Impaired CFTR-Dependent Amplification of FSH-Stimulated Estrogen Production in Cystic Fibrosis and PCOS

被引:44
作者
Chen, Hui [1 ]
Guo, Jing Hui [1 ]
Lu, Yong Chao [1 ,2 ]
Ding, Guo Lian [2 ]
Yu, Mei Kuen [1 ]
Tsang, Lai Ling [1 ]
Fok, Kin Lam [1 ]
Liu, Xin Mei [1 ,2 ]
Zhang, Xiao Hu [1 ]
Chung, Yiu Wa [1 ]
Huang, Pingbo [5 ]
Huang, Hefeng [2 ]
Chan, Hsiao Chang [1 ,3 ,4 ]
机构
[1] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Epithelial Cell Biol Res Ctr, Shatin, Hong Kong, Peoples R China
[2] Zhejiang Univ, Sch Med, Womens Hosp, Key Lab Reprod Genet,Minist Educ China, Hangzhou 310006, Zhejiang, Peoples R China
[3] Chinese Univ Hong Kong, Jinan Univ, Key Lab Regenerat Med, Minist Educ Peoples Republ China, Guangzhou 510632, Guangdong, Peoples R China
[4] Sichuan Univ, W China Second Univ Hosp, Minist Educ,Key Lab Obstet Gynecol & Pediat Dis &, Sichuan Univ Chinese Univ Hong Kong Joint Lab Rep, Chengdu 610041, Peoples R China
[5] Hong Kong Univ Sci & Technol, Nano Sci & Technol Program, Kowloon, Hong Kong, Peoples R China
关键词
POLYCYSTIC-OVARY-SYNDROME; SOLUBLE ADENYLYL-CYCLASE; GOOD CLINICAL STATUS; FOLLICULAR-FLUID; AROMATASE DEFICIENCY; HUMAN OOCYTE; EXPRESSION; FEMALE; CAMP; CELLS;
D O I
10.1210/jc.2011-1363
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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)
引用
收藏
页码:923 / 932
页数:10
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