Estren (4-Estren-3α,17β-diol) Is a Prohormone that Regulates Both Androgenic and Estrogenic Transcriptional Effects through the Androgen Receptor
| Autor: | David Labaree, Michael Centrella, Weizhong Chang, Thomas L. McCarthy, Richard B. Hochberg |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
medicine.medical_specialty
Transcription Genetic medicine.drug_class Biology Bone and Bones Rats Sprague-Dawley Endocrinology Internal medicine Gene expression medicine Animals Nandrolone Estrenes Receptor Molecular Biology Cells Cultured Regulation of gene expression Osteoblasts Hydroxysteroid Dehydrogenases Osteoblast General Medicine Androgen Rats Androgen receptor medicine.anatomical_structure Receptors Estrogen Nuclear receptor Receptors Androgen Estrogen |
| Zdroj: | Molecular Endocrinology. 18:1120-1130 |
| ISSN: | 1944-9917 0888-8809 |
| DOI: | 10.1210/me.2003-0491 |
| Popis: | 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-3alpha,17beta-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 3alpha-hydroxysteroid dehydrogenase-like activity. Moreover, recombinant 3alpha-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. |
| Databáze: | OpenAIRE |
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