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PubMed2026

From Gene Function to Precision Intervention: CRISPR/Cas9 and Stem Cell-Based Strategies as Emerging Disease-Modifying Approaches in PMOS.

Polyendocrine metabolic ovarian syndrome (PMOS) is a complex endocrine-metabolic disorder affecting up to 18% of women worldwide and remains the leading cause of anovulatory infertility. Despite extensive research, current treatments primarily target symptoms, including menstrual irregularities, hyperandrogenism, and metabolic dysfunction, without addressing the underlying molecular and tissue-level disturbances. Advances in multi‑omic profiling have identified disruptions across neuroendocrine, metabolic, inflammatory, and extracellular matrix pathways, alongside genetic susceptibility at loci such as DENND1A, CYP17A1, LHCGR, FSHR, IRS1, and PPARG. However, the functional roles of many variants remain unresolved. CRISPR/Cas9 gene editing enables precise interrogation of these pathways, while stem cell-based platforms, including mesenchymal stem cells (MSCs), exosomes, and gene-edited induced pluripotent stem cells (iPSCs), may serve as complementary platforms for regeneration and disease modeling. Preclinical studies demonstrate that MSCs and their derivatives modulate inflammation, restore ovarian structure, and improve metabolic parameters, while iPSC-based models enable patient-specific investigation of steroidogenic and metabolic abnormalities. Translational challenges remain, including targeted delivery, off-target effects, phenotypic heterogeneity, and regulatory considerations. Integrating CRISPR‑based functional genomics with stem cell research may shift PMOS management from symptom‑focused care to targeted, mechanism‑driven interventions that could modify the course of PMOS (Graphical Abstract).

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.

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PubMed2026

Genomic relationship between polyendocrine metabolic ovarian syndrome and bipolar disorder.

Women with bipolar disorder (BIP) have a higher risk of developing polyendocrine metabolic ovarian syndrome (PMOS). Shared genetic architecture may underlie this comorbidity. Valproate, a mood-stabilizer commonly used to treat BIP, increases the risk of PMOS. Still, the mechanism underlying PMOS in BIP remains unknown. Here, we aimed to identify genetic variants shared between BIP and PMOS, 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 PMOS (3609 cases and 229,788 controls). Using conditional false discovery rate, we discovered genetic variants jointly associated with BIP and PMOS. 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 PMOS. Among the 10 genes mapped to the locus on chromosome 8:11,444,837-11,463,015, GATA4, NEIL2, and FDFT1 showed expression profiles suggesting their role in the observed comorbidity. Mapped to the locus on chromosome 12:2499,849-2514,270, CACNA1C, FKBP4, DCP1B, and ITFG2 are expressed in both the ovaries and the brain. Valproate interacts with CACNA1C, and CACNA1C is part of biological pathways that also include other genes interacting with valproate. We identified shared genetic underpinnings of BIP and PMOS and highlighted genes that may potentially contribute to the biological mechanisms underlying their comorbidity and to a hypothesized role of valproate in these mechanisms.

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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.

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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

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↗

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.

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