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This version published online on February 5, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0491
Molecular Endocrinology Vol. 0, No. 2004 200304911-
doi:10.1210/me.2003-0491
Copyright © 2004 by the Endocrine Society.
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*NANDROLONE

Submitted on December 19, 2003
Accepted on January 28, 2004

Estren (4-Estren-3{alpha},17{beta}-diol) Is a Prohormone that Regulates Both Androgenic and Estrogenic Transcriptional Effects through the Androgen Receptor

Michael Centrella*, Thomas L. McCarthy, Wei-Zhong Chang, David C. Labaree, and Richard B. Hochberg

Departments of Surgery and Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520

* To whom correspondence should be addressed.

Alternative mechanisms of steroid action, through both traditional nuclear receptors and indirect pathways of gene activation, are emerging. Recent studies suggest that the synthetic steroid, 4-estrene-3{alpha},17{beta}-diol (estren), has nongenotropic as well as sex-nonspecific osteogenic effects in ovariectomized and orchidectomized mice. We found limited estrogen receptor dependent effects by estren on gene expression in primary osteoblast cultures and showed that it binds poorly to estrogen and androgen receptors in vitro. However, estren potently regulated direct and indirect, androgen receptor dependent effects on gene expression by osteoblasts. Consistent with this, osteoblasts produced the potent androgen 19-nortestosterone from estren by way of a 3{alpha}-hydroxysteroid dehydrogenase-like activity. Moreover, recombinant 3{alpha}-hydroxysteroid dehydrogenase (AKR1C9) and osteoblast-derived cell lysate each effectively converted estren to 19-nortestosterone in vitro, and mRNA encoding this enzyme occurs in osteoblasts. In addition to its androgenic activity, estren potently stimulated androgen receptor dependent effects on gene expression through conventional estrogen sensitive transcriptional elements in osteoblasts. Therefore, through local metabolism, estren indirectly activates the androgen receptor to regulate both androgen- and estrogen-like transcriptional responses by bone forming cells.
Key words: steroids • transcription factors • bone • osteoporosis

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  AR
Ligands:   17β-Estradiol  |  Dihydrotestosterone



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