Androgen and glucocorticoid crosstalk in granulosa cells: molecular insights into polyendocrine metabolic ovarian syndrome

Abstract

Polyendocrine metabolic ovarian syndrome (PMOS), previously named polycystic ovary syndrome (PCOS) is a multifaceted endocrine-metabolic disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. At the cellular level, impaired folliculogenesis represents a key feature, with granulosa cells failing to optimally support follicle maturation, steroidogenesis, and oocyte competence. This review evaluates the hypothesis that granulosa cell dysfunction in PMOS may, in selected phenotypes, be prompted by altered molecular crosstalk between the androgen receptor and the glucocorticoid receptor. These two nuclear receptors integrate reproductive, metabolic, and stress-related signals within the ovarian microenvironment. Because androgen and glucocorticoid receptors share partially overlapping DNA-binding motifs and co-regulatory networks, their interaction may shape transcriptional programs governing proliferation, steroidogenesis, mitochondrial metabolism, and stress adaptation. Emerging evidence also highlights the contribution of adrenal-derived 11-oxygenated androgens, potent androgen receptor agonists, which amplify androgen signaling and reinforce the hyperandrogenic milieu. By integrating evidence from molecular, experimental, and patient-derived studies, this review proposes androgen and glucocorticoid receptor crosstalk as a plausible and testable regulatory framework, in PMOS pathophysiology with potential implications for biomarker discovery and future mechanism-based therapeutic strategies.