Figure 6.

Mel prevents Cyc-induced over-activation of primordial follicles through inhibiting ovarian granulosa cell apoptosis and maintaining AMH expression. During normal follicle development, very few primordial follicles are selected and activated, whereas the vast majority of primordial follicles are maintained in a dormant state. AMH is mainly produced by granulosa cells in secondary follicles and early antral follicles. AMH can inhibit the activation of primordial follicles during recruitment and inhibit the sensitivity of antral follicles to FSH during recruitment cycle, thus maintaining AMH levels and selective activation of primordial follicle pool. Cyc exposure disturbs the balance of follicle activation by increasing apoptosis of AMH-secreting granulosa cells in growing follicles, resulting in further decrease of AMH levels and indirect over-activation of primordial follicle pool. Eventually, activated follicles undergo apoptosis and more primordial follicles are stimulated to become activated primary follicles, resulting in POF. With Mel co-treatment, activation of primordial follicles is reduced and apoptosis of AMH-secreting granulosa cells in growing follicles is decreased. Surviving granulosa cells maintained normal levels of AMH production, which regulates natural recruitment of primordial follicles and oogenesis. Hence, Mel restores the balance of follicle activation and returns ovaries to a healthy state.