Terhi T. Piltonen

Background: Induced pluripotent stem cells (iPSCs) from patients have been little used to model polyendocrine metabolic ovarian syndrome (PMOS, formerly polycystic ovary syndrome, PCOS), and differences between unrelated donors can masquerade as disease effects. Earlier comparisons of three or four donors per group reported hundreds to thousands of differentially expressed genes. We asked whether a disease signature is detectable in a larger, genotyped panel, balanced for BMI category and BMI-adjusted, of full-phenotype patients. Methods: We studied 14 clonal, transgene-free iPSC lines reprogrammed by CRISPR activation from endometrial stromal fibroblasts of seven women with PMOS meeting all three Rotterdam criteria, and seven controls frequency-matched for BMI category (30 kg/m²). Bulk RNA-seq (16,489 expressed genes) was related to diagnosis, hormones, metabolic traits, age, and X-inactive specific transcript (XIST) status using gene-wise models, exact enumeration of all 3,432 group splits, and permutation-calibrated gene-set tests. Donors were genotyped within a cohort of 140 women and scored with an imputation-based genome-wide PMOS polygenic risk score (PRS). PMOS risk-locus genes were examined against a 202-line iPSC proteome. Results: PMOS donors had higher anti-Müllerian hormone (AMH), testosterone and free androgen index than controls. No gene was differentially expressed between PMOS and control lines (false discovery rate < 0.1), and the number of nominally associated genes was no greater than for random 7-versus-7 splits of the lines (p = 0.75). This was unchanged with an alternative read quantification and with count-based models. With seven donors per group, the design could detect 1.8-fold differences per gene, compared with roughly 3-to 6-fold for the three-or four-donor designs used previously. Neither diagnosis nor any hormonal or metabolic trait explained more expression variance than chance, and neither PMOS GWAS-locus genes nor Hallmark pathways were enriched. Two control lines showed near-complete loss of XIST, potentially indicative of X-chromosome inactivation (XCI) erosion, and a third was borderline. Endocrine PMOS-locus genes (e.g., FSHR, AMH) were not expressed, whereas DNA-repair and growth genes were. Across 129 genotyped women, the PRS was higher in PMOS (odds ratio 1.81 per SD; AUC 0.65), but PMOS and control iPSC donors overlapped fully in polygenic risk. Conclusions: In this panel of 14 undifferentiated iPSC lines from women with the full PMOS phenotype, no robust PMOS-associated transcriptomic differences were detected. Expression variation was dominated by line-to-line differences, consistent with donor background as their main source, although with one clone per donor a contribution of clonal variation cannot be excluded. Reduced XIST expression in some control lines is potentially indicative of, but does not establish, X-chromosome inactivation erosion. Disease-associated differences in differentiated, hormone-responsive cells cannot be excluded, and differences reported in smaller panels may partly reflect inter-donor variability. Future studies should use adequately sized panels, control for XIST erosion, select donors by polygenic risk, and examine hormone-responsive derivatives.

Polycystic ovary syndrome (PCOS) has long been focused on the ovary and infertility aspects, rooted in the early observations by Stein and Leventhal (1935). The aggregated data, however, show that the syndrome has a wide comorbidity risk beyond fertility aspects involving several endocrine and metabolic derangements, yet without a true risk of ovarian cysts, benign or pathological, as expected with the old name. Moreover, with modern fertility care, women with the condition can reach cumulative childbirth rates comparable to those of unaffected women. The women may have spontaneous ovulations and pregnancies across the reproductive life course and, having high ovarian reserve, enter the menopause later. The endometrium and pregnancy complications have, however, been the blind spots in fertility care. Taking all this into account, in May 2026, a multi-step global consensus process culminating in a Lancet statement renamed the condition polyendocrine metabolic ovarian syndrome (PMOS), with transitional adoption already underway in current international guidance and consolidation into the next major international evidence-based guideline update scheduled for 2028. This opinion argues that the rename is not a cosmetic relabelling but a clinical mandate to widen fertility and pregnancy care, address fragmented care across primary, fertility, obstetric, and endocrine services, and acknowledge the endocrine, metabolic, psychological, and oncological burden. For Human Reproduction’s readership, the 2028 guideline update is the concrete deadline around which language, registry coding, trial protocols, education, and clinical practice can align.

Purpose: This population-based study aimed to characterize the distribution of inter-rectus distance (IRD) and its upper range in adult women using standardized multisite ultrasound measurements and a percentile-based interpretive framework. Methods: Data was driven from the Finnish Women’s Health Study (WENDY, 2020–2023), comprising women assigned female at birth with a mean age of 35 years (age range 33–37 years, SD 0,6). Women less than six months postpartum, exclusively breastfeeding, or with prior midline abdominal surgery or hernia repair involving a midline incision or abdominoplasty were excluded. Inter-recti distance was measured at six predefined locations along the linea alba in the supine, knee-flexed resting position using ultrasound. For the analysis, the maximal IRD of each examinee across all sites was used. Results: A total of 1,840 women with naturally occurring anatomy were examined. At the standard site 3 cm above the umbilicus, the mean IRD was 2.37 cm (SD 1.19 cm; range 0.35–9.86 cm). Nulliparous women had a lower mean IRD (1.52 cm, SD 0.70 cm; 0.35–4.37 cm, n = 539) than parous women (2.71 cm, SD 1.18 cm; 0.46–9.86 cm, n = 1,301). The cohort’s 80th percentile for IRD was 3.24 cm. Based on maximal IRD, 38.5% had IRD ≥ 3 cm and 5.4% exceeded 5 cm; the 95th percentile was 5.09 cm. Maximal IRD most often occurred at the level of the umbilicus (41.3%) or 3 cm above (44.1%) and rarely below the umbilicus. Maximal IRD correlated weakly with adiposity measures (body mass index (BMI) ρ = 0.227; waist ρ = 0.273; weight ρ = 0.199) and no correlation was observed with height. Regression analysis showed that each childbirth was associated with a 0.42 cm increase in maximal IRD, and BMI increased IRD by 0.061 cm per kg/m². Conclusion: IRD is a continuous anatomical characteristic exhibiting considerable normal variation among adult women. A maximal IRD of up to 5 cm may be regarded as being within the upper tail of the population reference distribution. Fixed cutoff values should be proportionate to clinical symptoms, in order to prevent unnecessary interventions. Altogether, our findings provide population-based reference data for interpreting IRD measurements.

Polyendocrine metabolic ovarian syndrome (PMOS), previously known as polycystic ovary syndrome, affects 10%–13% of women of reproductive age and remains underdiagnosed despite its substantial health burden. The introduction of the new PMOS nomenclature in 2026 reflects a fundamental shift in understanding the condition as a lifelong endocrine and metabolic disorder with prominent reproductive, psychological, dermatological, and cardiometabolic consequences. Once considered primarily a reproductive disorder, PMOS is now recognized as a multisystem condition. Insulin resistance and compensatory hyperinsulinemia are central pathophysiological mechanisms linking endocrine and metabolic features to reproductive dysfunction. In PMOS, insulin resistance affects 75% of lean and 95% of overweight women. Here we focus on the metabolic features. Recent advances in epidemiology include the first systematic review and meta‐analysis examining regional variations in PMOS prevalence. In parallel, contemporary population‐based studies of unselected women have confirmed that increased risks of metabolic complications observed in selected clinical cohorts also apply at the population level and have demonstrated increased risk of major adverse cardiovascular events (MACE). These studies report an almost 3‐fold increased risk of Type 2 diabetes (OR 2.9) and MACE (HR 1.2–2.5), with cardiovascular risk diverging from approximately 35 years of age. In this review, we summarize recent advances in epidemiology, pathophysiology, metabolic dysfunction, and cardiovascular risk of PMOS, together with their implications for diagnosis and clinical management. Recognizing PMOS as an early‐life marker of cardiometabolic disease highlights opportunities for earlier diagnosis, prevention, and individualized risk stratification, supporting integrated, patient‐centered care across the life course.

Reproduction is one of the most fundamental biological processes in the human body, yet the molecules governing it remain incompletely understood. Here, we have characterized the role of PKHD1L1 and its globally relatively common splice donor variant rs17368310 in female fertility. We demonstrate estrogen-responsive expression of PKHD1L1 in the human endometrial and Fallopian tube epithelium, identify the change in the rs17368310 mRNA sequence in endometrial tissue, and assess the possible effects of the variant on the PKHD1L1 protein through structural modeling. We reveal that women homozygous for rs17368310 have a persistently lower child count compared to other genotypes not only among all women but also among women who have undergone medical treatments for infertility in the Finnish population. We further show that rs17368310 associates with female infertility-related traits also in the Mexican population. These findings elucidate the effects of rs17368310 on fertility in millions of reproductive-age women across different populations.

STUDY QUESTION: Does the endometrium of oligo-ovulatory women with polyendocrine metabolic ovarian syndrome (PMOS) exhibit menstrual cycle phase-specific transcriptomic alterations compared to women without PMOS? SUMMARY ANSWER: Compared to healthy controls, women with PMOS exhibit endometrial transcriptomic dysregulations which are menstrual cycle phase-specific and, most notably, related to mitochondrial function. WHAT IS KNOWN ALREADY: Infertility and gestational dysfunction in women with PMOS are increasingly attributed to endometrial abnormalities, yet the underlying mechanisms behind PMOS-related endometrial dysfunction remain unclear. Previous studies have focused on anovulatory phenotypes, resulting in a poor understanding of cycle phase-specific defects in the endometria of women with PMOS. STUDY DESIGN, SIZE, DURATION: Endometrial biopsies were obtained from oligo-ovulatory women with PMOS and healthy controls at four distinct menstrual cycle phases (proliferative, early-, mid-, and late-secretory phases) and subjected to RNA sequencing. Parallel in vitro experiments were conducted using cultured endometrial stromal cells (ESCs) and epithelial organoids (EEOs) derived from an additional endometrial sample cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: RNA sequencing was performed on biopsies from 78 (oligo-)ovulatory women, age- and BMI-matched between PMOS (n = 39) and control (n = 39) groups. Phase-specific transcriptomic profiles and pathway enrichment analyses were performed. For functional assays, endometrial cells were isolated from four PMOS and four control donors per BMI group (lean: < 25 kg/m2; obese: ≥30 kg/m2). Mitochondrial function, including respiration, ATP and reactive oxygen species production, and membrane potential, was assessed in both cell types before and after hormonal exposure. MAIN RESULTS AND THE ROLE OF CHANCE: Endometrial transcriptomes clustered primarily by cycle phase; however, PMOS-specific dysregulation was observed related to extracellular matrix organization, estrogen receptor (ESR) signaling, ion transport, and mitochondrial respiratory function. Gene trajectory analyses revealed phase-specific alterations in progesterone-, insulin signaling-, and mitochondria-related gene expression during the early-secretory phase, and epithelial function during the mid-secretory phase. Functionally, decidualized ESCs from obese PMOS women displayed reduced mitochondrial respiration, whereas EEOs from lean PMOS patients exhibited increased mitochondrial activity. LARGE SCALE DATA: Sequencing data are available from the corresponding author upon request. LIMITATIONS, REASONS FOR CAUTION: Women with PMOS were oligo-ovulatory while controls exhibited regular cycles. The sample size for in vitro studies was modest, warranting validation in larger cohorts. Additionally, the use of bulk RNA sequencing may obscure cell-type-specific transcriptomic signatures, emphasizing the need for future single-cell approaches to dissect cellular heterogeneity in PMOS endometrium. WIDER IMPLICATIONS OF THE FINDINGS: This study uncovers dynamic, cycle phase-dependent molecular and bioenergetic alterations in the endometrium of oligo-ovulatory women with PMOS. Mitochondrial dysfunction, particularly during the implantation window, emerges as a key pathological feature. The observed BMI-dependent divergence in mitochondrial function suggests that personalized therapeutic strategies may be necessary to improve reproductive outcomes in women with PMOS. FUNDING: Funded by the Jusélius Foundation, Novo Nordisk Foundation, Research Council of Finland, and the Horizon 2020 Marie-Curie MATER Innovative Training Network (all to T.T.P.), with additional support from the University of Oulu Scholarship Foundation (L.L.), the Estonian Research Council (E.V.M. and I.R.), and the Estonian Research Council grant no. PRG1076, Swedish Research Council grant no. 2024-02530, Novo Nordisk Foundation grant no. NNF24OC0092384 and Horizon Europe grant NESTOR, grant no. 101120075 (A.S.). DISCLOSURES: The authors declare no competing interests.

Polyendocrine metabolic ovarian syndrome (PMOS) is a prevalent endocrine disorder with complex reproductive, metabolic, and psychological features. A total of fourteen induced pluripotent stem cell (iPSC) lines were generated from endometrial stromal fibroblasts using a CRISPRa-based reprogramming method, comprising seven iPSC lines obtained from women with PMOS (all three Rotterdam criteria) and seven from body mass index (BMI)-matched non-PMOS controls. This well-characterized resource provides a unique platform for investigating cell-intrinsic PMOS mechanisms, supporting targeted pathogenesis studies and translational advances.

Mammographic images are commonly used in cancer screening protocols, yet there is a lack of automated tools evaluating breast volume from the images, which could help preoperative planning of breast surgery or epidemiological research. The study aimed at creating and validating an automated workflow utilizing computer vision for quantifying breast volume from a large dataset of digital mammographic images. The study was conducted in two phases. First, an automated workflow for analyzing breast volume was developed using Python-based computer vision libraries. This was followed by the validation and analysis of the method by utilizing seventy-three mammographic images of women undergoing preoperative mammography. The performance of the automated volume calculation method was evaluated and validated with manually measured breast dimensions. In a retrospective register study, a total of seventy-three mammograms from 41 females ages 35–82 years (mean 60 years) were analyzed showing effective analysis process and excellent accuracy of the automated computer vision approach in estimating breast volume from mammographic data. The mean difference (bias) between manually measured and computer vision approach volumes was minimal (0.01 cm ³ ) resulting in an excellent correlation (R = 1.0, p < 0.001) between the techniques. The proposed automated method provides an accurate, fast, and cost-effective solution for obtaining breast volume measurements from large-scale mammography datasets, and it could be useful for preoperative planning and research on breast health.