This Article Full Text Full Text (PDF) All Versions of this Article: 18/5/1120    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Centrella, M. Articles by Hochberg, R. B. Search for Related Content PubMed PubMed Citation Articles by Centrella, M. Articles by Hochberg, R. B.

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

Departments of Surgery (M.C., T.L.M., W.-Z.C.) and Obstetrics, Gynecology and Reproductive Sciences (D.C.L., R.B.H.), Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Michael Centrella, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208041, New Haven, Connecticut 06520-8041. E-mail: michael.centerlla{at}yale.edu.

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-3,17ß-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-hydroxysteroid dehydrogenase-like activity. Moreover, recombinant 3-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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  AR

Ligands:   17β-Estradiol  |  Dihydrotestosterone

This article has been cited by other articles:

				T. L. McCarthy, M. E. Clough, C. M. Gundberg, and M. Centrella Expression of an estrogen receptor agonist in differentiating osteoblast cultures PNAS, May 13, 2008; 105(19): 7022 - 7027. [Abstract] [Full Text] [PDF]

				T. L. McCarthy, R. B. Hochberg, D. C. Labaree, and M. Centrella 3-Ketosteroid Reductase Activity and Expression by Fetal Rat Osteoblasts J. Biol. Chem., November 23, 2007; 282(47): 34003 - 34012. [Abstract] [Full Text] [PDF]

				S. Kousteni, M. Almeida, L. Han, T. Bellido, R. L. Jilka, and S. C. Manolagas Induction of Osteoblast Differentiation by Selective Activation of Kinase-Mediated Actions of the Estrogen Receptor Mol. Cell. Biol., February 15, 2007; 27(4): 1516 - 1530. [Abstract] [Full Text] [PDF]

				S. C. Hewitt, J. Collins, S. Grissom, K. Hamilton, and K. S. Korach Estren Behaves as a Weak Estrogen Rather than a Nongenomic Selective Activator in the Mouse Uterus Endocrinology, May 1, 2006; 147(5): 2203 - 2214. [Abstract] [Full Text] [PDF]

				V. Krishnan, H. A. Bullock, B. C. Yaden, M. Liu, R. J. Barr, C. Montrose-Rafizadeh, K. Chen, J. A. Dodge, and H. U. Bryant The Nongenotropic Synthetic Ligand 4-Estren-3{alpha}17{beta}-diol Is a High-Affinity Genotropic Androgen Receptor Agonist Mol. Pharmacol., March 1, 2005; 67(3): 744 - 748. [Abstract] [Full Text] [PDF]