Bone protection by estrens occurs through non–tissue-selective activation of the androgen receptor
Sara H. Windahl, … , Michèle Resche-Rigon, Roland Baron
Sara H. Windahl, … , Michèle Resche-Rigon, Roland Baron
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2500-2509. https://doi.org/10.1172/JCI28809.
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Research Article Bone biology

Bone protection by estrens occurs through non–tissue-selective activation of the androgen receptor

Abstract

The use of estrogens and androgens to prevent bone loss is limited by their unwanted side effects, especially in reproductive organs and breast. Selective estrogen receptor modulators (SERMs) partially avoid such unwanted effects, but their efficacy on bone is only moderate compared with that of estradiol or androgens. Estrens have been suggested to not only prevent bone loss but also exert anabolic effects on bone while avoiding unwanted effects on reproductive organs. In this study, we compared the effects of a SERM (PSK3471) and 2 estrens (estren-α and estren-β) on bone and reproductive organs to determine whether estrens are safe and act via the estrogen receptors and/or the androgen receptor (AR). Estrens and PSK3471 prevented gonadectomy-induced bone loss in male and female mice, but none showed true anabolic effects. Unlike SERMs, the estrens induced reproductive organ hypertrophy in both male and female mice and enhanced MCF-7 cell proliferation in vitro. Estrens directly activated transcription in several cell lines, albeit at much higher concentrations than estradiol or the SERM, and acted for the most part through the AR. We conclude that the estrens act mostly through the AR and, in mice, do not fulfill the preclinical efficacy or safety criteria required for the treatment or prevention of osteoporosis.

Authors

Sara H. Windahl, René Galien, Riccardo Chiusaroli, Philippe Clément-Lacroix, Frederic Morvan, Liên Lepescheux, François Nique, William C. Horne, Michèle Resche-Rigon, Roland Baron

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Figure 5

Estren-α, but not PSK3471, stimulates breast cancer cell proliferation.

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Estren-α, but not PSK3471, stimulates breast cancer cell proliferation. ...
(A) Estren-α significantly enhanced cellular proliferation in MCF-7 cells. Indeed, at 10 nM, estren-α and E2 displayed the same efficacy. PSK3471, in contrast, did not display any agonist activity on MCF-7 proliferation. (B) The experiment was performed as in A, but the ability of each compound to antagonize E2-induced cell proliferation was tested by cotreating the cells with E2 (0.1 nM) and increasing doses of compounds, as indicated. PSK3471, but not estren-α, antagonized E2-induced proliferation of MCF-7 cells. E2, filled diamonds; estren-α, filled triangles; PSK3471, filled squares.