Follicular development impairment in polyendocrine metabolic ovarian syndrome: multidimensional pathophysiological networks and frontier therapeutic targets

Abstract

Polyendocrine metabolic ovarian syndrome (PMOS) is a prevalent endocrine-metabolic disorder characterised by follicular arrest, anovulation, and elevated androgen levels. This review transcends single-dimensional analyses of PMOS pathology from neuroendocrine or metabolic perspectives, proposing an integrated multi-layered network model to systematically elucidate the pathological mechanisms underlying follicular arrest. Post-pubertal dysfunction of the hypothalamic-pituitary-ovarian axis interacts with systemic metabolic dysregulation, jointly establishing an ovarian microenvironment characterised by hyperandrogenism, hyperinsulinaemia, and chronic inflammation. This environment further induces self-reinforcing vicious cycles within follicles, manifesting as impaired granulosa-oocyte communication, immunometabolic reprogramming (e.g., M1 macrophage polarisation), and organelle stress (including mitochondrial dysfunction and endoplasmic reticulum stress). This localised cycle is consolidated and amplified by higher-level regulatory factors—including developmental epigenetic programming, the gut-brain-ovary axis, and circadian rhythms—ultimately establishing a pathologically entrenched state. Finally, this network-based understanding informs future research pathways, focusing on how emerging strategies—such as multi-omics integration, artificial intelligence, and stem cell secretome studies—can advance phenotype-directed precision interventions. This review aims to provide a systematic, dynamic theoretical framework for understanding the complex pathogenesis of PMOS and its potential therapeutic targets.