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

Jung-Chien Cheng; Lanlan Fang; Yiran Li; Sijia Wang; Yuxi Li; Yang Yan; Qiongqiong Jia; Ze Wu; Zhen Wang; Xiaoyu Han; Ying-Pu Sun

doi:10.1038/s12276-020-00491-w

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자료유형: 학술저널

저자정보: Jung-Chien Cheng (The First Affiliated Hospital of Zhengzhou University) Lanlan Fang (The First Affiliated Hospital of Zhengzhou University) Yiran Li (The First Affiliated Hospital of Zhengzhou University) Sijia Wang (The First Affiliated Hospital of Zhengzhou University) Yuxi Li (The First Affiliated Hospital of Zhengzhou University) Yang Yan (The First Affiliated Hospital of Zhengzhou University) Qiongqiong Jia (The First Affiliated Hospital of Zhengzhou University) Ze Wu (The First Affiliated Hospital of Zhengzhou University) Zhen Wang (The First Affiliated Hospital of Zhengzhou University) Xiaoyu Han (The First Affiliated Hospital of Zhengzhou University) Ying-Pu Sun (The First Affiliated Hospital of Zhengzhou University)

저널정보: 대한생화학·분자생물학회 Experimental and Molecular Medicine Experimental and Molecular Medicine 제52권

발행연도: 2020.8

수록면: 1 - 10 (10page)

DOI: 10.1038/s12276-020-00491-w

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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.

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