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PubMed2026

Single-cell expression quantitative trait locus Mendelian randomization reveals immune cell-specific causal regulatory networks and actionable targets in polycystic ovary syndrome.

ObjectiveTo systematically investigate whether the pathogenesis of polycystic ovary syndrome (PCOS) is causally related to dysregulated gene expression in specific immune cell subsets, and to evaluate the potential of these causal genes as actionable drug targets.MethodsThis study employed a two-sample Mendelian randomization (MR) framework using publicly available genome-wide association study (GWAS) summary statistics. The participant data included 797 PCOS cases and 140,558 controls (no direct patient recruitment was involved). Instrumental variables were derived from high-resolution immune cell-specific single-cell expression quantitative trait locus (sc-eQTL) data (OneK1K project) across 14 immune cell types. Primary analyses utilized the inverse-variance weighted (IVW) method. Shared causal variants were validated using Bayesian colocalization. Phenome-wide association analysis (PheWAS), external transcriptomic dataset validation (GSE8157), and DrugBank database screening were conducted for pleiotropy assessment and drug repositioning.ResultsMR analysis revealed genome-wide significant causal associations for GLIPR1 in non-classical monocytes (Mono NC) and XBP1 in CD4+ effector memory T cells (CD4 ET) with PCOS risk. Higher GLIPR1 expression was associated with a decreased PCOS risk (OR = 0.669, P = 4.34×10-6), whereas higher XBP1 expression was associated with an increased risk (OR = 1.406, P = 9.53×10-8). Colocalization analysis confirmed that GLIPR1 shares a causal variant with PCOS (PP.H4 = 96.73%). PheWAS and external validation confirmed the safety profile and significant upregulation (P = 0.03) of GLIPR1. Drug repositioning identified SOT-107, a Phase III protein therapy drug, as a potential interacting agent for GLIPR1.ConclusionsThis sc-eQTL MR study reveals immune cell-specific causal regulatory networks in PCOS. GLIPR1 in non-classical monocytes represents a high-confidence protective target, while XBP1 provides suggestive evidence for immune-mediated pathogenesis. The candidate drug SOT-107 highlights theoretical repositioning opportunities, though rigorous preclinical validation remains required.

Female↗

PubMed2025

Association of CYP19 gene SNPs (rs7176005 and rs6493497) with polycystic ovary syndrome susceptibility in Northern Chinese women.

PURPOSE: The objective of this study was to elucidate the relationship between two single nucleotide polymorphisms (SNPs) rs7176005 and rs6493497 in CYP19 gene and the risk of polycystic ovary syndrome (PCOS) in Northern Chinese women. METHODS: In this case-control study, a total of 340 women with PCOS and 340 matched healthy controls were recruited. Polymerase chain reaction ligase detection reaction (PCR-LDR) method was used to investigate two SNPs (rs7176005 and rs6493497) in the 5'-flanking region of CYP19 gene exon 1. RESULTS: We observed a significant association of rs7176005 and rs6493497 with reduced risk of PCOS. Compared with CC genotype, a significant association of CT genotype (p = 0.019), TT genotype (p < 0.001) and combined CT + TT genotype (p < 0.001) with reduced risk of PCOS was observed. The result of linkage disequilibrium analysis showed that these two SNPs are in complete linkage disequilibrium (r2 = 1). For rs7176005 SNP, compared with CC genotype, CT, TT and CT + TT genotypes reduced the risk of PCOS. The age, BMI-adjusted OR were 0.650 (95% CI = 0.460-0.917), 0.158 (95% CI = 0.066-0.376) and 0.545(95% CI = 0.391-0.759), respectively. CONCLUSIONS: These findings highlight a significant association between CYP19 gene polymorphisms and PCOS susceptibility, implying potential protective effects of T and A alleles. Of course, the major limitation of this study is the sample size of the case-control study. Larger cohort studies are needed to confirm these findings and investigate the underlying causes.

Adult↗

PubMed2026

Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Humans↗

PubMed2026

Metabolic Stress Testing Reveals Persistent Lipid-Handling Dysfunction in Women With Polycystic Ovary Syndrome Despite Exercise Training.

AIM: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and metabolic dysfunction, yet baseline metabolomic studies show inconsistent findings. We investigated whether metabolic abnormalities in PCOS emerge under physiological stress and how these responses are modified by exercise training. MATERIALS AND METHODS: Twelve women with PCOS and 10 controls completed hyperinsulinaemic-euglycaemic clamps with randomised saline or lipid infusion, before and after 8 weeks of supervised exercise. Plasma metabolomics (163 metabolites) were measured at baseline, post-infusion and post-clamp. Linear mixed-effects models assessed Group × Timepoint × Intervention interactions. RESULTS: No baseline metabolite differences were observed between groups. A significant three-way interaction (p = 0.008) indicated condition-dependent trajectory divergence. Post hoc analysis revealed a specific divergence during post-exercise lipid challenge (p = 0.048). Women with PCOS showed reduced suppression of ether-linked phosphatidylcholines during insulin-stimulated lipid loading (PC ae C44:4, p = 0.031), despite exercise-induced improvements in fitness and normalisation of amino acid profiles. Exploratory metabolite ratios suggested impaired substrate coordination under stress. CONCLUSIONS: Metabolic defects in PCOS are stress-dependent and not detectable at rest. Exercise training improves resting metabolism but reveals persistent impairment in adaptive lipid handling during combined insulin and lipid challenges, suggesting impaired coordination of substrate supply during metabolic stress. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ISRCTN42448814.

Humans↗

PubMed2026

Prenatal Androgenization Modifies H3K9me3 Binding in the Promoter of the Androgen Receptor Gene in the Arcuate Nucleus of the Adult Female Mouse.

Animal models have shown that prenatal exposure to excess androgens is associated with the development of polycystic ovary syndrome (PCOS) features. We have identified that prenatally androgenized (PNA) mice modelling PCOS show suppressed androgen receptor mRNA (Ar) expression in the arcuate nucleus (ARC) across development. This could contribute to PCOS-related impaired gonadal steroid hormone feedback to GnRH neurons. However, the mechanism of Ar mRNA suppression following PNA is not determined. We performed a chromatin immunoprecipitation (ChIP) assay coupled with quantitative PCR (qPCR) to investigate histone and transcription factor binding within the Ar gene promoter or enhancer regions in the ARC of female mice at postnatal day (P)60 or gestational day (GD)18.5. In comparison to adult vehicle control (VEH) mice, our ChIP-qPCR revealed that H3K9me3, a repressive histone mark, was increased in adult PNA mice at the promoter regions of the Ar gene. H3K27ac, an active histone mark, and SP1, a transcription factor that acts as a positive regulator of gene expression, were unchanged in the same regions. Increased H3K9me3 seen at the promoter region in adult PNA mice, however, was not observed in the GD18.5 mice ARC following PNA. These results suggest that the deposition of H3K9me3 on the Ar promoter is unlikely to be established by PNA at the time of excess androgen exposure, and instead is likely to be established later in postnatal development or in adulthood. These data provide greater understanding of the developmental mechanisms and timeline underpinning PNA-mediated female dysfunction and PCOS-like reproductive physiology.

Animals↗

PubMed1978

Pituitary response to bolus and continuous intravenous infusion of luteinizing hormone-releasing factor in normal women and women with polycystic ovarian syndrome.

Plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were measured in response to luteinizing hormone-releasing factor (LRF), given as a 100 microgram intravenous bolus and/or as a 4 hour infusion of 0.2 microgram per minute to 27 normal menstruating women and 15 women with the polycystic ovarian syndrome (PCOS). In PCOS, LH response to bolus LRF was significantly greater than those of normal women at days 1 to 4 and 8 to 10 of the cycle, whereas FSH responses were similar in all women studied. Continuous LRF infusion resulted in a biphasic LH release pattern. In normal women, the early phase was low until days 12 to 14 of the normal cycle, whereas the second phase rose progressively from the early follicular to the periovulatory period. In PCOS, the early phase was relatively large and qualitatively resembled the normal periovulatory pattern. The increased pituitary LH response to LRF in PCOS is associated with a relatively large early releasable LH pool and a low FSH response.

Adolescent↗

PubMed2026

Gut Dysbiosis in Selected Gynecological Diseases Associated with Female Infertility: A Scoping Review.

Background/Objectives: Female infertility represents a significant public health issue. Available evidence supports the hypothesis that the gut microbiota may play an essential role in women's reproductive health and may serve as a diagnostic or prognostic biomarker in specific gynecological disorders. A substantial part of current research concerns disturbed communication between the hypothalamic-pituitary-ovarian axis and the gut microbiota, providing the basis for analyzing this phenomenon as the gut-ovary axis or the gut-vagina-ovary axis. The primary aim of this scoping review was to map the available evidence on the relationship between gut microbiota composition and female infertility, with particular emphasis on polycystic ovary syndrome (PCOS, currently polyendocrine metabolic ovarian syndrome, PMOS) endometriosis, and uterine fibroids. Methods: The review was conducted in accordance with the PRISMA Extension for Scoping Reviews (PRISMA-ScR). PubMed, Scopus, and Google Scholar were searched using terms related to gut microbiota, female infertility, PCOS, endometriosis, and uterine leiomyomas. Peer-reviewed publications in English published between 2015 and 2025 were considered. The included studies were descriptively synthesized to identify recurring microbiota patterns and research gaps. Results: The reviewed evidence indicates that gut dysbiosis may be associated with selected gynecological disorders affecting fertility, including PCOS, endometriosis, and uterine fibroids. The gut microbiome may have potential value as a biomarker supporting diagnosis, treatment selection, and prognosis. Conclusions: The gut microbiome represents a promising but still insufficiently validated area in the management of gynecological diseases associated with female infertility. Further high-quality clinical studies are needed to verify the effectiveness of microbiome-based therapies and to develop evidence-based guidelines for managing infertility associated with gut dysbiosis.

dysbiosis↗

PubMed2026

Personalized approach to infertility treatment in a patient with polyendocrine metabolic ovarian syndrome and chronic pancreatitis.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in fertile women, with an estimated prevalence of 10-15%. It is a heterogeneous disease characterized by a complex pathogenesis. Genetic predisposition, neuroendocrine regulation disorders, and environmental influences play a key role. Dysregulation of the hypothalamic-pituitary-ovarian axis occurs with subsequent chronic anovulation, hyperandrogenemia, and metabolic abnormalities. Phenotypic variability reflects different pathophysiological mechanisms - based on genomic association studies, three subtypes of PCOS can be distinguished: reproductive, metabolic, and indeterminate. PCOS is one of the main causes of female infertility and a risk factor for the development of cardiometabolic diseases. Objective: The aim of the article is to summarize current recommendations of the European Society of Human Reproduction and Embryology (ESHRE 2023) regarding the diagnosis and treatment of polyendocrine metabolic ovarian syndrome (PMOS) in patients with fertility disorders and to demonstrate their practical application through a selected clinical case.

Humans↗

PubMed2025

CRISPR as a Tool to Uncover Gene Function in Polycystic Ovary Syndrome: A Literature Review of Experimental Models Targeting Ovarian and Metabolic Genes.

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by reproductive abnormalities such as hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology, and is frequently accompanied by metabolic disturbances such as insulin resistance, obesity and dyslipidemia. Genome-wide association studies (GWASs) have identified several susceptibility loci, yet little is known about their functional implications. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9) has emerged as a powerful gene editing tool in bridging this gap by allowing researchers to directly target candidate genes in ovarian and metabolic pathways. For instance, experimental models have highlighted the role of CYP17A1 and DENND1A.V2 in androgen excess, anti-Müllerian hormone (AMH) in follicular arrest, and insulin receptor substrate 1 (IRS1) and PPARγ in insulin signaling and adipogenesis. To highlight the multifactorial nature of PCOS, animal models, including zebrafish and rodents, have been used to reveal interactions between reproductive and metabolic phenotypes. Nevertheless, most studies remain restricted to single-gene models, and dual-gene models or combined gene editing and hormonal induction models remain underexplored. Future research integrating precision editing, multi-omic platforms, and patient-derived organoids may provide more accurate disease models and novel therapeutic strategies.

Polycystic Ovary Syndrome↗

PubMed2026

A novel 2D and 3D model for primary adrenocortical carcinoma of advanced and metastasized stage co-secreting cortisol, aldosterone, testosterone, 18-oxocortisol and 18-hydroxycortisol.

Adrenocortical carcinoma (ACC) is a highly aggressive malignancy with poor survival rates and few treatment options. Preclinical models are indispensable to further strengthen our understanding of disease progression and development of novel therapeutic treatments. Here, we report the establishment of a new cell line named ZUC-1 originating from the resection of an advanced primary ACC and its characterization at the genomic, cellular and molecular level. ZUC-1 cells were successfully propagated as monolayer cultures and three-dimensional spheroids. LC-MS/MS analysis revealed for ZUC-1 cells co-secretion of cortisol, aldosterone and testosterone, and the model represented in direct comparison with other current ACC pre-clinical models furthermore significantly elevated expression of SF-1, CYP11B1 and CYP11B2 genes. Whole genome sequencing identified various mutations in genes linked to DNA repair/stress response, stemness, and also steroidogenesis. Interestingly, ZUC-1 represents genotypic and phenotypic variations that might be of interest beyond ACC, including congenital adrenal hyperplasia (CAH) and polycystic ovary syndrome (PCOS). Moreover, 18-oxocortisol and 18-hydroxycortisol release was detected in ZUC-1, conditions which are often linked to hyperaldosteronism, but forskolin, potassium and, at higher concentration, angiotensin II modulability of CYP11B2 for this model is retained. ZUC-1 spheroids exhibited furthermore an intra-spheroidal heterogeneous mix of canonical and non-canonical Wnt pathway activation. We conclude that due to its origin and unique geno- and phenotypes, ZUC-1 represents an intriguing model to further gain a basic understanding of adrenal function, the pathogenesis of ACC, but it might be also of interest in the context of CAH and PCOS.

Humans↗

PubMed2026

Autophagy activation in granulosa cells as a mechanism of astaxanthin action: evidence from a pilot randomised trial in PMOS-associated infertility.

Astaxanthin (AST) has been reported to influence oxidative stress, endoplasmic reticulum stress, and apoptosis in women with polyendocrine metabolic ovarian syndrome (PMOS), formerly referred to as polycystic ovary syndrome (PCOS), but its effects on granulosa-cell (GC) autophagy remain unclear. Given the central role of autophagy in follicular development, this triple-blind, placebo-controlled pilot randomised trial evaluated whether AST modulates autophagy-related signalling in GCs and how these molecular effects relate to ovarian response. Fifty women with PMOS-related anovulatory infertility were enrolled between November 2023 and September 2024 and received AST (12 mg/day) or placebo for six weeks prior to oocyte retrieval; forty-four completed the study (21 AST, 23 placebo). Primary exploratory endpoints were molecular markers of adenosine monophosphate-activated protein kinase (AMPK)-autophagy signalling, and primary clinical outcomes included ovarian response indicators and cleavage stage embryo quality. AST supplementation increased autophagy-related gene 7 (ATG7) expression, enhanced autophagy flux, reduced apoptosis, and showed a trend toward increased AMPK activation. Before adjustment, AST improved oocyte maturity rate (OMR) and increased mature (metaphase II; MII) oocyte yield. After adjusting for age, body mass index, and anti-mullerian hormone level, total oocyte and MII oocyte yields remained significantly higher with AST, while OMR became non-significant. Among embryology outcomes, both the top-ranking embryo rate and the number of embryos suitable for cryopreservation were significantly higher with AST after adjustment. Pregnancy outcomes were numerically higher but not statistically significant. This pilot trial suggests that AST activates autophagy- and apoptosis-related pathways in GCs and may enhance oocyte competence and embryo quality in PMOS. Larger studies are needed to confirm these mechanistic and clinical effects.

Female↗

PubMed2026

Multimodal Therapy With Metformin, Inositol and Dietary Restriction Improves Insulin Resistance and Endocrine Outcomes in Women With Polyendocrine Metabolic Ovarian Syndrome: A Randomized Controlled Trial.

INTRODUCTION: Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is a common endocrine-metabolic disorder characterized by insulin resistance, hyperandrogenism and ovulatory dysfunction. Metformin, inositol supplementation and lifestyle modification are widely used treatments, but direct comparative evidence remains limited. Multimodal therapy combining metformin, inositol and dietary restriction produces greater metabolic and reproductive improvement than single-modality interventions. METHODS: We conducted a 12-week randomized controlled trial in 192 women aged 18-35 years diagnosed with PMOS according to Rotterdam criteria. Participants were allocated to metformin (1500-2000 mg/day), inositol (myo-inositol 2 g plus d-chiro-inositol 50 mg twice daily), calorie-restricted diet (1200-1500 kcal/day), or combination therapy. Primary outcomes included changes in body mass index (BMI) and insulin resistance assessed by HOMA-IR. Secondary outcomes included testosterone, LH/FSH ratio and menstrual regularity. Analysis was performed using analysis of covariance (ANCOVA), with post-intervention values as dependent variables and corresponding baseline values as covariates. Categorical outcomes were compared using the Chi-square test. RESULTS: All interventions improved metabolic and endocrine parameters. Combination therapy resulted in the greatest reduction in HOMA-IR (- 2.64, 95% CI - 2.82 to -2.46, p < 0.001) and BMI (- 2.8 kg/m2, 95% CI - 3.05 to -2.55, p < 0.001). Menstrual cyclicity improved across all groups, with the highest proportion of participants reporting cycle regularisation in the combination therapy group (85.4%), compared with dietary restriction (72.9%), inositol (64.6%), and metformin (39.6%) (p < 0.001). Given the short follow-up duration, these findings reflect early improvements rather than sustained normalisation. CONCLUSION: Multimodal therapy was associated with superior metabolic and reproductive outcomes compared with single-modality interventions in women with PMOS. CLINICAL TRIAL REGISTRATION: ClinicalTrials. gov (NCT07380841).

Humans↗

PubMed2026

Systems genetics approaches model the heritable architecture of polyendocrine metabolic ovarian syndrome.

Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is the most common endocrine disorder in women and is closely associated with complex diseases such as cardiovascular disease and type 2 diabetes. However, the mechanistic links between PMOS and its comorbidities remain poorly understood. Here, we present an integrative systems genetics platform that leverages genetic diversity in both mice and humans to dissect the drivers of PMOS and its associated complications. This framework uncovered conserved genetic and environmental factors underlying PMOS, identified susceptible cell types and organs, and elucidated mechanisms linking PMOS to subsequent pathologies. For instance, we showed that increased ovarian area contributes to both PMOS susceptibility and ovarian cancer progression, while specific ovary-heart signaling circuits modulate cardiac function with aging. We further identified ovarian SF3B1-mediated alternative splicing as a key mechanistic link between PMOS and metabolic traits. Pharmacologic inhibition of SF3B1 in mice reduced circulating testosterone, insulin, and glucose levels as well as fat mass expansion. Transcriptomics analysis of ovaries from mice and experiments using human cell lines localized these effects to exon skipping events in granulosa cells. Together, this study offers a mechanistic framework for modeling the diversity of PMOS pathologies and uncovers SF3B1-mediated splicing as a link between ovary function and systemic metabolism.

Female↗