Melatonin Protects against Primary Ovarian Insufficiency by Activating the PI3K/Akt/mTOR Pathway and Inhibiting Autophagy.

OBJECTIVE: Primary ovarian insufficiency (POI), which refers to the occurrence of ovarian insufficiency before the age of 40, is indicated by menstrual cycle changes as a precursor and is accompanied by menstrual disorders, elevated gonadotropin levels, and decreased estrogen levels. The incidence of POI is reportedly increasing worldwide and this disease markedly reduces the quality of life and affects the physical and mental health of patients. Treatment options for POI include hormone replacement therapy; however, its efficacy remains unsatisfactory. Therefore, exploring hormonal drugs with superior curative effects and clarifying the molecular mechanism underlying POI pathogenesis could afford new directions for POI therapy. METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays were used to detect the effects of melatonin (MT) on cell survival and mortality. Flow cytometry was performed to examine the effect of MT on apoptosis. The impact of MT on autophagosome formation was examined using electron microscopy, whereas the expression of autophagy-related proteins and phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway-related proteins following MT intervention was detected by western blotting. RESULTS: (1) MT exerted a protective effect on ovarian granulosa cells subjected to serum starvation. (2) MT inhibited serum starvation-induced apoptosis of ovarian granulosa cells. (3) MT inhibited serum starvation-induced autophagosome formation in ovarian granulosa cells. (4) MT inhibited the expression of autophagy-related proteins LC3II/I and Agt5. (5) MT suppressed autophagy in ovarian granulosa cells by activating the PI3K/Akt/mTOR signaling pathway. CONCLUSION: Collectively, our results demonstrate that MT can inhibit excessive autophagy in ovarian granulosa cells by activating the PI3K/Akt/mTOR pathway, thereby exerting its protective effect against POI.