Steroid 5α-reductase 2 deficiency

Between 1968 and 1973 a large body of evidence accumulated in our laboratory and by others demonstrated that the conversion of testosterone to dihydrotestosterone plays a crucial role in androgen action, including virilization of the external genitalia in male embryos (reviewed in Ref. 1). We had postulated that mutations that impair dihydrotestosterone formation might be the cause of some cases of human male pseudohermaphroditism (2), and a candidate disorder for 5α-reductase deficiency was the rare autosomal recessive disorder termed pseudovaginal perineoscrotal hypospadias (3–7). In 1974 two siblings with pseudovaginal perineoscrotal hypospadias were ascertained in Dallas, and as the result of endocrine, phenotypic, and enzymatic studies it was established that these sisters did have a defect in 5 α-reductase activity (8). At the same time an extensive family from the Dominican Republic was described in whom male pseudohermaphroditism was also due to impairment of the conversion of testosterone to dihydrotestosterone (9, 10). In the intervening years many additional patients have been described, and the pathogenesis of this disorder has been explored in considerable detail, culminating in the cloning of two genes that encode steroid 5α-reductase isoenzymes (11–13). 5α-Reductase deficiency is of interest not because of its frequency (it is rare) but because of its importance for understanding the mechanism of androgen action, the process of sexual differentiation, and the factors that influence normal sexual behavior.