Physiopathology of PMOS from a Neuroendocrine Perspective

Polyendocrine metabolic ovarian syndrome (PMOS) is the most common reproductive and cardiometabolic disorder in women of reproductive age. Once viewed as primarily an ovarian disease, it is now recognized as a neuroendocrine-metabolic disorder driven by dysregulation of the hypothalamic-pituitary-gonadal axis. A central feature of the syndrome is increased gonadotropin releasing hormone (GnRH) pulsatility, which drives excess luteinizing hormone (LH) secretion, disrupts the LH/follicle stimulating hormone (FSH) balance, and promotes ovarian androgen excess and anovulation. Hypothalamic Kisspeptin neurons, the principal regulators of GnRH pulse generation, show altered activity and impaired steroid feedback sensitivity. Anti-Müllerian hormone (AMH) has emerged as an ovary-to-brain signal that directly stimulates GnRH neurons and remodels the neuroendocrine interface, amplifying LH secretion and perpetuating reproductive dysfunction. Developmental programming, through interactions among genetic, environmental, and epigenetic factors, may durably alter the organization and function of hypothalamic circuits, predisposing to neuroendocrine dysfunction later in life. In parallel, metabolic dysfunction, including insulin resistance and adipose tissue dysfunction, can interact bidirectionally with reproductive and neuroendocrine pathways, reinforcing hyperandrogenism and perturbing both reproductive and energy homeostasis. This review summarizes current knowledge of the neuroendocrine mechanisms underlying PMOS and discusses emerging targeted therapies that may offer disease-modifying approaches for this prevalent and heterogeneous disorder.