Role of 5α-reductase in androgen physiology and pathophysiology

Normal androgen metabolism

During the last century, the identification and characterization of the major sex steroids, which include androgens, estrogens, and progestins, helped define their biologic functions. Androgens were demonstrated to be essential for normal male sexual differentiation in utero and for development and maintenance of male secondary sexual characteristics, including terminal body hair growth, muscle mass, sexual behavior and fertility. Androgens are steroid hormones and, as such, produce effects by binding to an intracellular receptor, forming a hormone-receptor complex that interacts with DNA to modulate protein transcription (Mainwaring 1977). Testosterone, the major circulating androgen in adult men, was logically suspected to be the hormone responsible for these effects. Observations in 46XY subjects with inborn androgen insensitivity (syndrome of testicular feminization) confirm that the sexual phenotype in humans is predominantly female in the absence of androgen effects (Morris et al. 1963, see Chapter 3). Specifically, despite normal circulating levels of testosterone, subjects with androgen insensitivity who have impaired responses to androgens secondary to a dysfunctional androgen receptor manifest female external genitalia (with blind vaginal pouch, cryptorchid testes and infertility) and breast development, no terminal sexual body hair growth, and a pre-pubertal pattern of scalp hair growth. Due to the absence of androgen action, no androgen-related disorders typical of aging men, such as disorders of the prostate or male pattern hair loss over the scalp, are observed. The latter finding is consistent with Hamilton's conclusions regarding the androgen dependence of typical male pattern scalp hair loss, based on observations of eunuchs compared to normal subjects (Hamilton 1942; 1951).