Pre-receptor regulation of the androgen receptor

The human androgen receptor (AR) is a ligand-activated nuclear transcription factor and mediates the induction of genes involved in the development of the male phenotype and male secondary sex characteristics, as well as the normal and abnormal growth of the prostate. We have identified the pair of hydroxysteroid dehydrogenases (HSDs) that regulate ligand access to the AR in human prostate. We find that type 3 3α-HSD (aldo-keto reductase (AKR)1C2) catalyzes the NADPH dependent reduction of the potent androgen 5α-dihydrotestosterone (5α-DHT) to yield the inactive androgen 3α-androstanediol (3α-diol). We also find that RoDH like 3α-HSD (RL-HSD) catalyzes the NAD+ dependent oxidation of 3α-diol to yield 5α-DHT. Together these enzymes are involved in the pre-receptor regulation of androgen action. Inhibition of AKR1C2 would be desirable in cases of androgen insufficiency and inhibition of RL-HSD might be desirable in benign prostatic hyperplasia.