Virilization in mammals is mediated by two steroid hormones, testosterone and dihydrotestosterone. Both hormones bind to a typical steroid hormone receptor, the androgen receptor, and activate genes containing androgen-re sponsive DNA sequences. Early studies implicated testosterone as the major androgenic hormone and postulated that dihydrotestosterone was an inactive metabolite of testosterone.

The notion that dihydrotestosterone is in fact a potent androgen with physiological roles distinct from those of testosterone came from two observations. First, androgen target tissues contained an enzyme activity (steroid 5a-reductase) capable of reducing testosterone to dihydrotestosterone (1), and second, the product of this enzyme accumulated in the nuclei of responsive cells, such as those of the rat ventral prostate (1, 2). The subsequent study of an inborn error of male phenotypic sexual differentiation, now termed steroid 5a-reductase 2 deficiency, provided formal genetic proof of the crucial role of dihydrotestosterone in androgen action (3, 4). Males with this genetic disease have a biochemical defect in the synthesis of dihydrotestosterone in the embryo, which in tum leads to a developmental defect in the formation of the external genitalia and the prostate (3, 4). They exhibit a striking phenotype in which the internal genitalia (epididymis, seminal vesicles, vas deferens) are normal, but the external genitalia resemble those of the female. In addition, these subjects appear to have less baldness and acne. The facts that dihydrotestosterone mediates growth of the prostate and that individuals who lacked 5a-reductase failed to develop a prostate led to the development of therapeutic inhibitors of the enzyme. These drugs are used in the treatment of endocrine disorders whose underlying etiology requires dihydrotestosterone action.