Lithium chloride inhibits StAR and progesterone production through GSK-3β and ERK1/2 signaling pathways in human granulosa-lutein cells

Lithium chloride (LiCl) is a widely-used medication to treat neurological disorders that has undesirable side effects on the female reproductive system. It has been show that LiCl can inhibit ovarian folliculogenesis, promote follicle atresia and suppress steroid hormone production in rodents. However, the effects of LiCl on human ovarian steroidogenesis remain completely unknown. In this study, both primary and immortalized human granulosa-lutein (hGL) cells were used to investigate the effects of LiCl on progesterone production and its related enzyme expression as well as the underlying mechanisms. Our results showed that LiCl significantly down-regulated the steroidogenic acute regulatory protein (StAR) expression and subsequent progesterone production in hGL cells. Additionally, LiCl induced the phosphorylation of GSK-3β and ERK1/2 but not AKT or CREB. Knockdown of endogenous GSK-3β or inhibition of ERK1/2 partially reversed LiCl-induced down-regulation of StAR. Furthermore, by using dual inhibition approaches, the results showed that both GSK-3β and ERK1/2 signaling mediated the regulatory effect of LiCl on StAR expression. Our findings deepen our understanding of the pathological effects and the underlying molecular mechanisms of how lithium might affect the female reproductive system.