New frontiers in androgen biosynthesis and metabolism

To summarize recent advances in androgen biosynthesis and metabolism in peripheral tissues (e.g., liver and prostate) and how these can be exploited therapeutically.

Human liver catalyzes the reduction of circulating testosterone to yield four stereoisomeric tetrahydrosteroids. Recent advances have assigned the enzymes responsible for these reactions and elucidated their structural biology. Data also suggest that for 5alpha-dihydrotestosterone (5alpha-DHT), conjugation reactions (phase II) may precede ketosteroid reduction (phase I) reactions. Human prostate is the site of benign prostatic hyperplasia and prostate cancer, which occur in the aging male. Although the importance of local androgen biosynthesis in these diseases is accepted, recent advances have identified enzymes that regulate ligand access to the androgen-receptor; a 'backdoor pathway' to 5alpha-DHT that does not require testosterone acting as an intermediate; and the finding that castrate-resistant prostate cancer (CRPC) has undergone an adaptive response to androgen deprivation, which involves intratumoral testosterone and 5alpha-DHT biosynthesis that can be targeted using inhibitors of (CYP17-hydroxylase/17,20-lyase), aldo-keto reductase 1C3, and 5alpha-reductase type 1 and type 2.

Enzyme isoforms responsible for the biosynthesis and metabolism of androgens in liver and prostate have been identified and those responsible for the biosynthesis of androgens in CRPC can be therapeutically targeted.