studied pregnancies (34.7% vs. 5.0%), experienced more hospitalizations during the pregnancy (27.4% vs. 19.8%), and more planned cesarean sections (14.0% vs. 8.7%). They, moreover, more often were nulliparous (51.7% vs. 43.4%) and more often experienced preterm births before 37 weeks (11.1% vs. 7.7%) and more often before 33 weeks gestational age (3.1% vs. 2.2%). Adjusted relative risks for confounding factors were also higher in the endometriosis group for preterm delivery <37 weeks and <33 weeks. Adjusted risk ratios for secondary outcomes, such as preeclampsia, placenta previa, postpartum hemorrhage, and small-for-gestational-age status of <10th and <5th percentiles, were also higher in the endometriosis group. The adjusted risk ratios for stillbirth and small-for-gestational-age status of <3rd percentile, and after stratification for preterm birth at <37 and <33 weeks, however, did not differ significantly for the secondary outcomes. Only the risk of placenta previa was higher in the medically assisted reproduction than non–medically assisted reproduction subgroups.
In short, endometriosis is a truly nasty disease when it comes to reproduction. It not only often makes conception difficult, but even once you are pregnant, you still have a harder time delivering a healthy baby.
These are important findings because they are further evidence for endometriosis being a truly systemic disease. Also very interesting is the association with preterm labor and delivery, which is, of course, a typical characteristic of autoimmune diseases (2). And the CHR’s Norbert Gleicher, MD, already decades ago noted the close association of endometriosis with autoimmunity, indeed raising the question whether endometriosis should not in itself be viewed as an autoimmune disease (3).
TREATING ENDOMETRIOSIS AND ADENOMYOSIS PERIIMPLANTATION TO IVF WITH TNF-α -? - TNF-α (Tumor Necrosis Factor-alpha), produced by monocytes and macrophages during inflammation, is a so-called inflammatory cytokine, responsible for a range of signaling events in cells, leading to their destruction (necrosis) and absorption (apoptosis). It also plays important roles in resistance to infections and cancer.
Several studies suggested that increased secretion of tumor necrosis factor alpha (TNF-α) has a key role in pro-inflammatory responses in women with endometriosis/adenomyosis. Moreover, the cytokine is also considered to be embryotoxic and and may impair endometrial receptivity. Consequently, inhibitors of TNF-α, such as etanercept (Enbrel®) and adalimumab (Humira®), have been used in very preliminary studies in attempts to improve IVF outcomes in endometriosis/adenomyosis patients (both are obviously inflammatory diseases). Chinese investigators now published a study on the use of adalimumab in frozen embryo transfer which, at times, can offer more controlled results than fresh IVF cycles regarding implantation chances (4).
Unfortunately, the study for several reasons was of very limited quality: First, it was designed as a retrospective study of 141 women diagnosed with endometriosis and/or adenomyosis. Though similar in composition, these two conditions, nevertheless, reflect distinctively different clinical phenotypes, and bunching them together into one study group, therefore, does not make much sense. As a retrospective study, it, moreover, is, of course, exposed to all the possible biases retrospective studies always reflect, including differences in ovarian stimulation. Most importantly, however, 84 women were, and 57 patients were not treated with adalimumab; and there must have been good reasons why some did and others did not receive this treatment, even though demographics and patient characteristics between the two groups were “comparable.”
The authors reported that adalimumab significantly improved implantation rates and clinical pregnancy rates, but no difference in ongoing pregnancy rates and live birth rates was found. After adjustments for age, BMI, number of prior failed transfers, and other factors in multiple regression analysis, untreated patients had a significantly lower clinical pregnancy rate and very similar chance of ongoing pregnancy and live birth rates. In short, even though the authors in their conclusions tried to “invent” what they called “clinical relevance” of TNF-α treatment, there was really absolutely nothing there.
Because of the poor quality of the paper, it, however, would also be inappropriate to consider this study as evidence that TNF-α does not improve IVF outcomes in endometriosis and/or adenomyosis patients because, conceptionally, such treatment would make sense. But—without properly obtained evidence of effectiveness—using TNF-α inhibitors, apparently without informed consent from patients that such treatment in fertility practice must still be considered experimental, appears ethically very questionable.
It is, of course, also of concern that a paper of such poor quality and with such very obvious ethical concerns made it through peer review and the editorial process at one of the two existing international reproductive immunology journals.
References
1. Vendittelli et al., Fertil Steril 2025;123(1):137-146.
2. Gleicher N. Clin Rev Allergy Immunol 2010;39(3):194-206
3. Gleicher et al., Obstet Gynecol 1987;70(1):115-122
4. Liu et al., J Reprod Immunol 2025;167:104415
Ovarian cancer detection by ultrasound; are we finally there?
As an important recent paper in Nature Medicine demonstrated, A.I.-trained detection models significantly outperformed expert as well as non-expert ultrasound examiners on all evaluated metrics (1). Based on these findings, the authors (from 20 participating centers) concluded that transformer-based models exhibit strong generalization and above-human expert-level diagnostic accuracy, with the potential of alleviating the shortage of expert ultrasound examiners.
Though, as already noted in the introductory sentence, this is an important paper, it at the same time raises several important questions before radiology departments should run to purchase marketed A.I. programs for the detection of ovarian cancers. We, for example, know that even trained sonographers vary in the accuracy of their findings. In other words, we don’t know how good the expert and non-expert sonographers in 20 participating centers in different countries were; but we know that they must have included many very good and at least some pretty bad sonographers. The question, therefore, remains open: how does A.I. compare to very good and not-so-good technicians?
A similar circumstance existed in the fertility field with the increasing use of closed incubation systems in embryology, which have been claimed to be cost-effective by saving valuable embryologist time (with IVF clinics these days experiencing similar shortages of embryologists as radiologists and infertility clinics experience with sonographers). Therefore, the real question to be asked from A.I.-based ovarian cancer detection systems is not whether they can “replace” sonographers. They, of course, sooner or later will be able to do so at least in some frameworks; the question is just, at what detection level?
And that, indeed, is the real question this paper failed to address: At what time point is the system able to detect ovarian cancer? The diagnostic problem is not that ovarian cancers are not detected; they are not detected early enough to improve the prognosis of the patient. Whether A.I.-driven ultrasound can lead to earlier diagnosis is, therefore, the real question that must be answered as quickly as possible.
Reference
1. Christiansen et al., Na Med 2025;31:189-196
Important news about breast cancer in women
Is sensitivity to chemotherapy dependent on fluctuations in ovarian hormones? - According to a recent paper in Nature magazine, based on mouse as well as human data, this, indeed, appears to be the case (1). As a Commentary in the same issue noted, these data suggest the possibility that—at least breast cancer survival rates (the cancer the study investigated)—could be improved simply by timing treatment—or at least treatment onset—to a specific stage of the menstrual cycle (2). As the Commentary, however, also noted, this article offers only proof of concept in support of a hypothesis. Now, clinical trials need to determine whether the hypothesis really improves cancer survival.
And if we are already talking about the female breast, it is well known that aneuploid (chromosomally abnormal) epithelial cells are a common finding in breast cancer. Indeed, aneuploidy is a very common feature in most cancers. A recent study in Nature magazine, now, however, reported that even normal breast tissue harbors rare populations of aneuploid epithelial cells, and these increase with age (3).
The authors in the discussion of their paper also ask and answer the logical follow-up question, which is: if aneuploid cells are “normal” in normal breast tissue, does this also apply to other tissues/organs? And they also answer this question with a likely—yes. If this were to be confirmed, further follow-up questions then are even more obvious: What is their purpose, and could they represent cells at increased risk of becoming the original stem cells of freshly arising cancers? And how do these cells interface with the host’s immune cells? Could they, maybe, even have the opposite function of just sensitizing the host’s immune system enough to kill off freshly arising initial cancers?
What an excellent example for how science works! An unexpected, seemingly coincidental finding, raising so many new and fascinating questions to be pursued.
References
1. Bornes et al., Nature 2025;637:195-204
2. Ingman WV. Nature 2025;637:39-41
3. Lin, Y., Wang, J., Wang, K. et al. Normal breast tissues harbour rare populations of aneuploid epithelial cells. Nature 636, 663–670 (2024). https://doi.org/10.1038/s41586-024-08129-x
The new science of menopause
RETURNING TO HRT AND TRYING TO STOP OVARIAN AGING - In over one-inch large letters, this was recently the title of a Feature article in Nature magazine, which tried to make the very obvious point that menopause for too long has been ignored in research (1). In reviewing what is going on in this arena of medical practice, the article concentrated on two major developments: First, for several good reasons, the return to popularity of hormone replacement therapy, and second, on attempts to delay menopause through such drugs as rapamycin, a drug widely used in solid organ transplantation—but also in anti-aging medicine. The article in this context also again referred to the clinical trial Zev Williams, MD, the REI division head at Columbia University in NYC, is conducting on rapamycin use.
On a theoretical basis, rapamycin may, indeed, be able to stop—or at least slow down—ovarian aging; but it will take time to, first, even work out dosages and length of treatments to reach still-to-be-defined endpoints for such treatments. There, however, can be no doubt that ovarian aging and menopause have been for too long overlooked—not only in their medical relevance but also in their societal importance. The article, therefore, was timely.
MENOPAUSAL HORMONE THERAPY AND CARDIOVASCULAR DISEASE RISK - In a register-based emulation targeted trial using the Swedish national register, Swedish investigators looked at a very old and still very controversial issue: cardiovascular risk from postmenopausal hormone replacement therapy (HRT) (2). They once again noted an increased risk of ischemic heart disease and venous thromboembolism with the use of oral, continuously combined contemporary menopausal hormone therapy.
Tibolone (Livial®), a selective tissue estrogen action regulator, not FDA-approved in the U.S. because of side effects, was associated with an increased risk of arterial thrombotic events including ischemic heart disease, cerebral infarction, and myocardial infarction, but not venous events.
The authors interpreted their results as reminders of how different hormone combinations affect cardiovascular (and other) risks in different ways.
References
1. Peeples L. Nature 2025;637:782784
2. Johansson et al., BMJ 2024;387:e078784
The first successful ovarian cortex allotransplant
Sherman J. Silber, MD, is undoubtedly one of the most successful REI practitioners since the establishment of this medical subspecialty, but he—undoubtedly—is also its most unique one. Not only is he almost alone in reaching such recognition as a urologist in a field so clearly dominated by obstetrician/gynecologists, but he has significantly contributed to the treatment of infertility for both sexes.
On the male fertility side of the field, he initially became one of the most successful microsurgeons worldwide in reversing vasectomies, but he also contributed very significantly to progress on the female side of infertility. And he did this in many different ways, but especially by becoming a world leader in fertility preservation through ovarian tissue freezing and reimplantation—a procedure initially developed for young women on the verge of losing their ovarian function due to a need for toxic medications for ovaries, but now even used more widely for other indications. And then, among many other accomplishments, he was also the first to report a successful ovarian transplant between identical twins.
The occasion for giving him his long-deserved credit here is a paper he recently published as lead author in Fertility and Sterility, in which he (and co-authors) reported the first successful ovarian cortex transplant to a Turner syndrome patient (1). And, as always, he is to be congratulated on this new achievement at an age when most of his colleagues are already enjoying retirement. We, however, in this case, also have to politely disagree with him on his conclusion that ovarian cortex allotransplantation now will become a much more frequently performed fertility preservation method and not only in cases of Turner syndrome or in replacement of whole ovary transplants.
While, in replacement of whole ovary transplants, this may, indeed, be a technically simpler and, therefore, valuable approach, otherwise we do not see the utility. Indeed, we do not even see the utility of doing such a transplant in the reported Turner syndrome case. If the purpose was pregnancy, why not do a simple egg donation cycle, which does not require surgery and does not require chemotherapy and, at some point, a second surgery to remove the allogeneic graft?
This circumstance, to a smaller degree, mimics the concept of uterine transplantation now offered in several centers (though, of course, regarding surgery, a much smaller feat). When the first uterine transplant was reported by Swedish colleagues, we were in total awe of their technical accomplishment, especially since—over years—they ethically did it right by developing the project initially in animal models before going into the human experience.
But even then—and, frankly speaking, to this day—we have had difficulties with the risk-benefit considerations of a uterine transplant surgery. The consideration in medicine should, of course, be “do no harm.” Uterine transplants require multiple surgeries for the donor as well as the recipient of the uterus and require at least temporary immune suppression for the recipient extending through pregnancy if the patient is lucky enough to conceive. Patients often, indeed, undergo transplants without then even having the benefit of a pregnancy. Though clearly not as big a a surgery, the same considerations also apply to ovarian cortex transplants. They, too, require at least two surgeries (removal of the graft is usually required) and immunosuppression without a guarantee of pregnancy. If pregnancy was the only ultimate goal, why not simply use an egg donor?
But this, of course, is not meant to take anything away from the intellectual and technical accomplishment this case report represents! We just don’t want to see it repeated too often!
Reference
1. Silber et al., Fertil Steril 2025;123(1):156-163