Steroid 5alpha-reductases and 3alpha-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 5alpha-dihydrotestosterone (5alpha-DHT). In androgen target tissues (e.g. prostate), 5alpha-DHT is formed from circulating testosterone by the action of the type 2 steroid 5alpha-reductase (5alpha-R) and its action is terminated by the action of a reductive 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) which forms the weak androgen 3alpha-androstanediol. Oxidative 3alpha-HSD isoforms, however, can provide an alternative source of potent androgens by converting 3alpha-androstanediol to 5alpha-DHT. Working in concert, 5alpha-Rs and 3alpha-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 5alpha-R and reductive 3alpha-HSD isoforms work consecutively to eliminate androgens and protect against hormone excess. Thus, different 5alpha-R and 3alpha-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.