Aysegul KARAHANOGLU, Mehmet Caner OZER, Yunus Kasim TERZI, Zerrin CELIK
Medical Science and Discovery - 2026;13(7):134-143
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-beta) 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.
