Premature pubarche (PP), defined as the early onset of pubic hair and often associated with mild androgen excess, is a common reason for referral to a pediatric endocrinologist. A small proportion of cases may progress to central precocious puberty (CPP). Data on the factors determining pubertal tempo and associated growth outcomes in these individuals are limited. To identify predictors of pubertal progression and final height (FH) in girls with PP and to evaluate growth outcomes in those progressing to CPP. We retrospectively analyzed 88 girls with PP who attained FH; 13 progressed to CPP (PP-to-CPP). Auxological data, bone age (BA), pubertal development, and plasma androgen profiles were evaluated. At presentation, corrected height SDS (CH-SDS) in girls with PP correlated with BA-SDS and BA/chronological age (BA/CA) ratio (p=0.03 and p=0.007). Corrected FH-SDS was positively associated with baseline CH-SDS in both PP and PP-to-CPP groups (p<0.001 and p=0.0002). Compared with PP, the PP-to-CPP group had higher baseline CH-SDS, BA-SDS and BA/CA ratio (all p=0.02). Baseline CH-SDS was the strongest independent predictor of corrected FH-SDS (p<0.001), while BMI-SDS showed a negative association (p=0.003). Baseline dehydroepiandrosterone-sulfate (DHEA-S) was not associated with CH-SDS, BA advancement, progression to CPP, or corrected FH-SDS in either group. Receiver operating characteristic (ROC) analyses for progression to CPP identified a BA/CA cutoff of 1.2; and a CH-SDS cutoff of 1.8 (p=0.01). Growth relative to genetic potential and skeletal maturation at presentation were the strongest predictors of progression to CPP and FH outcomes in girls with PP. Although DHEA-S reflects adrenal maturation and early androgen exposure, baseline DHEA-S concentrations were not associated with progression to CPP or long-term growth outcomes in our cohort.

Few conditions in reproductive medicine rival polycystic ovary syndrome (PCOS) in terms of clinical breadth and global impact. Affecting roughly 6-21% of women of childbearing age depending on which diagnostic criteria are applied PCOS sits at the intersection of endocrinology, metabolism, and gynecology, making it difficult to capture within any single disciplinary lens. Its hallmarks are well rehearsed: excess androgens, disrupted ovulation, and the characteristic follicular architecture seen on pelvic ultrasound. Yet what makes PCOS genuinely challenging is the degree to which these reproductive features overlap with far-reaching metabolic consequences, including insulin resistance, type 2 diabetes, lipid abnormalities, and a meaningfully elevated cardiovascular risk profile that persists well beyond the fertile years. Despite several decades of sustained investigation, the origins of PCOS remain imperfectly understood. Genetic susceptibility, epigenetic programming, environmental chemical exposures, and modern dietary habits all appear to play contributory roles, though no single culprit has emerged. The molecular picture is equally layered: aberrant insulin signaling feeds androgen overproduction, gonadotropin secretion goes out of balance, inflammatory cytokines accumulate, oxidative injury mounts, and more recently the gut microbial community has been implicated as an additional participant in this cascade. Diagnosis is further complicated by the phenotypic variability of the syndrome, with different criteria yielding meaningfully different patient populations. Treatment, in turn, requires individualization; lifestyle change, hormonal therapies, insulin sensitizers, and an expanding repertoire of repurposed drugs and plant-based agents each address different facets of a fundamentally heterogeneous disorder. This review provides a comprehensive and integrated account of PCOS across its full biological and clinical spectrum. It covers epidemiology, clinical presentation, risk factors, and current diagnostic frameworks. Pathophysiological mechanisms are examined in depth. A central and distinctive focus of this review is the experimental preclinical landscape. Established animal induction models, letrozole, dehydroepiandrosterone (DHEA), testosterone/dihydrotestosterone propionate, and high-fat diet protocols are critically evaluated for their translational relevance. Drawing on these models, we comprehensively catalogue protective agents across four systematic tables, encompassing both repurposed pharmaceuticals (metformin, GLP-1 receptor agonists, SGLT-2 inhibitors, statins, melatonin) and bioactive natural compounds (curcumin, berberine, quercetin, fisetin, myricetin, apigenin, and others), detailing their induction models, mechanistic pathways, and therapeutic outcomes. Together, this review aims to serve as a single, authoritative reference bridging basic science, translational pharmacology, and clinical practice in PCOS, while identifying the most promising avenues for future research and personalized therapeutic development.

Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age and is frequently associated with hyperandrogenic manifestations, including hirsutism and acne. These symptoms significantly impair quality of life and are closely linked to metabolic dysfunction, insulin resistance, and hormonal imbalance. The heterogeneous nature of PCOS contributes to variability in treatment response and complicates the development of optimal therapeutic strategies. Aim: This narrative review aimed to evaluate current therapeutic approaches for hirsutism and acne in women with PCOS, focusing on clinical efficacy, mechanisms of action, and future therapeutic perspectives. Materials and Methods: A narrative review of the literature was conducted using PubMed/MEDLINE and Google Scholar databases. Publications from 2015–2026 were analyzed, including randomized controlled trials, systematic reviews, meta-analyses and international clinical guidelines. Results: Combined oral contraceptives remain the first-line treatment for hirsutism and acne due to their efficacy in reducing androgen excess and regulating menstrual cycles. Antiandrogens, particularly spironolactone, effectively reduce hirsutism, whereas metformin primarily improves metabolic abnormalities and insulin resistance. Emerging evidence suggests that GLP-1 receptor agonists may provide additional benefits through weight reduction, improved insulin sensitivity, and decreased androgen levels. However, current evidence is limited by heterogeneity of study populations, varying diagnostic criteria, short follow-up periods and lack of standardized outcome measures. Conclusions: Management of hirsutism and acne in PCOS requires an individualized and multidimensional therapeutic approach. Further high-quality long-term studies are needed to optimize treatment strategies and improve clinical outcomes.

Excess androgenic steroid exposure during development in female sheep alters metabolic and reproductive function in postnatal life, with phenotypes reminiscent of health-relevant aspects of Polyendocrine Metabolic Ovarian Syndrome (PMOS) in women. We hypothesised that altered steroid exposure during in utero life would alter female postnatal adrenal function. Prenatal steroid excess was created by fetal steroid injections, on d62 and d82 of gestation, designed to separately create excess androgenic exposure (testosterone propionate, n = 14), oestrogenic exposure (diethylstilbestrol, n = 7) and glucocorticoid excess exposure (dexamethasone, n = 11) with controls (n = 11) treated with vehicle alone. Adrenal function tests and qPCR measurement of adrenal steroidogenic genes were the outcomes measured. In post-pubertal female offspring, specifically prenatal androgenic excess was associated with exaggerated testosterone secretory response to ACTH (P < 0.05), in the absence of alterations in cortisol secretion. Altered androgen secretory response was associated with increased STAR, HSD3B1 and HSD17B mRNA (P < 0.05). Neither adrenal androgen secretion nor steroidogenic gene expression was altered prior to puberty. During fetal life (day 90 of gestation), only STAR was altered in prenatal androgenic excess females (P < 0.05), to a similar level as observed in a control cohort of male fetuses. We conclude that the postnatal, post-pubertal ovine adrenal gland is hyperandrogenic because of prenatal androgen excess.Lay summarySteroid hormones are responsible for our development in fetal life. If there is too much or too little of a steroid hormone before we are born, it can affect our health in the future. If a female fetus is exposed to too much male-type hormone in the middle of pregnancy, after puberty, they develop features seen in women with Polyendocrine Metabolic Ovarian Syndrome (PMOS). The classic feature of PMOS is increased male-type hormones from the ovaries where cells in the ovaries are set up to make more male-type hormone. In women, half of all the male-type hormones come from the adrenal gland. We looked at the effects of giving more male-type hormones in the middle of pregnancy to female sheep fetuses as we know that they get the features of PMOS after puberty. In this study, we showed that the cells in the adrenal gland are also set up to make more male-type hormone after puberty. We checked if this was specifically due to the effects of male hormone exposure before birth and found that increased female hormone or stress hormone does not have the same effect. This means that it is likely not just the ovary whose function is altered in PMOS but also the adrenal gland.

Polycystic ovary syndrome (PCOS) is frequently accompanied by visceral obesity, insulin resistance, low-grade chronic inflammation, and metabolic syndrome (MetS). These alterations promote significant dysfunction in adipose tissue and liver metabolism through cytokine production. Growing evidence indicates that the interaction between hepatokines and adipokines plays a central role in the development of metabolic and hepatic abnormalities in women with PCOS. This narrative review was conducted to analyze the relationship between adipose tissue dysfunction and liver metabolic impairment in women with PCOS, emphasizing the involvement of hepatokines and adipokines in insulin resistance, inflammation, hepatic steatosis, hepatic fibrosis and MetS. From this perspective, contemporary clinical, biochemical, and molecular studies were reviewed to evaluate how adipocyte-derived factors and hepatocyte-derived cytokines influence metabolic homeostasis in the liver and adipose tissue in women with PCOS. Increased visceral adiposity in PCOS enhances the release of free fatty acids (FFAs) to the liver, resulting in hepatotoxicity, oxidative stress, and hepatic inflammation. Several hepatokines, including fetuin-A, angiopoietin-like protein 3 (ANGPTL3), selenoprotein P(Sep-P), and hepassocin (HPS), show abnormal circulating levels in PCOS and are strongly associated with insulin resistance, dyslipidemia, and progression to hepatic steatosis. In contrast, fibroblast growth factor 21 (FGF-21), follistatin, and interleukin (IL-6) may exert dual effects. Adipokines, such as resistin, visfatin, apelin, and retinol-binding protein 4 (RBP-4), contribute to chronic inflammation, impaired glucose metabolism, androgen excess, and hepatic steatosis and fibrosis. Some of these adipokines, such as leptin and vaspin, may exert both beneficial and detrimental effects, while others, including chemerin and omentin, appear to play predominantly beneficial roles in metabolism. Reduced adiponectin-to-leptin levels further aggravate metabolic dysfunction. These changes indicate that adipose tissue-liver crosstalk is a key mechanism linking PCOS and MetS. Overall, metabolic disturbances in PCOS are strongly mediated by dysregulated communication between adipose tissue and the liver. Altered hepatokine and adipokine profiles contribute to insulin resistance, liver dysfunction, hypertension and the development of MetS in women with PCOS. Understanding these intricate interactions may support the early identification of high-risk patients and the development of targeted therapeutic strategies.

3037-LB: Androgen Receptor Action in Arcuate Nucleus Impairs Estrogen Insulin-Sensitizing Actions and Insulin Suppression of Hepatic Glucose Production in Female Mice

Hirsutism is a prevalent androgen-dependent condition that significantly affects women's physical and psychological health. Despite decades of study, major gaps persist in understanding local androgen metabolism, the role of insulin resistance, and individualized treatment responses. This review aims to provide a contemporary update that integrates recent molecular, diagnostic, and therapeutic advances. To critically appraise the current understanding of hirsutism, with an emphasis on: (1) emerging concepts in local androgen action and follicular sensitivity, (2) evolving assessment methods, (3) updated pharmacologic and mechanical treatment options aligned with current endocrine and dermatologic evidence. A narrative review of the literature was conducted in PubMed, Scopus, and Web of Science for studies published between January 2000 and September 2025, using the terms: "hirsutism," "hyperandrogenism," "androgen excess," "idiopathic hirsutism," "PCOS," "5α-reductase," "antiandrogens," "oral contraceptives," "laser hair removal," and "insulin resistance." human studies, English language, adult females, and peer-reviewed original or review articles. An integrated understanding of systemic and local androgenic activity is transforming the management of hirsutism from a purely cosmetic issue to a complex endocrine disorder with metabolic and psychological dimensions. This review proposes a personalized, multidisciplinary framework that bridges endocrinology, gynecology, and dermatology. Future directions should focus on elucidating local androgen metabolism, tissue-specific enzyme activity, and the role of insulin resistance in idiopathic cases to refine both diagnostic precision and treatment efficacy.

Failure of podocalyxin suppression and HOXA10/HOXA11 activation characterizes endometrial dysfunction in hyperandrogenic PCOS.

Analytical validation of a dried blood microsampling method to measure androstenedione, 17α‑hydroxyprogesterone, and 11‑ketotestosterone for congenital adrenal hyperplasia monitoring.

Androgen excess in postmenopausal women presents a challenging clinical conundrum. A crucial component in management involves identification of the underlying aetiology with a focus on detection of potentially malignant pathology or underlying genetic syndromes. A basic understanding of androgen physiology in women and the associated alterations during the menopausal transition is required to accurately risk stratify this cohort and streamline investigations. Over the course of this article, we will propose an approach to investigation and management of postmenopausal androgen excess that focuses on clinical, biochemical and radiological cues. Additionally, we will suggest an algorithmic approach to clinical and biochemical diagnostics that is underpinned by identification of red flag features of underlying pathology.

Congenital adrenal hyperplasia (CAH), most commonly caused by 21-hydroxylase deficiency, remains associated with substantial morbidity despite life-saving glucocorticoid replacement. This review is timely because several novel therapies have recently emerged with the potential to improve disease control while reducing glucocorticoid burden. Recent advances in CAH management include modified-release hydrocortisone, which better mimics physiological cortisol secretion and may improve androgen control with lower glucocorticoid exposure. Steroid-reducing agents have advanced rapidly, particularly the corticotropin-releasing factor type 1 receptor antagonist crinecerfont and the melanocortin 2 receptor (MC2R) antagonist atumelnant, both of which show promise in lowering adrenocorticotropic hormone (ACTH)-driven androgen excess and facilitating glucocorticoid dose reduction. Additional emerging approaches include insurmountable MC2R antagonists and the anti-ACTH monoclonal antibody Lu AG13909. Gene therapy and genome editing strategies are also progressing, although important biological and technical barriers remain, particularly for durable adrenal targeting. The therapeutic landscape for CAH is evolving rapidly beyond conventional steroid replacement. These innovations may improve biochemical control and long-term outcomes, but challenges remain regarding adrenal crisis risk, long-term safety, durability, cost, and global equity of access.

Adrenarche, characterized by rising adrenal dehydroepiandrosterone (DHEA) levels, precedes puberty and has been implicated in reproductive maturation, and disorders like polycystic ovary syndrome (PCOS). However, the mechanisms by which DHEA influences the hypothalamic-pituitary-gonadal (HPG) axis remain poorly understood, largely due to the absence of an appropriate animal model. The spiny mouse (genus Acomys), which has a prolonged juvenile phase and endogenous prepubertal DHEA production, provides a valuable system to investigate the effects of early-life exposure to DHEA. We confirmed the spiny mouse prepubertal rise in circulating DHEA levels, which occurs independently of HPG axis activation, and concomitantly with increased expression of pituitary Prl and various ovarian steroidogenic and estrogen-responsive genes, including Prlr. In cultured cells, DHEA induced Prlr and Prl expression seemingly via the estrogen receptor. Adrenalectomy (Adx) revealed that DHEA is synthesized outside the adrenal glands, possibly the ovaries. Treatment of these mice with DHEA led to extensive changes in their ovarian transcriptomes, including upregulation of immune response-related genes, and downregulation of cholesterol metabolism and estrogen synthesis genes, most notably Cyp19a1. The reduced Cyp19a1 expression is likely due to the elevated Amhr2, and was accompanied by a high androgen-to-estrogen ratio, comprising DHEA-induced, PCOS-like characteristics. The rise in DHEA during an extended juvenile phase establishes the spiny mouse as a suitable model for studying the consequences of adrenarche. Our findings also reveal that increasing further these prepubertal DHEA levels alters ovarian gene expression and steroidogenesis, offering insights into how early androgen excess may predispose to reproductive dysfunction.

What is the impact of PCOS and the hyperandrogenic (HA) PCOS phenotype on the risk of developing hypertension and dyslipidemia? PCOS is an independent risk factor for the development of hypertension and dyslipidemia, with the risk being higher among women with the HA PCOS phenotype. PCOS is an established risk factor for insulin resistance and the metabolic syndrome. However, prospective data regarding the risk of hypertension and dyslipidemia in population-based cohorts of women with PCOS are limited. This nationwide multiregister-based cohort study included a total of 297215 women with PCOS and matched controls followed for up to 20 years. Data were retrieved from the Swedish Patient Register, the Prescribed Drug Register, the Medical Birth Register, the Cause of Death Register, the Total Population Register, and the Education Register. Study participants resided in Sweden and were born between 1950 and 1999. The median age at study entry was 28 years. Women with a diagnosis of PCOS, androgen excess, or anovulatory infertility recorded in the Swedish Patient Register between 1 January 1997 and 31 December 2016 constituted the study population (n = 50 969). For each woman with PCOS, five controls matched by birth year and municipality were randomly selected from the Total Population Register (n = 246 246). The primary outcomes were incident hypertension and dyslipidemia after PCOS diagnosis, defined by International Classification of Diseases-10 codes and/or filled prescriptions for antihypertensive or lipid-lowering medications, respectively. Women with PCOS were further classified as hyperandrogenic (HA) if they had been diagnosed with androgen excess or had a filled prescription for anti-androgenic drugs in the Prescribed Drug Register; otherwise, they were classified as normoandrogenic (NA). Cox regression analyses were performed, adjusted for birth period, country of birth, and education. Overweight and obesity were accounted for in separate models using either BMI or an obesity ICD-10 diagnosis. Women with PCOS had a higher risk of developing hypertension compared with non-PCOS women [adjusted Hazard Ratio (aHR) 2.25 (95% CI: 2.13-2.39), adjusted for obesity]. Those with the HA-PCOS phenotype had more than 5-fold increased risk [aHR 5.51 (95% CI: 4.97-6.10)]. Similarly, PCOS was associated with a higher risk of dyslipidemia [aHR 3.05 (95% CI: 2.69-3.46), adjusted for obesity], and women with the HA phenotype exhibited a more than 7-fold increased risk [aHR 7.82 (95% CI: 6.34-9.64)]. Inclusion of the most severe cases of PCOS could have led to an overestimation of risk estimates. Information on BMI was only available among parous women. The study comprised mainly women with Nordic origin and should be replicated in cohorts with other ethnicities. Women with PCOS, especially those with the HA phenotype, face a substantially increased long-term risk of hypertension and dyslipidemia, highlighting the need for early cardiovascular risk assessment and preventive strategies in this population. The findings underscore that PCOS is not only a reproductive disorder but also a significant cardiovascular risk factor, warranting tailored prevention and management strategies. The study was funded by the Family Planning Fund, Uppsala, and the Selanders Fund, Uppsala University (grant number 464251850). Furthermore, E.E. has a part-time research position funded by Uppsala University Hospital (grant number ALF 937815). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. E.E. has received lecture fees from Merck AB, none in any way related to this manuscript. The rest of the authors declare no conflicts of interest. n/a.

Cardiovascular-kidney-metabolic (CKM) syndrome represents a continuum of interrelated adiposity, insulin resistance, cardiovascular disease, kidney dysfunction, and metabolic disturbances that evolve across the lifespan. Emerging evidence demonstrates that both biological sex and sociocultural gender significantly shape CKM risk, progression, and clinical expression. CKM syndrome pathogenesis reflects complex multisystem interactions involving adipose tissue dysfunction, neurohormonal activation, inflammatory signaling, and vascular impairment, all of which exhibit important sex-specific patterns. This review examines CKM syndrome from a sex- and gender-informed perspective, highlighting how endogenous and exogenous sex hormones, reproductive transitions, pregnancy-related complications, and dietary exposures shape the long-term CKM syndrome risk. Particular attention is given to the roles of estrogen and testosterone in modulating adipose biology, vascular function, and metabolic regulation. Polycystic ovary syndrome is discussed as a model of androgen excess and multisystem metabolic vulnerability that accelerates CKM features. Finally, we address brain vulnerability within CKM syndrome, emphasizing shared inflammatory, vascular, and neuroendocrine mechanisms linking metabolic dysfunction to cognitive decline and neuropsychiatric disorders. Recognizing these interconnected and sex-specific influences is critical for advancing precision prevention and treatment strategies across the CKM syndrome spectrum.

Polycystic ovarian syndrome (PCOS) is a complex hormonal condition marked by polycystic ovaries, inconsistent ovulation, and excess androgens. PCOS affects people of normal weight as well, yet it has historically been associated with obesity, which makes diagnosis challenging. Current diagnostic guidelines, like the Rotterdam criteria and the Androgen Excess and PCOS Society's, mostly concentrate on biochemical and clinical indicators. However, there is growing evidence that fasting insulin levels, C-peptide, and serum testosterone levels should be measured as further diagnostic criteria, especially for PCOS populations that are lean and obese. Online databases, including PubMed, Google Scholar, and Scopus, were searched to identify articles, review papers, and clinical guidelines published up to 2023. The justification, new data, and clinical implications of incorporating fasting insulin, C-peptide, and serum testosterone measurement into the diagnostic framework for PCOS were explored in this review. It also acknowledges the difficulties and potential avenues for future research. Metabolic markers like fasting insulin, C-peptide, and serum testosterone levels are increasingly being recognized as important in PCOS diagnosis, particularly in cases of lean PCOS. To standardize these tests and successfully incorporate them into clinical practice, however, further study and cooperation are required.

Asprosin, a fasting-induced adipokine, has been reported to exhibit altered circulating levels in women with polycystic ovary syndrome (PCOS); however, its tissue-specific regulation and the role of its receptor, OLFR734, in PCOS remain poorly understood. In this study, we present the first histological evidence of asprosin and OLFR734 expression in reproductive tissues using dehydroepiandrosterone-induced PCOS mouse models maintained on chow or a high-fat diet (HFD). Metabolic profiling revealed distinct phenotypes, with HFD-fed PCOS mice showing pronounced metabolic disturbances, including increased body weight, glucose intolerance, dyslipidemia, and elevated serum asprosin levels, compared with chow-fed PCOS mice. Asprosin was immunodetected in adipose tissue, ovary, oviduct, and uterus, with increased expression in both PCOS groups. In control ovaries, asprosin was restricted to the theca layer of Graafian follicles. In contrast, PCOS ovaries showed distinct asprosin expression patterns in the theca, granulosa cells, and the antrum of cystic follicles. Asprosin-positive cells were also observed in the oviduct and uterus, with distinct uterine localization in PCOS. OLFR734 showed a similar broad tissue distribution to asprosin, with upregulated expression in both PCOS diet groups. Notably, androgen excess and dietary fat exposure did not produce uniform or additive effects on tissue-level asprosin-OLFR734 expression but instead revealed tissue-specific response patterns under different dietary conditions. Collectively, our findings suggest a potential association of the asprosin-OLFR734 axis with reproductive changes in PCOS, linking metabolic and reproductive dysfunction under diet-induced stress. This work provides a histological and comparative framework, highlighting asprosin and OLFR734 as emerging molecular candidates in PCOS that warrant further investigation for their potential roles in disease pathophysiology.

Polycystic Ovary Syndrome i.e. PCOS is intricate endocrine-metabolic condition that alter women of reproductive age. It is differentiated by excess androgen, ovulatory failure, insulin resistance, and other metabolic anomalies. Despite the availability of traditional pharmaceutical medications, current treatment techniques are essentially symptomatic and are frequently limited by side effects, poor long-term adherence, and failure to address the disease's complex nature. As a result, there is increased interest in alternative and complementary therapies, notably herbal therapy, because of their multi-targeted mechanisms and favourable safety profiles. This review integrates evidence from experimental and clinical research to assess medicinal plants' potential for managing PCOS. The overall literature search was executed using databases such as ScienceDirect, PubMed, and Google Scholar. Medicinal plants like Glycyrrhiza glabra, Vitex agnus-castus, Cinnamomum verum, and Trigonella foenum-graecum have shown promise in altering critical pathophysiological pathways. These herbs have many pharmacological effects, including regulating the hypothalamic-pituitary-ovarian axis, improving insulin responsiveness, lowering androgen levels, and reducing oxidative stress and inflammation. Herbal remedies have been shown to enhance metabolic and reproductive parameters, although diversity in study design, formulations, and endpoints restricts their generalizability. Validating efficacy and safety requires welldesigned, large-scale randomized controlled trials and standardized formulations. Herbal treatments show promise for managing PCOS holistically and should be integrated into clinical practice based on research.

Polycystic ovary syndrome (PCOS) is associated with excessive ovarian androgen production, an increased number of ovarian follicles and a wide range of other endocrine and metabolic derangements, including endotoxemia. Metformin is often used in the treatment of PCOS, especially to improve glucose metabolism. This study evaluated the effects of metformin on endotoxemia, folliculogenesis and endocrine profiles. In a prospective trial, women with PCOS received metformin (500 mg t.i.d.) for three months and underwent baseline and post-treatment evaluations of their endocrine and metabolic profiles as well as detailed ultrasonographic evaluations of ovaries. Metformin treatment was associated with reduced lipopolysaccharides (LPSs) by 19% (P < 0.0001) and LPS-binding protein (LPB) by 26% (P < 0.0001). In parallel, the number of small antral follicles (<6 mm) declined by 8% (P = 0.005), total testosterone decreased by 13% (P = 0.0003), ovarian testosterone production in response to hCG declined by 73% (P = 0.03), and fasting insulin decreased by 19% (P = 0.02). The reduction in testosterone following treatment with metformin may be due to a combination of multiple effects of metformin, including improvement in endotoxemia, reduction in folliculogenesis and decreased insulin.Clinical trial registration number NCT03489668

Introduction: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting women of reproductive age, with multiple diagnostic criteria currently in use including Rotterdam, NIH, and AES criteria. However, the diagnostic accuracy of these criteria remains variable across populations. This systematic review aimed to evaluate and compare the diagnostic accuracy of different clinical diagnostic criteria for identifying PCOS in reproductive-age women. Methods: A systematic review of diagnostic accuracy studies was conducted. Studies were included if they evaluated at least one of the three specified diagnostic criteria (Rotterdam, NIH, or AES) against a reference standard in women of reproductive age (15-45 years). Diagnostic accuracy measures including sensitivity, specificity, and area under the ROC curve (AUC) were extracted. The quality of included studies was assessed using appropriate diagnostic accuracy assessment tools. Results: Eighty studies encompassing diverse populations across North America, Europe, Asia, Africa, and the Middle East were included. The Rotterdam criteria demonstrated strong diagnostic utility with follicle number per ovary showing the highest accuracy (sensitivity 84%, specificity 91%, AUC 0.905). NIH criteria identified fewer women (27.1% prevalence) compared to Rotterdam (40%) and showed an AUC of 0.80 for AMH as a diagnostic marker. AES criteria yielded intermediate prevalence (29.3%) with AMH sensitivity of 84.4% and specificity of 72% (AUC 0.857). Anti-Müllerian hormone emerged as a promising biomarker with age-specific thresholds ranging from 5.7 ng/mL (20-27 years) to 3.72 ng/mL (35-40 years). Replacing PCOM with AMH in Rotterdam criteria improved diagnostic accuracy (AUC 0.934-0.97). Significant geographic and ethnic variations in optimal thresholds were observed. Discussion: The Rotterdam criteria demonstrate superior sensitivity but may overdiagnose milder phenotypes, while NIH criteria identify metabolically high-risk women with greater specificity. AES criteria provide an intermediate approach emphasizing androgen excess. Age-stratified and population-specific thresholds are essential for optimal diagnostic accuracy. AMH shows promise as an objective alternative to ultrasound assessment of PCOM. Conclusion: No single diagnostic criterion is universally optimal; the choice of criteria should be guided by clinical context, population characteristics, and available resources. Age-stratified and population-specific thresholds, particularly for AMH and ultrasound parameters, are recommended to improve diagnostic accuracy.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hormonal and metabolic abnormalities. Mitsugumin-53 (MG53), a multifunctional E3 ubiquitin ligase, is implicated in insulin signaling and oxidative stress regulation, yet its role in PCOS remains unclear. This study aimed to investigate serum MG53 levels in women with PCOS and explore their associations with hormonal, metabolic, and ovarian parameters. In this case–control study, 64 women with PCOS and 64 healthy controls with comparable age were enrolled. Serum MG53 concentrations were measured by ELISA. Associations between MG53 and continuous variables were assessed using Spearman’s rank correlation. Independent determinants of MG53 were evaluated using multivariable linear regression (including age and BMI as covariates), and diagnostic performance for PCOS was assessed using receiver operating characteristic (ROC) analysis. Serum MG53 concentrations were lower in women with PCOS than in controls (median [IQR]: 124.4 [104.25–202.15] vs. 206.4 [131.63–316.58] pg/mL; p = 0.001). MG53 correlated positively with sex hormone–binding globulin (SHBG) (ρ = 0.274, p = 0.002) and inversely with ovarian follicle count (ρ = − 0.223, p = 0.011). In multivariable analysis, SHBG remained an independent positive determinant of MG53, whereas hirsutism and follicle count were independent negative predictors. MG53 demonstrated modest discrimination for PCOS (AUC = 0.667, 95% CI 0.569–0.762), with 57.8% sensitivity and 75.0% specificity at an exploratory cut-off of 131.1 pg/mL. Serum MG53 is reduced in PCOS and is associated with SHBG and features related to androgen excess and ovarian morphology. These cross-sectional findings support MG53 as a candidate biomarker reflecting metabolic–reproductive associations in PCOS; however, its diagnostic performance is modest and requires external validation.Trial registration Prospectively registered on ClinicalTrials.gov (NCT07094776) as an observational study.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-026-48800-z.