The transition from polycystic ovary syndrome (PCOS) to polyendocrine metabolic ovarian syndrome (PMOS) acknowledges that ovarian cysts do not define the disorder and that endocrine-metabolic dysfunction is central to its biology. However, PMOS remains anatomically ovarian in terminology. The Experts Group on Inositol in Basic and Clinical Research and on PCOS∙PMOS (EGOI PCOS∙PMOS) has proposed a further reclassification in which the hyperandrogenic insulin-resistant forms formerly corresponding to Rotterdam phenotypes A, B, and C are considered endocrine-metabolic syndrome (EMS). In contrast, normoandrogenic phenotype D is separated as multi-follicular ovarian disorder (MFOD). This article proposes that the pathophysiology of EMS may involve tissue-specific myo-inositol depletion and an altered myo-inositol/D-chiro-inositol ratio. Myo-inositol supports insulin signaling, glucose uptake, FSH responsiveness, granulosa-cell function, and cellular phosphoinositide signaling; D-chiro-inositol participates in insulin-mediated glycogen storage and, in the ovary, may promote an androgenic microenvironment through insulin-dependent steroidogenesis and aromatase down-regulation. We hypothesize that systemic insulin resistance induces hyperinsulinemia, while ovarian insulin sensitivity is preserved, thereby increasing local epimerase activity and conversion of myo-inositol to D-chiro-inositol. The resulting ovarian myo-inositol depletion and altered myo-inositol/D-chiro-inositol ratio may impair dominant follicular selection and promote androgen excess. The model may also help explain thyroid, cardiometabolic, neuroendocrine, and respiratory comorbidities, while valproate-associated PMOS-like phenotypes and lithium-induced inositol perturbation provide complementary pharmacological clues. This hypothesis generates testable predictions for follicular-fluid metabolomics, ovarian tissue studies, and phenotype-stratified trials.
