Abstract
Steroidogenic acute regulatory protein (StAR) mediates the rate-limiting step in ovarian steroidogenesis and progesterone (P4) synthesis. Melatonin and its receptors are expressed in human granulosa cells, and have been shown to influence basal P4 production. However, previous studies addressing the regulation of StAR expression by melatonin and its impact on P4 secretion yielded contradictory results. Here, we demonstrate that melatonin upregulates StAR expression in primary cultures of human granulosa-lutein (hGL) cells obtained from women undergoing in vitro fertilization (IVF). Using pharmacological inhibitors, we show that the stimulatory effect of melatonin on StAR expression is mediated via both MT1 and MT2 melatonin receptors. Melatonin exposure activates the PI3K/AKT signaling pathway and its inhibition attenuates the stimulatory effect of melatonin on StAR expression. Moreover, siRNA-mediated knockdown of StAR abolishes melatonin-induced P4 production. Importantly, clinical analyses demonstrate that melatonin levels in human follicular fluid are positively correlated with P4 levels in serum. By illustrating the potential physiological role of melatonin in the regulation of StAR expression and P4 production in hGL cells, our results may serve to improve current strategies used to treat clinical infertility.
Highlights
Human reproduction is profoundly influenced by age [1]
To examine the effect of melatonin on steroidogenic acute regulatory protein (StAR) expression, human granulosa-lutein (hGL) cells isolated from follicular aspirates of women undergoing oocyte retrieval during in vitro fertilization (IVF) treatment were treated with different concentrations of melatonin for 24 h
Time-course expression experiments revealed that 12 h melatonin treatment caused a slight, non-significant upregulation of StAR protein levels, while significant upregulation was observed after 24 h of treatment (Figure 1C)
Summary
Human reproduction is profoundly influenced by age [1]. Ovarian granulosa cells transform into granulosa-lutein (hGL) cells that produce progesterone (P4), an essential steroid hormone that regulates luteinization and maintains the early stages of pregnancy. In patients undergoing in vitro fertilization (IVF), premature luteinization is defined as an increase in serum P4 levels before or on the day of human chorionic gonadotropin (hCG) administration. Several studies have demonstrated that premature luteinization is associated with decreased implantation and pregnancy rates [2, 3]. Insufficient ovarian P4 production (i.e. luteal phase deficiency) is associated with dysfunction of the secretory endometrium, which compromises successful embryo implantation and growth [4]. A precise regulation of P4 secretion in hGL cells is required to maintain normal reproductive functions
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