The Non-Aromatic Δ5-Androstenediol Derivative of Dehydroepiandrosterone Acts as an Estrogen Agonist in Neonatal Rat Osteoblasts through an Estrogen Receptor α-related Mechanism.

: It has been proposed that DHEA influences bone formation through, bioconversion to 17β-estradiol; however, DHEA is converted to Δ5-androstenediol (Δ5-Adiol), a metabolite with estrogenic potential involved in diverse biological process. To gain new insight into the role of Δ5-Adiol in bone cells, we examined DHEA and Δ5-Adiol effects in neonatal rat and human hFOB1.19 osteoblasts. : Osteoblast activity was assessed by analyzing proliferation, alkaline phosphatase activity, and expression of and . We also examined binding affinities for osteoblast-ER and transcriptional activation of human (h)ERα, hERβ or hAR in U2-OS cells. : The most striking finding was that Δ5-Adiol had greater stimulatory effect than DHEA on rat osteoblast proliferation and differentiation, as well as expression in human osteoblasts. Interestingly, the Δ5-Adiol or DHEA-induced effects were not precluded with letrozole or trilostane, consistent with bioconversion of DHEA to Δ5-Adiol due to elevated expression of in neonatal rat osteoblasts, suggesting a high level of 17β-hydroxysteroid dehydrogenase type 1 activity. Conversely, Δ5-Adiol and DHEA-induced proliferative effects were inhibited with ICI 182780 alone or combined with trilostane, which correlates with the higher binding affinity of Δ5-Adiol for ER compared to DHEA. Furthermore, Δ5-Adiol showed a greater relative agonist activity for hERα than for hERβ or hAR. : This study is the first to show that a bioactive DHEA derivative stimulates E-dependent osteoblast activities, including proliferation and differentiation in rat and human osteoblasts, through ERα-related mechanisms.