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PubMed2026

Evaluation of metabolic, reproductive, and gut microbiota alterations in a comparative study of different preclinical models of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a multifaceted, complex metabolic and endocrine disease where gut flora is considered an important factor in causing PCOS. This study aimed to identify a suitable PCOS model that contributes to gut microbial dysbiosis and metabolic and hormonal disturbances. Prepubertal SD rats were administered with normal control (NC), dihydrotestosterone (DHT), DHT with fructose (F), DHT+ high fat diet (HFD) for 91 days, dehydroepiandrosterone (DHEA), DHEA with fructose, DHEA with HFD for 30 days, sodium valproate (SV), sodium valproate with fructose, and sodium valproate with HFD for 21 days. The estrous cycles were assessed over this timeframe. At the end of the experiment, superoxide dismutase and uterine and ovarian morphology were evaluated, along with hormone levels, lipid profiles, and 16S rRNA genomic sequencing. All models exhibited PCOS characteristics, including hormonal imbalances, insulin resistance (p ≤ .001), multiple follicular cysts on ultrasonography, and histological alterations. Gut microbial dysbiosis was observed across all PCOS-induced groups; however, the DHT alone group showed more pronounced alterations in microbial composition than the other experimental groups. Specifically, the DHT alone group exhibited reduced abundance of Firmicutes and increased abundance of Proteobacteria. Among the evaluated models, the DHT-only model showed more pronounced metabolic, hormonal, reproductive, and gut microbial alterations and may serve as a suitable model for PCOS research.

Animals↗

PubMed2025

Gut microbiota: a hidden player in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects reproductive-aged women worldwide, causing hormonal imbalances and ovarian dysfunction. PCOS affects metabolic health and increases the risk of obesity, insulin resistance, and cardiovascular disease, in addition to infertility. This review delves deeper into the connections of gut microbiota with PCOS pathophysiology, particularly into its impact on hormone metabolism, obesity, inflammation, and insulin resistance by way of short-chain fatty acids, lipopolysaccharides, and gut-brain axis. Studies also show that changes in the metabolic processes and immune responses are seen in changes in the gut microbiota in PCOS subjects, such as changes in the Bacteroidetes and Firmicutes groups. Some bacteria, like Escherichia and Shigella, have been associated with dysbiosis in patients with PCOS, leading to systemic inflammation and changed hormone levels, which further worsen the clinical symptoms. Therapeutic interventions targeting the gut microbiota comprise probiotics, prebiotics, and fecal microbiota transplantation; these have potential to alleviate the symptoms of PCOS. Other precision microbiome-based therapies include postbiotics, and CRISPR-Cas9 genome editing, which are relatively new avenues toward precision treatment. This complex interlink of gut microbiota and PCOS pathophysiology will open the avenues for possible treatments for hormonal imbalances and metabolic problems that characterize these complex disorders. The review here focuses on the requirement of further studies to be able to elucidate the specific pathways relating gut microbiota dysregulation to PCOS and, thus, improve microbiome-based therapies for better clinical outcomes in affected individuals.

Humans↗

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

Exploring the Genetic Link between Irritable Bowel Syndrome and Polycystic Ovary Syndrome: Bidirectional Mendelian Randomization and Machine Learning Approaches.

BACKGROUND: Research has shown a certain correlation between polycystic ovary syndrome (PCOS) and irritable bowel syndrome (IBS). The study aims to determine the directionality and underlying biological processes influencing the relationship between these two disorders. METHODS: We explored the causal relationship between IBS and PCOS by conducting a comprehensive bidirectional Mendelian randomization (MR) analysis using five different methods and conducted robustness assessments. We extracted differentially expressed genes from the IBS and PCOS datasets for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Additionally, we developed a protein-protein interaction (PPI) network and applied the Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine (SVM) methodologies to pinpoint key diagnostic markers. Diagnostic efficacy was further assessed through Receiver Operating Characteristic (ROC) curve analysis for selected genes. Finally, single-sample gene set enrichment analysis (ssGSEA) was carried out to examine immune cell infiltration in IBS and PCOS. RESULTS: MR analysis identified a causal effect of PCOS on IBS (IVW, OR = 1.034, 95% CI: 1.003-1.065, P = 0.029). Conversely, no relationship between IBS and PCOS was observed in the reverse analysis. Furthermore, integrative bioinformatics and machine learning analyses identified CD14 and CASP1 as key diagnostic biomarkers for both IBS and PCOS, which were significantly associated with immune cell infiltration. CONCLUSION: MR analysis has demonstrated a significant positive causal relationship between PCOS and IBS, though the reverse causality from IBS to PCOS appeared non-significant. The genes CD14 and CASP1 emerged as potential shared diagnostic markers between these two conditions.

Polycystic Ovary Syndrome↗

PubMed1979

Isolation of urinary C-20 alpha- and C-20 beta-hydroxy-C21-steroid metabolites in cases of congenital adrenal hyperplasia, postpubertal virilizing syndrome and polycystic ovary syndrome.

The proportion of 20 alpha/20 beta-epimers of the urinary C21-steroid metabolites was estimated in normal volunteers and in patients with congenital adrenal hyperplasia (CAH), postpubertal virilizing syndrome (PVS) and polycystic ovary syndrome (POS). In the normal individuals 20 alpha- and 20 beta-epimers of 5 beta-pregnane-3 alpha, 17 alpha, 20-triol (pregnanetriol) and 5-pregnene-3 beta, 17 alpha, 20-triol (5-pregnenetriol) were measured. In the other case 20 alpha- and 20 beta-epimers of the characteristic, representative metabolites were also investigated. In 26 of 27 normal persons and in all the patients with normotensive CAH, PVS and POS the 20 beta-epimer comprised 0-10% of the total pregnanetriol. The 20 beta-epimer of 5-pregnenetriol was found in only one normal case (6% of the total). The percentage of 20 beta-epimers of 3 alpha, 17 alpha, 20-trihydroxy-5 beta-pregnan-11-one, 5 beta-pregnane-3 alpha, 11 beta, 17 alpha, 20-tetrol (in the normotensive CAH, PVS and POS) and 5 alpha- or 5 beta-pregnane-3 alpha, 17 alpha, 20, 21-tetrol (in the hypertensive CAH) varied from nil to 76%. The effect of functional groups and the stereochemistry of the molecule on the direction of C-20-keto group reduction is discussed; the existence of additional factors determining this reduction in certain pathological conditions is suggested.

Adolescent↗

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↗

PubMed1976

Biochemical and Clinical Effect of Ovarian Wedge Resection in the Polycystic Ovary Syndrome.

Twelve patients with histologically verified polycystic ovary syndrome were investigated with special regard given to the effect of wedge resection on androgen status. Adrenal disorders were excluded in every case by determination of cortisol and corticosterone metabolites. Prior to and at least 6 months after surgery all patients were subjected to adrenal stimulation followed by adrenal suppression and ovarian stimulation. Comparison between pre- and postoperative studies revealed that only an insignificant reduction in the excretion of 17-ketosteroid had occurred and, although at lower levels, the stimulatory effect of hCG on ovarian androgens was still present. Clinically, 10 patients had had regular periods at followup, and 3 had become pregnant. In no case had hair growth slowed, bu the rate had declined. Seemingly, wedge resection does not significantly influence the biochemical pattern connected with the polycystic ovary syndrome.

17-Ketosteroids↗

PubMed1977

The polycystic ovary syndrome:psychosexual correlates.

Eleven women with the polycystic ovary syndrome (POS) were interviewed prior to treatment to assess psychosexual and behavioral characteristics. Because the polycystic ovary syndrome is characterized by an elevated plasma level of free testosterone that presumably develops after birth, we examined specifically the six areas traditionally explored in prenatally androgenized women--play preference, energy expenditure level, interest in dress and appearance, career vs. family preference, sexual arousal to narrative and visual stimuli, and sexual initiative. While these women described patterns in all categories similar to those reported in the earlier studies of prenatally androgenized women, their behavior was significantly different only in sexual initiative from that of two normal groups. These findings suggest that increased sexual initiative may be a heretofore unemphasized clinical feature of the polycystic ovary syndrome and conceivably a concomitant of elevated free plasma testosterone.

Adolescent↗

PubMed1976

Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome.

To evaluate gonadotropin release in polycystic ovary syndrome (PCO), one or more of the following hypothalamic-pituitary function tests were performed on 24 patients with the syndrome. These tests included (a) the pulsatile pattern and day-to-day fluctuation of gonadotropin release; (b) effects of exogenous estrogen and antiestrogen (clomiphene) administration on gonadotropin release; and (c) pituitary responsiveness to maximal (150 mug) and submaximal (10 mug) luteinizing hormone-releasing factor (LRF) injections. In 10 of the 14 patients sampled frequently (15 min) for 6 h, luteinizing hormone (LH) levels were elevated above the concentration seen in normal cycling women (except the LH surge). These high LH concentrations appeared to be maintained by and temporally related to the presence of exaggerated pulsatile LH release, either in the form of enhanced amplitude or increased frequency. In all subjects, levels of follicle-stimulating hormone (FSH) were low or low normal, and a pulsatile pattern was not discernible. In four patients, daily sampling revealed marked day-to-day fluctuation of LH but not FSH. That the elevated LH levels were not related to a defect in the negative-feedback effect of estrogen was suggested by the appropriate fall of LH in four patients given an acute intravenous infusion of 17beta-estradiol. This infusion had no effect on FSH levels. In addition, clomiphene elicited rises of both LH and FSH that were comparable to the ones observed in normal women given the same treatment. The clomiphene study also suggested that the positive-feed-back mechanism of estrogen on LH release was intact when the preovulatory rises of 17beta-estradiol induced appropriate LH surges. The elevated LH levels appeared to be related to a heightened pituitary responsiveness to the LRF. This was found in the 11 and 2 patients given maximal (150 mug) and submaximal (10 mug) doses of LRF, respectively. The augmented pituitary sensitivity for LH release correlated with the basal levels of both estrone (P less than 0.025) and 17beta-estradiol (P less than 0.02). The net increase in FSH was significantly greater (P less than 0.001) in the PCO patients than the normal women with maximal doses of LRF. With the smaller dose study none of the injections had a discernible effect on FSH concentrations in either subject. The disparity between LH and FSH secretion could be explained by the preferential inhibitory action of estrogen on FSH release, coupled with a relative insensitivity of FSH release. These data indicate that in these PCO patients the abnormalities of the hypothalamic-pituitary regulation of gonadotropin secretion was not an inherent defect but represented a functional derangement consequent to inappropriate estrogen feedback, which led to a vicious cycle of chronic anovulation and inappropriate gonadotropin secretion.

Adult↗

PubMed1977

Clinical aspects of the polycystic ovary syndrome.

One hundred and one patients with polycystic ovary syndrome (PCO) were treated during an 11-year interval. Sixty-seven cases were classified as typical PCO with enlarged ovaries of probable ovarian origin (Type I) and 34 as atypical PCO of probable adrenal origin (Type II). Fifty-five patients were treated for anovulatory infertility with clomiphene citrate or other endocrine therapy as indicated. There was a 91% ovulatory response and 51% conception rate from therapy in cases of Type I PCO. In Type II PCO, adrenal suppressive therapy resulted in a 55% ovulatory response. Our data support the concept that anovulation of ovarian origin as seen in PCO Type I responds to clomiphene therapy, while anovulation secondary to adrenal hyperandrogenization should be treated by adrenal suppressive therapy.

17-Ketosteroids↗

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

Genomic relationship between polycystic ovary syndrome and bipolar disorder.

Women with bipolar disorder (BIP) have a higher risk of developing polycystic ovary syndrome (PCOS). Shared genetic architecture may underlie this comorbidity. Valproate, a mood-stabilizer commonly used to treat BIP, increases the risk of PCOS. Still, the mechanism underlying PCOS in BIP remains unknown. Here, we aimed to identify genetic variants shared between BIP and PCOS, as well as their interaction with valproate. We used the results of large-scale genome-wide association studies of BIP (41,510 cases and 354,340 controls), and PCOS (3,609 cases and 229,788 controls). Using conditional false discovery rate, we discovered genetic variants jointly associated with BIP and PCOS. Gene mapping of identified variants was performed using the Open Targets platforms. We analyzed the tissue-specific expression, interaction with valproate, and involvement in biological pathways of the mapped genes. We identified two loci shared between BIP and PCOS. Among the 10 genes mapped to the locus on chromosome 8:11455262, GATA4, NEIL2, and FDFT1 showed expression profiles suggesting their role in the observed comorbidity. Mapped to the locus on chromosome 12:2499849, CACNA1C, FKBP4, DCP1B, and ITFG2 are expressed in both the ovaries and the brain. CACNA1C expression is affected by valproate, and CACNA1C plays a role in biological pathways involving other valproate-affected genes. We identified shared genetic underpinnings of BIP and PCOS, and implicated genes which may explain the biological mechanisms of the comorbidity between these disorders and a potential mechanism for the role of valproate.

bipolar disorder↗

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

Gene by environment interaction effects on the metabolic subtype of Polycystic Ovary Syndrome in Hispanic Community Health Study/Study of Latinos.

Polycystic Ovary Syndrome (PCOS) is a common polygenic endocrine disorder that is heterogenous in clinical presentation across genetic ancestry groups. PCOS is characterized by an array of symptoms such as hyperandrogenism, impaired mental health, and metabolic dysregulation. Studying the interaction of environmental factors (such as diet, physical activity, anxiety, and depression) with genetic variants on PCOS and its subtypes in populations with high cardiometabolic burden, e.g., Hispanic/Latinas, could aid in unraveling pathophysiological and genetic pathways through which PCOS functions. We sought to study gene by environment interactions with PCOS and its metabolic subtype (mPCOS) in a sample of US Hispanic/Latina female adults from the Hispanic Community Heath Study/Study of Latinos. In this large community-based study, we derived PCOS using self-reported condition and menstrual cycle information. We classified females with PCOS as having mPCOS if they had high metabolic impairment (fasting glucose, fasting insulin, or body mass index higher than the 75th percentile). There were 451 individuals with PCOS and 221 of them had mPCOS in our sample. We found that PCOS and mPCOS were significantly associated with hyperglycemia and high triglycerides in this population. While a polygenic risk score derived in European ancestry did not generalize to Hispanic/Latina females with PCOS, we identified the best proxy genetic variants in this population in known PCOS regions and investigated their interactions with four environment variables (diet, physical activity, anxiety and depression). Associations with known PCOS loci were generalized in our study at STAG3L4 and CACNA1G genomic regions. We observed GxE interactions between variants in/near three genes and physical activity on PCOS and mPCOS, including FGGY, FAT1, and PTHLH. Additionally, we noted interactions between diet and a variant in FANCC on PCOS, and diet and a variant near CMAS on both PCOS and mPCOS. We also detected GxE interactions between anxiety and depression and a variant in FGGY on PCOS, and depression and a variant near FBP1 on mPCOS. Our results point to potential protective effects of physical activity in females with PCOS and could inform future research on the mitigating effects of lifestyle management on PCOS genetic risk in Hispanic/Latino populations.

GxE↗

PubMed1976

Ovarian enzymatic divergence in patients with polycystic ovary syndrome excreting urinary pregnanetriolone.

When ovarian mitochondria from patients with polycystic ovary syndrome (POS) were incubated with [7-3H]17alpha-hydroxypregnenolone and [4-14C]-17alpha-hydroxyprogesterone, 11beta-hydroxylated metabolites were obtained. The mitochondria, prepared from pooled, frozen, polycystic ovarian tissue of 5 patients, converted [7-3H]17alpha-hydroxypregnenolone to 3beta, 11beta, 17alpha--trihydroxy-5-pregnen-20-one (yield 0.065%) and to 3beta, 17alpha-dihydroxy-5-pregnene-11,20-dione (0.22%), while [4-14C]17alpha-hydroxyprogesterone was converted to 21-deoxycortisol (0.1%). Incubation of mitochondria, prepared from 4 pooled samples of frozen, normal ovarian tissue, yielded no evidence of 11beta-hydroxylation of either of the substrates. Mitochondria obtained from fresh, polycystic ovarian tissue of a single patient with POS converted [7-3H]17alpha-hydroxypregnenolone to 3beta,17alpha-dihydroxy-5-pregnene-11,20-dione (2.1%) and [4-14C]17alpha-hydroxyprogesterone to 21-deoxycortisol (0.1%). When the same mitochondrial preparation was incubated simultaneously with [7-3H]17alpha-hydroxypregnenolone and [4-14C]11-deoxycortisol, it converted 17alpha-hydroxypregnenolone to 3beta,17alpha-dihydroxy-5-pregnene-11,20-dione (1.9%), but no 11beta-hydroxylated derivatives of 11-deoxycortisol were found. These results demonstrate that ovaries of patients with POS contain an 11beta-hydroxylase active towards C-21-deoxysteroids but inert to C-21-hydroxysteroids such as 11-deoxycortisol.

17-alpha-Hydroxypregnenolone↗

PubMed1978

Diagnostic value of androgen measurements in polycystic ovary syndrome.

A group of 51 women with a diagnosis of polycystic ovary syndrome (PCO) were investigated. They were further classified into PCO Type I and PCO Type II based on clinical and laboratory investigations. Serum levels of unbound (free) and total testosterone, testosterone binding globulin (TBG), and androstenedione were measured in these women and compared with values in normal women. Mean levels of all these steroids were elevated in women with PCO. No difference in adrogen levels was found between women with PCO Type I and PCO Type II. Serum unbound testosterone concentrations correlated better with the presence and severity of hirsutism than did the total testosterone.

Androgens↗

PubMed2024

Polycystic Ovary Syndrome Physiologic Pathways Implicated Through Clustering of Genetic Loci.

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, with disease loci identified from genome-wide association studies (GWAS) having largely unknown relationships to disease pathogenesis. OBJECTIVE: This work aimed to group PCOS GWAS loci into genetic clusters associated with disease pathophysiology. METHODS: Cluster analysis was performed for 60 PCOS-associated genetic variants and 49 traits using GWAS summary statistics. Cluster-specific PCOS partitioned polygenic scores (pPS) were generated and tested for association with clinical phenotypes in the Mass General Brigham Biobank (MGBB, N = 62 252). Associations with clinical outcomes (type 2 diabetes [T2D], coronary artery disease [CAD], and female reproductive traits) were assessed using both GWAS-based pPS (DIAMANTE, N = 898,130, CARDIOGRAM/UKBB, N = 547 261) and individual-level pPS in MGBB. RESULTS: Four PCOS genetic clusters were identified with top loci indicated as following: (i) cluster 1/obesity/insulin resistance (FTO); (ii) cluster 2/hormonal/menstrual cycle changes (FSHB); (iii) cluster 3/blood markers/inflammation (ATXN2/SH2B3); (iv) cluster 4/metabolic changes (MAF, SLC38A11). Cluster pPS were associated with distinct clinical traits: Cluster 1 with increased body mass index (P = 6.6 × 10-29); cluster 2 with increased age of menarche (P = 1.5 × 10-4); cluster 3 with multiple decreased blood markers, including mean platelet volume (P = 3.1 ×10-5); and cluster 4 with increased alkaline phosphatase (P = .007). PCOS genetic clusters GWAS-pPSs were also associated with disease outcomes: cluster 1 pPS with increased T2D (odds ratio [OR] 1.07; P = 7.3 × 10-50), with replication in MGBB all participants (OR 1.09, P = 2.7 × 10-7) and females only (OR 1.11, 4.8 × 10-5). CONCLUSION: Distinct genetic backgrounds in individuals with PCOS may underlie clinical heterogeneity and disease outcomes.

Humans↗

PubMed2026

A Risk Score for Polycystic Ovary Syndrome Based on Meta-Analysis and Machine Learning of Gut Microbiota Signatures.

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine and metabolic disorder among reproductive-age women, in which emerging evidence suggests a substantial role played by the gut microbiota. To comprehensively evaluate gut microbiota alterations in PCOS and identify microbial biomarkers through integrated analysis, a systematic search of PubMed, Web of Science, and Embase was conducted for studies employing 16S rRNA gene sequencing of fecal samples from PCOS cohorts. Ten eligible PCOS cohorts, comprising 858 individuals, were included in the study, from which a risk score was derived using a 20-gene gut microbial signature associated with PCOS. Meta-analysis at the genus level identified that Subdoligranulum, NK4A214_group, and Collinsella significantly decreased, and Bacteroides increased in PCOS across multiple cohorts. Machine learning analysis identified a 20-genus microbial signature using the least absolute shrinkage and selection operator (LASSO) method, which was used to construct a risk score with an AUC of 0.835 in diagnosis prediction. Network analysis further identified Negativibacillus and Lachnospiraceae_UCG_010 as potential driver microbes in PCOS. The analysis in this study highlights key alterations in the gut microbiota across PCOS cohorts. The identified gut microbial signature and derived LASSO-based risk model offer novel insights and a potential tool for PCOS diagnosis.

Polycystic Ovary Syndrome↗