Redox-endocrine triad in PCOS: can vitamin D, myo-inositol, and melatonin synergize as bioactive cocktails?

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine–metabolic disorder in which reproductive dysfunction coexists with insulin resistance, chronic low-grade inflammation, and heightened oxidative stress (OS). Increasing evidence indicates that these abnormalities are not independent phenomena but components of a self-perpetuating redox-endocrine network that sustains hyperandrogenism, anovulation, and metabolic impairment. This review critically synthesizes experimental, translational, and clinical data to examine whether vitamin D, myo-inositol, and melatonin, three widely used but often studied in isolation bioactives, can act synergistically as a mechanistically coherent ‘bioactive cocktail’ in PCOS. Vitamin D modulates inflammatory tone and steroidogenic signaling through vitamin D receptor-dependent transcription and immune–metabolic crosstalk; myo-inositol restores insulin signaling via inositolphosphoglycan second-messenger pathways, thereby attenuating hyperinsulinemia-driven androgen excess; and melatonin exerts pleiotropic effects on mitochondrial function, circadian regulation, and redox balance. Therefore, these agents converge on shared molecular hubs, including NF-κB, Nrf2, PI3K/Akt, and AMPK, linking OS reduction with endocrine and metabolic recalibration. The review further integrates emerging insights into gut microbiota-adipokineinteractions, highlighting how dysbiosis and altered adipokine profiles amplify oxidative and hormonal disturbances, and how these bioactives may counteract such system-level disruptions. While existing clinical trials report improvements in ovulatory function, insulin resistance indices, and OS biomarkers, outcomes remain heterogeneous due to differences in dosing, duration, and phenotype stratification. We propose a redox-guided, phenotype-aware framework for future trials, emphasizing biomarker-anchored outcomes and systems-level integration. If validated, combined vitamin D, myo-inositol, and melatonin supplementation may represent a precision nutraceutical strategy that targets the pathogenic core of PCOS rather than its isolated clinical manifestations.