Induction of autophagy by Beclin-1 in granulosa cells contributes to follicular progesterone elevation in ovarian endometriosis

Abstract

Endometriosis is a common gynecological disease in which ovarian dysfunction can be an important cause of infertility. Elevated progesterone (P4) levels during the follicular phase is possibly associated with impaired oocyte quality and pregnancy outcome in endometriosis. Beclin-1 (BECN1), an essential mediator of autophagy, has been shown to be related to the development and progression of endometriosis. This study aimed to investigate the autophagic activity in ovarian granulosa cells (GCs) of patients with endometriosis and to clarify the role of BECN1 in preovulatory P4 elevation. Our results demonstrated that serum P4/estradiol (E2) ratio and P4-to-follicle index (the average P4 secretion per follicle) on the day of human chorionic gonadotropin administration were elevated in women with ovarian endometriosis. Increased expression of BECN1 and enhanced autophagy were observed in GCs of patients with ovarian endometriomas. In cultured GCs, BECN1 knockdown reduced P4 secretion and the expression of key steroidogenic enzymes; whereas overexpression of BECN1 resulted in induced P4 production with activated biosynthesis pathway. Moreover, inhibition of autophagy by BECN1 knockdown significantly attenuated low-density lipoprotein (LDL)-induced P4 synthesis. These findings provide new insights into the role of BECN1 in late follicular P4 elevation in patients with endometriosis by promoting the degradation pathway of LDL for P4 biosynthesis via lysosome activation in GCs, and have potential therapeutic implications for the improvement of oocyte quality in women affected by endometriosis.