ROLE OF 5-ALPHA-REDUCTASE IN HEALTH AND DISEASE

The mechanism of androgen action varies in different tissues, but in the majority of androgen target tissues either testosterone or 5α-dihydrotestosterone (DHT) binds to a specific androgen receptor to form a complex that can regulate gene expression. Testosterone is metabolized to DHT by the enzyme 5α-reductase. The autosomal recessive genetic disorder of 5α-reductase deficiency has clearly shown that the requirement for DHT formation varies with different tissues. In this syndrome genetic males contain normal male internal structures including testes, but exhibit ambiguous or female external genitalia at birth; at puberty they undergo partial virilization which includes development of a male gender identity even if brought up as females. Their development suggests that testosterone itself is able to stimulate psychosexual behaviour, development of the embryonic wolffian duct, muscle development, voice deepening, spermatogenesis, and axillary and pubic hair growth; DHT seems to be essential for prostate development and growth, the development of the external genitalia and male patterns of facial and body hair growth or male-pattern baldness. How different hormones operate to regulate genes via the same receptor is currently unknown, but appears to involve cell-specific factors. The 5α-reductase enzyme has proved difficult to isolate biochemically, but recently at least two human isoenzymes have been identified using molecular biological methods. All the various 5α-reductase-deficient kindreds have been shown to have mutations in 5α-reductase 2, the predominant form in the prostate. The biological role of 5α-reductase 1 has not yet been ascertained, but at present it cannot be ruled out that some of the actions ascribed to testosterone are indeed in cells producing DHT via this enzyme. The activity of 5α-reductase is also implicated in benign prostatic hypertrophy, hirsutism and possibly male-pattern baldness; recent evidence discounts the role of 5α-reductase 2 in sebaceous glands and acne. Specific inhibitors of both enzymes are now available and finasteride, a 5α-reductase 2 inhibitor, has been used successfully in clinical trials of benign prostatic hypertrophy. Knowledge of 5α-reductase is expanding dramatically at the moment with the application of molecular biological methods. The advent of antibodies to the isoenzymes should herald further understanding of their biological and clinical roles. © 1994 Baillière Tindall.