Androgen physiology: Unsolved problems at the millennium

Androgen physiology differs from that of other steroid hormones in two major regards. First, testosterone, the predominant circulating testicular androgen, is both an active hormone and a prohormone for the formation of a more active androgen, the 5α-reduced steroid dihydrotestosterone. Genetic evidence indicates that testosterone and dihydrotestosterone work via a common intracellular receptor, and studies involving in vitro reporter gene assays and intact mice in which both steroid 5α-reductase isoenzymes have been disrupted by homologous recombination indicate that dihydrotestosterone acts during embryonic life to amplify hormonal signals that can be mediated by testosterone at higher concentrations. However, in post-embryonic life dihydrotestosterone plays unique roles that have not been elucidated. Studies of other 5α-reduced steroids, including the plant hormone brassinolide, the hog pheromones androstanol and androstenol, and 5α-dihydroprogesterone (in horses and elephants) indicate that this reaction serves different functions in different systems. Second, during embryonic life androgen causes the formation of the male urogenital tract and hence is responsible for development of the tissues that serve as the major sites of androgen action in postnatal life. It has been generally assumed that androgens virilize the male fetus by the same mechanisms as in the adult, namely by the conversion of circulating testosterone to dihydrotestosterone in target tissues. However, in marsupial mammals there is no sexual dimorphism in the levels of testosterone or dihydrotestosterone at the time the male phenotype forms, and in the pouch young of one marsupial, the tammar wallaby, the testes secrete another 5α-reduced steroid, 5α-androstane-3α, 17β-diol (5α-adiol), into plasma. The administration of 5α-adiol to female pouch young causes profound virilization of the urogenital sinus and external genitalia, but within target tissues 5α-adiol appears to work after oxidation to dihydrotestosterone. Thus, two separate mechanisms evolved for the formation of dihydrotestosterone in target tissues. 5α-adiol is the predominant androgen in neonatal testes in several placental mammals, but it is unclear whether it plays a similar role in other mammalian species.