The developmental, genetic, and epigenetic basis of polyendocrine metabolic ovarian syndrome

Polycystic ovary syndrome (PCOS) is the most common reproductive and endocrine disorder affecting women in their reproductive age. PCOS is characterized by clustering of reproductive disturbances, including, but not limited to, hypothalamus-pituitary-ovarian axis dysfunction, chronic anovulation, excess androgen, and subfertility. PCOS extends beyond reproductive dysfunction to involve metabolic, endocrine, and cardiometabolic abnormalities. Therefore, it has recently been redefined as polyendocrine metabolic ovarian syndrome (PMOS). Despite the evolution of diagnostic criteria for PMOS in recent decades, there persists a knowledge gap regarding its origins and pathophysiology. Genetic studies have identified candidate genes associated with PMOS, but genetic factors alone cannot account for its varied phenotypes. The diverse phenotypes observed in PMOS instead point to a complex gene-environment interaction, thereby paving the way for epigenetic mechanisms to explain this heterogeneous trait. Emerging evidence suggests that epigenetic alterations during critical developmental periods, particularly in utero and during puberty, may contribute to the reproductive, metabolic, and endocrine manifestations of PMOS. These observations may re-frame PMOS as a developmental disorder that follows the developmental origin of health and disease (DOHaD) theory. In this review, we propose a comprehensive framework to address the complexity of PMOS pathogenesis and phenotypes. We investigated how environmental exposures during critical windows may shape the epigenome and contribute to PMOS development. The review also examines the biological rationale of the 2023 International Evidence-based Guideline for PCOS, including the use of anti-Müllerian hormone, postponing diagnosis until after puberty, and recommendations for healthy lifestyle behaviors.