Melatonin stimulates aromatase expression and estradiol production in human granulosa-lutein cells: relevance for high serum estradiol levels in patients with ovarian hyperstimulation syndrome.
Melatonin stimulates aromatase expression and estradiol production in human granulosa-lutein cells: relevance for high serum estradiol levels in patients with ovarian hyperstimulation syndrome.
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DOI：
10.1038/s12276-020-00491-w
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发表时间：
2020-08
影响因子：
12.8
通讯作者：
Sun YP
中科院分区：
文献类型：
--
作者：
Cheng JC;Fang L;Li Y;Wang S;Li Y;Yan Y;Jia Q;Wu Z;Wang Z;Han X;Sun YP
卵巢过度刺激综合征（OHSS）是体外受精（IVF）治疗中与控制性卵巢过度刺激（COH）相关的最危及生命和潜在致命的并发症之一。虽然OHSS的发病机制尚不清楚，但在人绒毛膜促性腺激素（hCG）给药前血清雌二醇（E2）水平升高与OHSS的风险相关。松果体激素褪黑激素及其受体在人类颗粒细胞中表达，并已被证明刺激E2的产生。然而，褪黑激素对人颗粒细胞芳香化酶（负责E2生物合成关键步骤的酶）表达的影响仍有待确定。在这里，我们证明褪黑激素通过褪黑激素受体介导的PKA-CREB途径上调原代培养的人颗粒黄体（hGL）细胞中芳香酶的表达。使用小鼠OHSS模型，我们证明了褪黑素受体抑制剂luzindole的管理抑制OHSS的发展。此外，卵巢芳香化酶的表达和血清E2水平上调OHSS小鼠相比，对照组小鼠，但这种上调减弱的褪黑素的功能的抑制。此外，临床结果表明，芳香化酶的表达水平上调hGL细胞从OHSS患者。OHSS患者卵泡液中褪黑素和E2水平显著高于非OHSS患者。此外，褪黑激素水平与卵泡液中的E2水平呈正相关。本研究有助于阐明芳香化酶在hGL细胞中表达的介导机制，并为解释OHSS患者高E2水平提供了一个潜在的机制。阻断褪黑激素的活性有助于防止雌性小鼠卵巢肿胀，这是辅助受精技术的一种可能危及生命的并发症。来自中国郑州大学第一附属医院的一个研究小组，由Jung-Chien Cheng和Ying-Pu Sun领导，证明了褪黑激素，一种在发育中的卵子周围的液体中发现的激素，可以诱导卵巢细胞促进芳香化酶的表达。这种酶负责合成雌二醇，一种参与女性生殖的激素。那些卵巢因生育药物而过度刺激的妇女，其褪黑激素、芳香酶和雌二醇水平升高。抑制褪黑激素的功能可以减轻卵巢过度刺激综合征小鼠模型的症状。研究结果揭示了褪黑激素在卵巢增大中的重要作用，并为接受体外受精的妇女提供了新的治疗策略。
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. 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.
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影响因子：
5.8
作者：
DOODY, KJ;LORENCE, MC;SIMPSON, ER
通讯作者：
SIMPSON, ER
影响因子：
5.8
作者：
Chen, Hui;Guo, Jing Hui;Chan, Hsiao Chang
通讯作者：
Chan, Hsiao Chang
影响因子：
2.1
作者：
Bódis, J;Koppán, M;Török, A
通讯作者：
Török, A
DOI：
10.1023/b:jarg.0000027016.65749.ad
发表时间：
2004-03-01
影响因子：
3.1
作者：
Hendriks, DJ;Klinkert, ER;Broekmans, FJ
通讯作者：
Broekmans, FJ
影响因子：
--
作者：
Kumar P;Sait SF;Sharma A;Kumar M
通讯作者：
Kumar M