Melatonin stimulates aromatase expression and estradiol production in human granulosa-lutein cells: relevance for high serum estradiol levels in patients with ovarian hyperstimulation syndrome

摘要

Ovarian hyperstimulation syndrome (OHSS) is one of the most life-threatening and potentially fatal complications associated with controlled ovarian hyperstimulation (COH) during in vitro fertilization (IVF) treatment. Although the pathogenesis of OHSS remains unclear, elevated serum estradiol (E2) levels before human chorionic gonadotropin (hCG) administration are associated with the risk of OHSS. The pineal hormone melatonin and its receptors are expressed in human granulosa cells and have been shown to stimulate E2 production. However, the effect of melatonin on the expression of aromatase, an enzyme responsible for a key step in the biosynthesis of E2, in human granulosa cells remains to be determined. Here, we demonstrate that melatonin upregulates aromatase expression in primary cultured human granulosa-lutein (hGL) cells through the melatonin receptor-mediated PKA-CREB pathway. Using a mouse model of OHSS, we demonstrate that administration of the melatonin receptor inhibitor luzindole inhibits the development of OHSS. In addition, the expression of ovarian aromatase and serum E2 levels are upregulated in OHSS mice compared to control mice, but this upregulation is attenuated by inhibition of the function of melatonin. Moreover, clinical results reveal that aromatase expression levels are upregulated in hGL cells from OHSS patients. Melatonin and E2 levels in the follicular fluid are significantly higher in OHSS patients than in non-OHSS patients. Furthermore, melatonin levels are positively correlated with E2 levels in follicular fluid. This study helps to elucidate the mechanisms mediating the expression of aromatase in hGL cells and provides a potential mechanism explaining the high E2 levels in patients with OHSS. Reproductive medicine: Melatonin implicated in complication of assisted fertilization Blocking the activity of melatonin helps prevent female mice from developing swollen ovaries, a potentially life-threatening complication of assisted fertilization techniques. A research team from China’s First Affiliated Hospital of Zhengzhou University, led by Jung-Chien Cheng and Ying-Pu Sun, demonstrated that melatonin, a hormone found in the fluid that surrounds developing eggs, can induce ovarian cells to boost expression of aromatase. This enzyme is responsible for synthesizing estradiol, a hormone involved in female reproduction. Women whose ovaries became over-stimulated in response to fertility medications showed elevated levels of melatonin, aromatase and estradiol. Inhibiting the function of melatonin reduced symptoms in mouse models of ovarian hyperstimulation syndrome. The findings reveal an important role of melatonin in ovarian enlargement and point to new therapeutic strategies for women undergoing in vitro fertilization.