ER Stress Activated by Androgen Enhances Apoptosis of Granulosa Cells via Induction of Death Receptor 5 in PCOS.

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and growth arrest of antral follicles. Previously, we found that endoplasmic reticulum (ER) stress is activated in granulosa cells of antral follicles in PCOS, evidenced by activation of unfolded protein response (UPR) genes. Based on this observation, we hypothesized that ER stress is activated by androgens in granulosa cells of antral follicles, and that activated ER stress promotes apoptosis via induction of the UPR transcription factor C/EBP homologous protein (CHOP) and subsequent activation of death receptor (DR) 5. In this study, we found that testosterone induced expression of various UPR genes, including CHOP, as well as DR5, in cultured human granulosa-lutein cells (GLCs). Pretreatment with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) inhibited testosterone-induced apoptosis and expression of DR5 and CHOP. Knockdown of CHOP inhibited testosterone-induced DR5 expression and apoptosis, and knockdown of DR5 inhibited testosterone-induced apoptosis. Pretreatment with flutamide, as well as knockdown of androgen receptor (AR), decreased testosterone-induced DR5 and CHOP expression, as well as apoptosis. Expression of DR5 and CHOP was upregulated in GLCs obtained from PCOS patients, and in granulosa cells of antral follicles in ovarian sections obtained from PCOS patients and dehydroepiandrosterone (DHEA)-induced PCOS mice. Treatment of PCOS mice with TUDCA decreased apoptosis and DR5 expression in granulosa cells of antral follicles, with a concomitant reduction in CHOP expression. Together, our findings indicate that ER stress activated by hyperandrogenism in PCOS promotes apoptosis of granulosa cells of antral follicles via induction of DR5.