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% 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/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: Hui Chen, Jing Hui Guo, Yong Chao Lu, Guo Lian Ding, Mei Kuen Yu, Lai Ling Tsang, Kin Lam Fok, Xin Mei Liu, Xiao Hu Zhang, Yiu Wa Chung, Pingbo Huang, Hefeng Huang, Hsiao Chang Chan
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 97 Issue 3 Pg. 923-32 (Mar 2012) ISSN: 1945-7197 [Electronic] United States
• PMID: 22170719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP Response Element-Binding Protein
• Estradiol
• Follicle Stimulating Hormone
• Aromatase

Topics

• Animals
• Aromatase (metabolism)
• Cells, Cultured
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cystic Fibrosis (metabolism, pathology)
• Estradiol (biosynthesis)
• Female
• Follicle Stimulating Hormone (metabolism, pharmacology)
• Granulosa Cells (drug effects, metabolism, pathology)
• Mice
• Mice, Inbred ICR
• Phosphorylation (drug effects)
• Polycystic Ovary Syndrome (metabolism, pathology)
• Rats
• Rats, Sprague-Dawley