title: Impaired CFTR-dependent amplification of FSH-stimulated estrogen production in cystic fibrosis and PCOS.
abstract: BACKGROUND
  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).
  
  
  OBJECTIVE
  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/ΔF508 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.
authors.affiliation: Epithelial Cell Biology Research Center, Room 408 Basic Medical Sciences Building, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Jing Hui
authors.initials: JH
authors.lastname: Guo
authors.forename: Yong Chao
authors.initials: YC
authors.lastname: Lu
authors.forename: Guo Lian
authors.initials: GL
authors.lastname: Ding
authors.forename: Mei Kuen
authors.initials: MK
authors.lastname: Yu
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Tsang
authors.forename: Kin Lam
authors.initials: KL
authors.lastname: Fok
authors.forename: Xin Mei
authors.initials: XM
authors.lastname: Liu
authors.forename: Xiao Hu
authors.initials: XH
authors.lastname: Zhang
authors.forename: Yiu Wa
authors.initials: YW
authors.lastname: Chung
authors.forename: Pingbo
authors.initials: P
authors.lastname: Huang
authors.forename: Hefeng
authors.initials: H
authors.lastname: Huang
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000096:biosynthesis*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism / Q000494:pharmacology*; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D010766:Phosphorylation / Q000187:drug effects; D011085:Polycystic Ovary Syndrome / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D001141:Aromatase