Impaired CFTR-dependent amplification of FSH-stimulated estrogen production in cystic fibrosis and PCOS

Abstract

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% ofwomenof reproductive age, and cystic fibrosis (CF), acommongenetic 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, andestradiol production are found to be enhanced by HCO 3- and a HCO 3- 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 humangranulosacells,supportingits 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. Copyright © 2012 by The Endocrine Society.