Melatonin as an endogenous hormone to slow down the exhaustion of ovarian follicle reserve in mice–a novel insight into its roles in early folliculogenesis and ovarian aging

Abstract Previous studies have shown that long-term intake of exogenous melatonin can effectively delay ovarian aging, but the mechanism has not been fully elucidated. We observed that SNAT, the rate-limiting enzyme in the melatonin synthetic pathway, is localized in primordial and early follicle, and that granulosa cells isolated from follicle can synthesize melatonin. In vitro cultured neonatal mice ovaries with melatonin inhibited primordial follicle activation and early follicle growth. In vivo experiments further indicated that daily injections of melatonin to neonatal mice during the primordial follicle activation phase can reduce the number of activated follicles by inhibiting the PI3K-AKT-FOXO3 pathway; during the early follicle growth phase, injections of melatonin significantly suppressed early follicle growth and atresia, and transcriptome data showed that multiple pathways involved in folliculogenesis, including PI3K-AKT, were suppressed. Further, SNAT knockout in mice resulted in a significant increase in follicle activation and atresia, and eventually accelerated ovarian aging. We also demonstrated that prolonged high-dose melatonin intake had no obvious adverse effect on the health condition of mice. This study confirms that endogenous melatonin is involved in the regulation of ovarian aging, and reveals that melatonin delays ovarian aging by inhibiting primordial follicle activation, early follicle growth and atresia.