AKT1 and neoplasm: Life signals are induced by estradiol via AKT-pathway through the nuclear receptor and a membrane GPCR, resulting in the regulation of ovarian functions [47], trophoblast invasion [48], cell tumor growth [49], etc. The experimental evidence that pro-apoptotic effects mediated by gonadotropins are blocked by estradiol may explain why high doses of exogenous gonadotropins used for ART, i.e., FSH and hCG, induce multi-follicular ovulation instead of atresia in vivo.