Steroid 5α-reductases and 3α-hydroxysteroid dehydrogenases: key enzymes in androgen metabolism

Androgen action in mammals can be regulated at the pre-receptor level by the intracellular formation and degradation of potent androgens, such as 5α-dihydrotestosterone (5α-DHT). In androgen target tissues (e.g. prostate), 5α-DHT is formed from circulating testosterone by the action of the type 2 steroid 5α-reductase (5α-R) and its action is terminated by the action of a reductive 3α-hydroxysteroid dehydrogenase (3α-HSD) which forms the weak androgen 3α-androstanediol. Oxidative 3α-HSD isoforms, however, can provide an alternative source of potent androgens by converting 3α-androstanediol to 5α-DHT. Working in concert, 5α-Rs and 3α-HSDs determine the amount and the type of androgen available for the androgen receptor and hence affect transcription of genes under androgen control. In peripheral tissues (e.g. liver), type 1 5α-R and reductive 3α-HSD isoforms work consecutively to eliminate androgens and protect against hormone excess. Thus, different 5α-R and 3α-HSD isoforms participate in distinct anabolic and catabolic processes and their important roles in androgen action render them drug targets for the treatment of androgen-dependent diseases.