Abstract
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.
Highlights
Estradiol (E2), the most active form of natural estrogens, is a steroid hormone synthesized from ovarian granulosa cells that plays an important role in female reproduction
Melatonin stimulates aromatase expression in human granulosa-lutein (hGL) cells To examine the effect of melatonin on aromatase expression, primary hGL cells isolated from the follicular aspirates of women undergoing oocyte retrieval during in vitro fertilization (IVF) treatment were treated with different concentrations of melatonin (5, 50, or 500 μM) for 24 h
enzyme-linked immunosorbent assay (ELISA) showed that treatment of hGL cells with melatonin increased the release of E2 into the culture medium
Summary
Estradiol (E2), the most active form of natural estrogens, is a steroid hormone synthesized from ovarian granulosa cells that plays an important role in female reproduction. Cheng et al Experimental & Molecular Medicine (2020) 52:1341–1350 and hormones have been reported to regulate aromatase expression in granulosa cells. Ovarian hyperstimulation syndrome (OHSS) is a serious complication associated with COH. During COH, OHSS occurs after gonadotropin stimulation followed by human chorionic gonadotropin (hCG) administration. The risk of severe OHSS in an unselected population is ~2%; the incidence may be as high as 20% among high-risk patients. Some known risk factors for the development of OHSS have been identified, such as age 3500 pg/mL) are significantly associated with the development of OHSS7,8. It is known that a high ovarian follicle count may contribute to high serum E2 levels in OHSS. Whether the expression of aromatase varies between non-OHSS and OHSS patients has not been determined
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
