Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies—2nd Edition

Background: The most common female endocrinopathy is polycystic ovary syndrome (PCOS), affecting 10–20% of women of reproductive age. It is associated with a wide range of hormonal and biochemical abnormalities and long-term metabolic and cardiovascular risks. It is characterized by infertility due to chronic anovulation, hyperandrogenism, polycystic ovarian morphology, and is often associated with insulin resistance (IR) and obesity. Hyperinsulinemia further increases androgen production and reduces sex hormone-binding globulin (SHBG) levels, thereby aggravating symptoms. In addition, vitamin D deficiency is often present in PCOS patients, and increasing evidence suggests that it may also be associated with insulin resistance and hyperandrogenism. Objective: This study aimed to evaluate the relationships between insulin resistance, vitamin D deficiency, body mass index (BMI), and androgen levels in women with PCOS. Method: A cross-sectional study was conducted in which data from 195 women diagnosed with PCOS and not yet receiving therapy at a gynecologic endocrinology unit of a university-based tertiary clinical center, between 2019 and 2024, were analyzed. The parameters recorded were age, body mass index (BMI), 25(OH) vitamin D levels, androgen hormone levels (testosterone, androstenedione), glucose-insulin responses during a 3-point oral glucose tolerance test (OGTT). Statistical analyses, including linear regression, Pearson, and Spearman correlation tests were used to assess associations between variables. Results: The mean age of the patients was 24.8 years (18–42), and the mean BMI was 30.6 kg/m² (17–51). Vitamin D deficiency was observed in 84.1% of patients, hyperandrogenism in 45.8%, and insulin resistance in 44.5%. A significant inverse correlation was found between BMI and vitamin D levels (r = −0.31, p =< 0.01) indicating that higher BMI is associated with lower vitamin D status. Similarly, BMI also showed a significant negative correlation with SHBG levels (r = –0.45, p < 0.01), suggesting that increasing body weight is linked to reduced SHBG concentrations. In addition, BMI was significantly positively correlated with 2 h insulin levels (r = 0.43, p =< 0.01) and with testosterone levels (r = 0.21, p = 0.01). These findings suggest that increased adiposity intensifies insulin resistance and is linked to both vitamin D deficiency and elevated androgen levels. Moreover, the combination of hyperinsulinemia and low vitamin D further disrupts hormonal balance by promoting ovarian androgen production and decreasing SHBG levels, thereby increasing the bioavailability of testosterone. A significant inverse correlation was found between vitamin D levels and 2 h insulin levels (r = −0.28, p =< 0.01), indicating that lower vitamin D status is associated with increased insulin resistance. Furthermore, 2 h insulin levels showed a significant positive correlation with testosterone levels (r = 0.32, p =< 0.01), suggesting that greater insulin resistance is linked to higher androgen production. Additionally, vitamin D levels were inversely correlated with testosterone (r = −0.18, p = 0.02), demonstrating that a lower vitamin D status may further contribute to the hyperandrogenic environment. Vitamin D levels also showed a significant positive correlation with SHBG concentrations (r = 0.29, p < 0.01), indicating that a higher vitamin D status may be associated with increased SHBG levels. In contrast, 2 h insulin levels were inversely correlated with SHBG (r = −0.43, p < 0.01), reflecting the suppressive effect of hyperinsulinemia on SHBG production. Conclusions: Insulin resistance, BMI, and vitamin D deficiency are closely related to each other and to the severity of PCOS, which is confirmed by the correlations with androgen levels. The revealed relationships draw attention to the special importance of vitamin D supplementation and the correction of carbohydrate metabolism in alleviating the symptoms of the disease and reducing long-term health risks. Full article

Background: Recent literature suggests that ferroptosis (FPT) may be a key player in polycystic ovary syndrome (PCOS) pathogenesis, but the underlying mechanism(s) remain(s) unclear. Aim: Therefore, herein, we made an effort to reproduce the molecular signature of the syndrome by including FPT and exploring novel drug targets for PCOS. Methods: (a) Our previously constructed PCOS interactions molecular network was extended with the addition of FPT–associated genes (interaction score above 0.7) and (b) gene set enrichment analysis was performed so as to detect over-represented KEGG pathways. Results: The updated interactome includes 140 molecules, 20 of which are predicted/novel, with an interaction score of 7.3, and 12 major hubs. Moreover, we identified 16 over-represented KEGG pathways, with FPT being the most overexpressed pathway. The FPT subnetwork is connected with the PCOS network through KDM1A. Conclusions: FPT cell death is involved in PCOS development, as its major hub TP53 was shown to be the most important hub in the whole PCOS interactome, hence representing a prioritized drug target. Full article

Background: Polycystic ovary syndrome (PCOS) is a complex and multifactorial disorder affecting reproductive, endocrine, and metabolic functions in women of reproductive age. While environmental and lifestyle factors play a role, increasing evidence highlights the contribution of genetic and epigenetic mechanisms to its pathogenesis. Objective: This narrative review aims to provide an updated overview of the current evidence regarding the role of genetic variants, gene expression patterns, and epigenetic modifications in the etiopathogenesis of PCOS, with a focus on their impact on ovarian function, fertility, and systemic alterations. Methods: A comprehensive search was conducted across MEDLINE, EMBASE, PubMed, Web of Science, and the Cochrane Library using MeSH terms including “PCOS”, “Genes involved in PCOS”, and “Etiopathogenesis of PCOS” from January 2015 to June 2025. The selection process followed the SANRA quality criteria for narrative reviews. Seventeen studies published in English were included, focusing on original data regarding gene expression, polymorphisms, and epigenetic changes associated with PCOS. Results: The studies analyzed revealed a wide array of molecular alterations in PCOS, including the dysregulation of SIRT and estrogen receptor genes, altered transcriptome profiles in cumulus cells, and the involvement of long non-coding RNAs and circular RNAs in granulosa cell function and endometrial receptivity. Epigenetic mechanisms such as the DNA methylation of TGF-β1 and inflammation-related signaling pathways (e.g., TLR4/NF-κB/NLRP3) were also implicated. Some genetic variants—particularly in DENND1A, THADA, and MTNR1B—exhibit signs of positive evolutionary selection, suggesting possible ancestral adaptive roles. Conclusions: PCOS is increasingly recognized as a syndrome with a strong genetic and epigenetic background. The identification of specific molecular signatures holds promise for the development of personalized diagnostic markers and therapeutic targets. Future research should focus on large-scale genomic studies and functional validation to better understand gene–environment interactions and their influence on phenotypic variability in PCOS. Full article