Aromatase-independent testosterone conversion into estrogenic steroids is inhibited by a 5α-reductase inhibitor

Estrogens are generated mainly by the action of aromatase, which converts testosterone to estradiol and androstenedione to estrone. However, in addition to estradiol and estrone, a variety of other steroids, whose synthesis is not dependent on aromatase, can stimulate the estrogen receptor. Here we show that testosterone is converted into such estrogenic steroids by aromatase-negative HeLa cells. This aromatase-independent generation of estrogenic steroids is seen in aromatase-positive MCF-7 cells as well. In both cell lines, the synthesis of estrogenic steroids was blocked by inhibition of testosterone conversion into dihydrotestosterone using a 5α-reductase inhibitor finasteride, suggesting that they are generated downstream of dihydrotestosterone. This finding raises the possibility that the combination of a 5α-reductase inhibitor and an aromatase inhibitor may reduce estrogenic steroids in vivo more completely than an aromatase inhibitor alone.