Inhibitors of 17 beta-hydroxysteroid dehydrogenases.

Abstract

The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play an important role in the regulation of steroid hormones, such as estrogens and androgens, by catalysing the reduction of 17-ketosteroids or the oxidation of 17beta-hydroxysteroids using NAD(P)H or NAD(P)(+) as cofactor. The enzyme activities associated with the different 17beta-HSD isoforms are widespread in human tissues, not only in classic steroidogenic tissues, such as the testis, ovary, and placenta, but also in a large series of peripheral intracrine tissues. In the nineties, several new types of 17beta-HSD were reported, indicating that a fine regulation is carried out. More importantly, each type of 17beta-HSD has a selective substrate affinity, directional (reductive or oxidative) activity in intact cells, and a particular tissue distribution. These findings are important for understanding the mode of action of the 17beta-HSD family. From a therapeutic point of view, this means that selectivity of drug action could be achieved by targeting a particular 17beta-HSD isozyme. Consequently, each study that leads to better knowledge of the inhibition of 17beta-HSDs deserves attention from scientists working in this and related fields. Being involved in the last step of the biosynthesis of sex steroids from cholesterol, the 17beta-HSD family constitutes an interesting target for controlling the concentration of estrogens and androgens. Thus, inhibitors of 17beta-HSDs are useful tools to elucidate the role of these enzymes in particular biological systems or for a therapeutic purpose, especially to block the formation of active hydroxysteroids that stimulate estrogeno-sensitive pathologies (breast, ovarian, and endometrium cancers) and androgeno-sensitive pathologies (prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc). Few review articles have however focussed on 17beta-HSD inhibitors although this family of steroidogenic enzymes includes interesting therapeutic targets for the control of several diseases. Furthermore, inhibitors of 17beta-HSDs constitute a growing field in biomedical research and there is a need for an exhaustive review on this topic. In addition to giving an up-to-date description of inhibitors of all 17beta-HSD isoforms (types 1-8), the present review will also address, when possible, the isoform selectivity and residual estrogenic or androgenic activity often associated with steroidal inhibitors.