Abstract / Summary
Polyendocrine metabolic ovarian syndrome (PMOS) is the name adopted in 2026 by the Global Name Change Consortium for the condition previously called polycystic ovary syndrome (PCOS); diagnostic criteria are unchanged, and a managed three-year transition to the new terminology is under way [1]. We use PMOS throughout, with PCOS retained where the historical term is needed for clarity. PMOS affects 5–20% of reproductive-age women worldwide, making it the single most common endocrine disorder in this population. Yet its pathogenesis defies simple explanation. What was once framed as an ovarian problem is now understood as a systemic, lifelong condition that interweaves metabolic, endocrine, immune, and neurological disturbances—carrying consequences that extend well beyond infertility to encompass type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), metabolic dysfunction-associated steatotic liver disease, significant psychiatric morbidity, adverse pregnancy outcomes, endometrial pathology, and impaired sexual function [2–5]. This review synthesizes current evidence around three deeply interconnected pathogenic axes. The first is neuroendocrine disruption: aberrant firing of Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons in the hypothalamic arcuate nucleus, coupled with a breakdown in steroid negative feedback, sustains the GnRH pulse generator at a pathologically rapid cadence. The second is immuno-metabolic dysregulation: a chronic low-grade inflammatory state, characterized by Treg/Th17 imbalance and NLRP3 inflammasome activation, engages in bidirectional amplification with insulin resistance and hyperandrogenism. The third is the genetic–epigenetic–environmental triad: GWAS-identified susceptibility loci, DNA methylation reprogramming, non-coding RNA networks, gut microbiome dysbiosis, and endocrine-disrupting chemical exposure collectively sculpt individual disease trajectories. Adopting a systems biology framework, we trace multi-organ crosstalk among the hypothalamus, ovary, adipose tissue, liver, and gut, and examine how the Developmental Origins of Health and Disease (DOHaD) paradigm accounts for intergenerational PMOS transmission through epigenetic memory. Because the syndrome is expressed differently at different life stages, we give particular attention to the adolescent diagnostic grey zone, in which physiological hypothalamic–pituitary–ovarian maturation overlaps with early disease, and we discuss 17-hydroxyprogesterone as a steroidogenic phenotyping and differential-diagnosis marker rather than as a PMOS-specific causal biomarker. From this integrated model, we identify emerging therapeutic targets—NK3R antagonists, NLRP3 inflammasome inhibitors, microbiome-directed interventions, and GLP-1 receptor agonists—that may enable precision management of this heterogeneous syndrome.Throughout, we distinguish association, experimental sufficiency, and established clinical utility, and a dedicated subsection sets out the evidential limits of the integrated model.