Possible mechanisms of androgen resistance in 5 alpha-reductase deficiency: implications for the physiological roles of 5 alpha-reductases.

Studies of testosterone and 5 alpha-dihydrotestosterone (DHT) binding in 5 alpha-reductase deficient human genital skin fibroblasts demonstrated the presence of a single class of androgen receptor which bound both steroids in cytoplasm and nucleus. The dissociation constant (Kd = 0.44 nmol/l) and dissociation rate of testosterone-receptor complexes were greater than for DHT-receptor complexes (Kd = 0.20 nmol/l). As judged by competition with testosterone and DHT, progesterone bound to the androgen receptor with a Kd of about 7 nmol/l. The affinity of 5 alpha-pregnane-3,20-dione for androgen receptors was about 5-times less than that of progesterone; 3 alpha/beta or 20 alpha reduction lowered the affinity even further. It is suggested that one function of the high levels of 5 alpha-reductase in human embryonic external genitalia and urogenital sinus may be to prevent the antagonism of androgen binding to its receptor by progesterone. In support of this concept it has been found that the concentrations of progesterone required to inhibit testosterone or DHT binding to androgen receptors are lower in 5 alpha-reductase deficient fibroblasts than in control cells with high 5 alpha-reductase activity. Studies of the specificity of the 5 alpha-reductase activity in human prostate microsomes have shown that conversion of testosterone into DHT (Km = 12 nmol/l) was competitively inhibited by crotonyl CoA (Ki = 125 mumol/l), a model substrate for enoyl CoA reductase of the microsomal fatty acid elongase system. It is speculated that 5 alpha-reduction of testosterone and reduction of enoyl CoA could be properties of a single enzyme.