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This version published online on November 20, 2003
Endocrinology, doi:10.1210/en.2003-1046
A more recent version of this article appeared on March 1, 2004
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Submitted on August 12, 2003
Accepted on November 12, 2003

Feedback Inhibition of Steroidogenic Acute Regulatory Protein Expression In Vitro and In Vivo by Androgens

Christopher P. Houk1, Elliot J. Pearson1, Nina Martinelle1, Patricia K. Donahoe1, and Jose Teixeira1*

1 Pediatric Surgical Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.

* To whom correspondence should be addressed. E-mail: teixeira{at}helix.mgh.harvard.edu.

MIS reduces testosterone synthesis in Leydig cells by inhibiting cytochrome P450C17 hydroxylase/C17-20 lyase expression. However, in mouse Leydig MA-10 cells, MIS also enhances the cAMP-induced expression of mRNA for Steroidogenic Acute Regulatory Protein (StAR), which transports cholesterol to the inner mitochondrial membrane for conversion to pregnenolone. We hypothesized that the MIS-induced StAR expression is the indirect result of reduced testosterone synthesis in Leydig cells caused by MIS. We show that, in addition to MIS, flutamide, an androgen receptor antagonist, enhanced StAR mRNA expression when added to cAMP-treated MA-10 cells, while dihydrotestosterone (DHT), a potent androgen receptor agonist, attenuated these responses. Progesterone, dexamethasone, and estradiol also inhibited StAR mRNA expression. Addition of MIS to cAMP-treated MA-10 cells transfected with a StAR-promoter luciferase reporter, resulted in increased StAR promoter activity over cAMP alone; this effect was inhibited by DHT, suggesting that androgens inhibit StAR mRNA expression at the transcriptional level. Androgen-mediated inhibition of StAR expression was also observed in primary Leydig cell culture and in vivo using both hypophysectomized mice and mice treated with the GnRH antagonist, Acyline. These results suggest that the induction of StAR expression by MIS occurs secondary to the MIS-mediated reduction in testosterone synthesis by relieving a hitherto uncharacterized androgen-dependent feedback inhibition on StAR expression. These findings may impact future treatment strategies aimed at reducing androgen; for example, in the treatment of prostatic cancer, anti-androgen treatment might benefit from adjuvant therapy to inhibit StAR expression.




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