Clinical, endocrinological, and enzymatic characterization of two patients with 5a-reductase deficiency: Evidence that a single enzyme is responsible for the 5a-reduction of cortisol and testosterone

Two siblings with 46, XY male pseudohermaphroditism were demonstrated to have the phenotype characteristic of 5α-reductase deficiency, namely normal testes and male Wolffian duct derivatives (epididymis, vas deferens, and seminal vesicle) terminating in a blind-ending vagina. Clitoromegaly was present at birth and increased further at the time of expected puberty. The diagnosis of 5α-reductase deficiency was confirmed by demonstration of male levels of testosterone and testosterone precursors before and after hCG administration, elevated plasma testosterone to dihydrotestosterone and urinary etiocholanolone to androsterone ratios, and by in vitro studies indicating 5 areductase enzyme deficiency in the epididymis of one patient. Studies of control and mutant epididymal microsomes indicated that a single enzyme is responsible in the normal person for the 5α-reduction of testosterone and cortisol (and probably other Δ⁴-3-ketosteroids as well) and that 5α-reductase activity is undetectable for all substrates examined in the mutant. This finding explains why the formation of 5a-reduced glucocorticoids is also defective in the disorder.