17α-Methyl testosterone is a competitive inhibitor of aromatase activity in Jar choriocarcinoma cells and macrophage-like THP-1 cells in culture

Abstract

17α-Methyl testosterone is a synthetic androgen with affinity for the androgen receptor. 17α-Methyl testosterone is used widely as a component of hormone replacement therapy. Previous reports have indicated that contrary to testosterone, 17α-methyl testosterone is not aromatized. However, 17α-methyl testosterone still could affect local estrogen formation by regulating aromatase expression or by inhibiting aromatase action. Both possibilities have important clinical implications. To evaluate the effect of 17α-methyl testosterone on the expression and activity of aromatase, we tested the choriocarcinoma Jar cell line, a cell line that express high levels of P 450 aromatase, and the macrophage-like THP-1 cells, which express aromatase only after undergoing differentiation. We found that in both cell lines, 17α-methyl testosterone inhibits aromatase activity in a dose-related manner. The curve of inhibition parallels that of letrozole and gives complete inhibition at 10 −4 M 17α-methyl testosterone, determined by the tritium release assay. 17α-Methyl testosterone does not have detectable effects on aromatase RNA and protein expression by Jar cells. Undifferentiated THP-1 cells had no aromatase activity and showed no effect of 17α-methyl testosterone, but differentiated THP-1 (macrophage-like) cells had a similar inhibition of aromatase activity by 17α-methyl testosterone to that seen in Jar cells. The Lineweaver–Burke plot shows 17α-methyl testosterone to be a competitive aromatase inhibitor. Our results show for the first time that 17α-methyl testosterone acts as an aromatase inhibitor. These findings are relevant for understanding the effects of 17α-methyl testosterone as a component of hormone replacement therapy. 17α-Methyl testosterone may, as a functional androgen and orally active steroidal inhibitor of endogenous estrogen production, also offer special possibilities for the prevention/treatment of hormone-sensitive cancers.