Impaired CFTR-Dependent Amplification of FSH-Stimulated Estrogen Production in Cystic Fibrosis and PCOS
Impaired CFTR-Dependent Amplification of FSH-Stimulated Estrogen Production in Cystic Fibrosis and PCOS
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DOI：
10.1210/jc.2011-1363
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发表时间：
2012-03-01
影响因子：
5.8
通讯作者：
Chan, Hsiao Chang
中科院分区：
文献类型：
--
作者：
Chen, Hui;Guo, Jing Hui;Chan, Hsiao Chang
背景：雌激素在广泛的生理和病理过程中发挥着重要作用，其生物合成受到FSH的深刻影响，FSH是雄激素转化为芳香酶的限速酶。雌激素水平异常常见于多囊卵巢综合征(PCOS)的卵巢疾病，这是一种影响5%-10%育龄妇女的内分泌疾病，以及囊性纤维化(CF)，这是一种由囊性纤维化跨膜传导调节因子(CFTR)突变引起的常见遗传病。目的：我们开展了这项研究，以探讨这些卵巢疾病的机制，但目前尚不清楚。结果：FSH刺激的cAMP反应元件结合蛋白的磷酸化、芳香化酶的表达和雌二醇的产生被发现在HCO3-和HCO3-传感器、可溶性腺酰环化酶、CFTR基因敲除/Delta F508突变小鼠卵巢或颗粒细胞中CFTR的抑制作用可显著降低。在人类颗粒细胞中，cftr的表达与芳香酶的表达呈正相关，支持其在调节人类雌激素产生中的作用。在PCOS啮齿动物模型和人类患者中也发现CFTR和芳香酶表达降低。结论：CFTR通过核可溶性腺苷环化酶放大FSH刺激的信号来调节卵巢雌激素的生物合成。目前的发现表明，CFTR依赖的雌激素产生调节缺陷可能是CF和PCOS卵巢功能障碍的基础。(临床内分泌代谢酶97：923-932,2012)
Context: Estrogens play important roles in a wide range of physiological and pathological processes, and their biosynthesis is profoundly influenced by FSH that regulates the rate-limiting enzyme aromatase-converting estrogens from androgens. Abnormal estrogen levels are often seen in diseases such as ovarian disorders in polycystic ovarian syndrome (PCOS), an endocrine disorder affecting 5-10% of women of reproductive age, and cystic fibrosis (CF), a common genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR).Objectives: We undertook the present study to investigate the mechanism underlying these ovarian disorders, which is not well understood.Results: FSH-stimulated cAMP-responsive element binding protein phosphorylation, aromatase expression, and estradiol production are found to be enhanced by HCO3- and a HCO3- sensor, the soluble adenylyl cyclase, which could be significantly reduced by CFTR inhibition or in ovaries or granulosa cells of cftr knockout/Delta F508 mutant mice. CFTR expression is found positively correlated with aromatase expression in human granulosa cells, supporting its role in regulating estrogen production in humans. Reduced CFTR and aromatase expression is also found in PCOS rodent models and human patients.Conclusions: CFTR regulates ovarian estrogen biosynthesis by amplifying the FSH-stimulated signal via the nuclear soluble adenylyl cyclase. The present findings suggest that defective CFTR-dependent regulation of estrogen production may underlie the ovarian disorders seen in CF and PCOS. (J Clin Endocrinol Metab 97: 923-932, 2012)