Aug 2026· Journal of Clinical Investigation· 0 citations
Medicine
TL;DR
It is shown that increased ovarian area contributes to both PMOS susceptibility and ovarian cancer progression, while specific ovary-heart signaling circuits modulate cardiac function with aging, and SF3B1-mediated splicing is uncovered as a link between ovary function and systemic metabolism.
Abstract
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 uncovers conserved genetic and environmental factors underlying PMOS, identifies susceptible cell types and organs, and elucidates mechanisms linking PMOS to subsequent pathologies. For instance, we show 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 identify 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.
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.
M. Forslund, J. Melin, A. Joham et al.· Journal of Internal Medicine· 0 citations
Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder characterized by significant reproductive and metabolic complications. Insulin resistance (IR) plays a central role in the pathophysiology of PCOS and contributes to several associated metabolic abnormalities. This review highlights the key mechanisms underlying PCOS, including IR, hyperandrogenism, cardiovascular disease, gut microbiota dysbiosis, and the increased risk of type 2 diabetes mellitus (T2DM), along with current and emerging therapeutic strategies for improving disease outcomes. Accumulating evidence suggests that genetic predisposition contributes to PCOS susceptibility. Polymorphisms in genes such as the androgen receptor (AR), cytochrome P450 17A1 (CYP17), and follicle-stimulating hormone receptor (FSHR) have been associated with altered steroidogenesis and ovarian dysfunction, thereby influencing disease severity. In addition to genetic factors, environmental influences, including exposure to endocrine-disrupting chemicals (EDCs) and air pollution, may exacerbate metabolic disturbances and increase the risk of developing PCOS. Conventional therapeutic approaches focus on improving insulin sensitivity and correcting hormonal imbalances. These include pharmacological treatments such as metformin, oral contraceptives, and lifestyle modifications involving diet and physical activity. Recently, novel therapeutic strategies have emerged, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), microRNA-based therapies, and interleukin-22 (IL-22)-mediated interventions, which show potential in targeting IR and metabolic dysfunction in PCOS. Furthermore, modulation of gut microbiota through probiotics, prebiotics, and fecal microbiota transplantation (FMT) represents an emerging strategy for restoring metabolic homeostasis. Overall, a comprehensive and personalized therapeutic approach integrating pharmacological, lifestyle, and microbiome-targeted interventions may significantly improve PCOS management and reduce long-term metabolic and reproductive complications.
J. Singla, Shubhi Yadav, J. Gayen· Journal of Reproductive Immu...· 0 citations
Polycystic ovary syndrome (PCOS) is the most prevalent endocrine-metabolic disorder in women of reproductive age, and is characterized by hyperandrogenism, anovulation, and polycystic ovarian morphology. Emerging molecular evidence has identified dysregulated ovarian steroidogenesis as a major contributing mechanism linking reproductive and metabolic phenotypes in PCOS, acting in concert with neuroendocrine and metabolic dysfunction. This review synthesizes current knowledge on enzymatic and regulatory perturbations driving androgen excess and estrogen deficiency in PCOS, emphasizing their mechanistic, diagnostic, and therapeutic implications. Dysregulated steroidogenic enzymes and associated signaling pathways contribute to androgen excess, impaired folliculogenesis, and metabolic dysfunction in PCOS. Importantly, these steroidogenic alterations are not uniform across all patients with PCOS but vary according to hyperandrogenic, anovulatory, ovulatory, lean, obese, reproductive, and metabolic phenotypes. Particular focus is placed on how these molecular derangements disrupt theca-granulosa cell communication, impair folliculogenesis, and promote hyperandrogenism, oxidative stress, and insulin resistance in the ovaries. This review also discusses therapeutic strategies according to evidence level, distinguishing established PCOS treatments such as lifestyle intervention, insulin sensitizers, ovulation-induction agents, hormonal regulators, and anti-androgens from investigational enzyme-specific inhibitors and speculative precision approaches such as gene editing and exosome-based delivery systems. Collectively, these insights underscore that the pathophysiology of PCOS extends beyond endocrine imbalance to encompass multi-omic alterations in metabolism and signaling. Understanding enzyme-level dysregulation offers opportunities for mechanism-based interventions that can restore steroidogenic homeostasis, improve fertility outcomes, and mitigate long-term metabolic risk. Future research should prioritize enzyme-signal interdependencies and develop personalized therapeutic strategies targeting the biochemical dysfunctions of PCOS.
Thirumurugan Ayyadurai, S. Ravi, Aravinth Annamalai· Journal of Steroid Biochemis...· 0 citations
Polyendocrine Metabolic Ovarian Syndrome (PMOS), referred to clinically as polycystic ovary syndrome (PCOS), is a common endocrine disorder associated with reproductive dysfunction, hyperandrogenism, insulin resistance, obesity, and chronic low-grade inflammation. Although gut microbiome alterations have been implicated in PMOS pathophysiology, data from Hispanic populations remain limited.
This cross-sectional study evaluated fecal samples from 51 reproductive-age, non-menopausal women living in Puerto Rico, including 41 with PMOS, diagnosed following the Rotterdam criteria, and 10 healthy controls. Genomic DNA was obtained from fecal samples and subjected to 16S rRNA gene sequencing for bacterial identification. Microbial assessment included associations with metabolic, androgenic, and reproductive variables.
After adjustment for age, body mass index (BMI), and recent antibiotic use, PMOS status was not significantly associated with alpha nor beta diversity (p>0.05). However, host factors such as BMI and age explained more variation in microbial communities than PMOS status. Indicator species analysis identified several taxa preferentially associated with controls, including
Phocaeicola_A dorei
,
Alitiscatomonas aceti
,
Brotaphodocola
, and
Schaedlerella
. Specifically,
Fusicatenibacter saccharivorans
was significantly reduced in the PMOS group. Metabolic markers, androgen levels, and reproductive features were not significantly associated with global microbiome diversity or composition; however, irregular menses was associated with greater microbiome dispersion.
These findings suggest that PMOS is not characterized by major gut microbiome shifts but may involve subtle depletion of health-associated commensals and increased microbial heterogeneity.
Loida A. González-Rodríguez, Keishla M. Jimenez-Ortega, D. Vargas-Robles et al.· Frontiers in Endocrinology· 0 citations
Polycystic ovary syndrome (PCOS) is a common endocrine disorder influenced by genetic and environmental factors, yet the molecular mechanisms linking endocrine-disrupting chemicals (EDCs) to ovarian dysfunction remain unclear. Here, we establish a letrozole-induced PCOS-like rat model and integrate bulk RNA-seq, single-cell RNA-seq of human granulosa cells (GCs), and functional validation to identify CBX2 as a critical epigenetic regulator connecting EDC exposure to PCOS pathogenesis. Transcriptomic profiling revealed dysregulated cell cycle progression, disrupted cholesterol homeostasis, and chronic inflammation in PCOS ovaries. Of these, cholesterol biosynthesis genes (e.g., Ebp, Dhcr7) were broadly suppressed, while efflux (Abca1) and metabolism-related (Cyp27a1) genes showed opposing alterations. Cross-species analysis identified CBX2 as consistently upregulated in both rat and human PCOS GCs, where it strongly correlated with accelerated cell proliferation and impaired cholesterol homeostasis. Mechanistically, exposure to EDCs (BPA and DDT) significantly induced CBX2 expression in human GCs. ChIP-seq analysis demonstrated that CBX2 directly binds to and represses genes from cholesterol-homeostasis-associated transcriptional networks-including CSRNP1, DDIT3, and FOSL1-through H3K27me3-mediated epigenetic silencing. Functional validation showed that CBX2 knockdown suppressed GCs proliferation, reduced lipid droplet accumulation while restoring normal cell cycle distribution. Single-cell RNA-seq confirmed elevated CBX2 activity specifically in PCOS GCs, particularly during G2/M phase, where it exhibited the strongest negative correlation with cholesterol homeostasis signatures (rs = -0.23). These findings reveal a novel EDC-CBX2-H3K27me3 epigenetic axis that decouples GC proliferation from metabolic support functions, establishing CBX2 as both a molecular biomarker and potential therapeutic target for environment-associated PCOS.
Chan Zhu, Xianliang Qiu, Hong Yang et al.· Journal of Steroid Biochemis...· 0 citations
Objective: Polycystic ovary syndrome (PCOS) represents the primary endocrine dysfunction among women of reproductive age, characterized by marked phenotypic diversity across reproductive, metabolic, and neuroendocrine domains. Despite extensive clinical characterization, its precise etiology remains unresolved, involving complex interactions between genomic susceptibility, embryonic programming, and environmental inputs.
Materials and Methods: A comprehensive literature search was conducted across PubMed, Scopus, and Google Scholar databases for studies published between 1999 and March 2026. The search strategy utilized key term combinations including "polycystic ovary syndrome", "ovarian development", "gonadal differentiation", "WNT4", "RSPO1", "FOXL2", "Hippo signaling pathway", "YAP1", "epigenetics", and "developmental origins". Original research articles, genome-wide association studies (GWAS), and systematic reviews focusing on molecular pathways, genetic susceptibility, and epigenetic mechanisms in PCOS pathogenesis were evaluated for inclusion.
Results: Ovarian morphogenesis, folliculogenesis, and steroidogenesis depend on tightly regulated transcriptional networks and signaling cascades. Key regulatory genes—including WNT4, RSPO1, FOXL2, FST, and members of the transforming growth factor-beta (TGF-β) superfamily—play pivotal roles in ovarian cell lineage commitment and functional preservation. Furthermore, genome-wide association studies and functional analyses have linked developmental loci such as YAP1 (Hippo pathway) to PCOS risk, underscoring how disruptions in early gonadal patterning exert lifelong effects on ovarian homeostasis. Epigenetic & Prenatal Factors: The developmental origins framework suggests that intrauterine stressors—such as fetal androgen excess, elevated anti-Müllerian hormone (AMH) exposure, and maternal metabolic dysfunction—permanently alter neuroendocrine and ovarian sensitivity. Epigenetic modifications, including DNA methylation, histone remodeling, microRNAs, and long non-coding RNAs, act as molecular bridge mechanisms translating these prenatal exposures into variable postnatal phenotypes.
Conclusion: This narrative review synthesizes evidence at the intersection of developmental biology, genomic architecture, and epigenetics to delineate how dysregulated ovarian developmental pathways contribute to PCOS pathogenesis. Clarifying these early lineage-specific and epigenetic mechanisms is essential for refining disease taxonomy, resolving phenotypic heterogeneity, and advancing targeted, etiology-driven diagnostic and therapeutic modalities.
Ayşegül Karahanoğlu, Mehmet Ozer, Y. Terzi et al.· Medical Science and Discover...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
