Pathophysiological Mechanisms and Systemic Complications of Polycystic Ovary Syndrome: Endocrine, Metabolic, and Neuroendocrine Targets in Infertility Management

Background: Polycystic Ovary Syndrome (PCOS) is a complex, heterogeneous endocrine disorder affecting women of reproductive age. It is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology, with substantial metabolic and neuroendocrine involvement. Beyond infertility, PCOS is associated with insulin resistance, chronic inflammation, cardiometabolic risk, and psychological comorbidities. Understanding the integrated mechanisms underlying reproductive dysfunction is critical for targeted infertility management. Objective: To review the endocrine, metabolic, and neuroendocrine mechanisms contributing to infertility in PCOS and to summarize current and emerging therapeutic targets aimed at restoring ovulation and improving long-term health outcomes. Methods: This narrative review synthesizes current evidence from clinical trials, mechanistic studies, and international guidelines focusing on ovarian dysfunction, insulin resistance, neuroendocrine dysregulation, systemic complications, and therapeutic interventions in PCOS-related infertility. Results: PCOS pathophysiology involves disrupted folliculogenesis, theca cell hyperactivity, and altered steroidogenesis leading to hyperandrogenism. Abnormal pulsatile secretion of gonadotropin-releasing hormone (GnRH) contributes to elevated LH/FSH ratios and ovulatory failure. Insulin resistance and compensatory hyperinsulinemia exacerbate androgen excess and impair ovarian function through PI3K/Akt and MAPK signaling pathways. Chronic low-grade inflammation and adipose tissue dysfunction further amplify metabolic disturbances. Therapeutic strategies include ovulation induction (letrozole, clomiphene citrate), gonadotropin therapy, insulin sensitizers (metformin, inositols), lifestyle modification, neuroendocrine modulation (kisspeptin analogs), and emerging agents such as GLP-1 receptor agonists. Integrated, phenotype-driven approaches demonstrate improved reproductive and metabolic outcomes. Conclusion: Infertility in PCOS results from intertwined endocrine, metabolic, and neuroendocrine abnormalities. Effective management requires multi-target strategies that address both reproductive dysfunction and systemic risk factors. Future directions emphasize biomarker-guided therapy, precision medicine approaches, and translational research to optimize individualized infertility care and long-term health.