The mechanism of polycystic ovarian syndrome induced by circadian rhythm disturbance and the therapeutic effect of melatonin

Environmental factors are crucial causes of polycystic ovary syndrome (PCOS). There is growing evidence of an association between circadian rhythm disturbance and PCOS, but the underlying molecular mechanisms This study aimed to explore the molecular mechanism of PCOS induced by circadian rhythm disturbance and evaluate the therapeutic potential of melatonin. A rat model of circadian rhythm disturbance was established via 24-hour continuous light exposure. Rats were randomly divided into the Control group (normal circadian rhythm), Model group (continuous light exposure), and Model+Melatonin treatment group (continuous light exposure + melatonin). Reproductive endocrine indicators, ovarian histomorphology, and ovarian granulosa cell (GC) function were assessed. Additionally, circadian rhythms of serum hormones, autophagy-related markers (LC3), and hypothalamic clock genes were detected at six zeitgeber time (ZT) points. Autophagy and apoptosis levels in GCs, as well as the activation of MAPK and PI3K/Akt/mTOR pathways, were also detected. Continuous light exposure induced PCOS-like phenotypes in rats, characterized by disrupted estrous cycles, cystic ovarian changes, and loss of circadian rhythms in serum hormones, autophagy marker LC3, and hypothalamic clock genes. Moreover, continuous light exposure reduced GC viability, increased GC autophagy and apoptosis, activated the MAPK pathway, and inhibited the PI3K/Akt/mTOR pathway in GCs. Melatonin treatment significantly ameliorated these PCOS-like phenotypes. Our study showed circadian rhythm disturbance induced PCOS via MAPKs and PI3K/Akt/mTOR signaling pathways and increased autophagy level in rat ovarian GCs. Melatonin had a therapeutic effect on PCOS by reversing these signaling pathway abnormalities and reducing autophagy and apoptosis levels in GCs.