Hyperandrogen-induced imbalance of FOXO4-AR regulatory loop contributes to ovulatory disorders in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility, and its underlying mechanisms remain largely unknown. Our study aimed to investigate the role of FOXO4 in PCOS and its possible regulatory mechanisms. Decreased FOXO4 and CDKN1A expressions and increased androgen receptor (AR) and CCND1 expressions were observed in granulosa cells (GCs) from patients with PCOS. Luteinizing hormone (LH) surge induced upregulation of FOXO4 and CDKN1A and downregulation of AR and CCND1 <i>in vitro</i> and <i>in vivo</i>. FOXO4 inhibited cell proliferation and cell cycle progression and partially mediated the induction of CCND1 and CDKN1A expressions by LH surge. Knockdown of FOXO4 in rat ovaries led to a PCOS-like model, and hyperandrogenism was responsible for reduced FOXO4 expression in ovaries of PCOS <i>in vitro</i> and <i>in vivo</i>. AR-mediated androgen action is known to play a key role in the development of PCOS. Notably, AR repressed FOXO4 expression by binding to its promoter, whereas FOXO4 inhibited AR protein levels through protease degradation, thus establishing a regulatory loop between AR and FOXO4 that was disrupted by hyperandrogenism. This study demonstrates that hyperandrogenism inhibits LH surge formation and disrupts the regulatory balance between FOXO4 and AR, which may contribute to the continued exacerbation of PCOS.