Androgens - There are still major gaps in our understanding of the reasons of male balding. It is clear, however, that balding is an androgen-dependent trait, that it requires a genetic predisposition and that its severity and frequency in the population increase with advancing age.

Testosterone is the major circulating androgen in men. However, it is the more potent androgen dihydrotestosterone (DHT), the 5-alfa-reduced metabolite of testosterone, that is responsible for driving hair loss. The conversion of testosterone to DHT is catalyzed by the enzyme 5-alfa-reductase. There are two isoforms of 5-alfa-reductase, which are encoded by different genes. Although both enzymes catalyse the conversion of testosterone to DHT they differ in their pH optima, substrate affinities and tissue distributions. Type 1 5-alfa-reductase is widely distributed in the skin, but expression of the type 2 isoform appears to be restricted to certain androgen target tissues such as the prostate, the epididymis and hair follicles in certain regions of the skin.

The biological role of DHT in hair growth first became apparent in studies of men with a genetic deficiency of type 2 5-alfa-reductase. In this autosomal-recessive disorder, genetic males (46XY) are born with normally differentiated, but usually undescended, testes. Partial virilization of the genitals occurs at puberty, the voice deepens and the musculature assumes a typical male distribution. Circulating testosterone levels are within or above the normal male range but DHT levels remain low with testosterone:DHT ratios 3.5-5 times higher than normal. These men show a female pattern of androgen-dependent hair growth with terminal hair largely restricted to the axillae and the lower pubic triangle. In the large group of subjects studied in the Dominican Republic, beard growth was absent or sparse. More facial hair has been observed in affected men from other parts of the world, perhaps reflecting underlying racial differences in normal androgen-dependent hair growth, although this was reduced compared with normal males in the same communities. None of the cases studied has shown temporal recession of the hair line or balding. These observations were extended by the demonstration that treatment with a 5-alfa-reductase inhibitor prevented the development of balding or increased scalp hair growth in macaques, a primate that reliably develops androgen dependent hair loss. Confirmation of the importance of DHT in humans came from the results of large clinical trials showing that finasteride, an inhibitor of type 2 5-alfa-reductase, prevents progression of balding in most men and stimulates some recovery of hair growth in about two-thirds. This latter finding also illustrates that, contrary to Hamilton's conclusions from his observations in eunuchs, male balding is partially reversible.

Androgens act on tissues via binding to a specific intracellular protein, the androgen receptor, a member of the steroid-thyroid nuclear receptor superfamily. In the presence of ligand, androgen receptors undergo a change in conformation, resulting in an activated form that binds as a homodimer with a specific androgen response element on the target gene. The hormone-receptor complex then activates transcription of target genes. A large number of proteins (co-regulators) regulate the activity of the hormone-receptor complex, both enhancing (co-activators) and suppressing (co-repressors) transcriptional activation.