Testosterone metabolism in the androgen-insensitive rat: a model for testicular feminization

Although it has long been known that the lack of androgen dependent differentiation in patients with testicular feminization is secondary to end organ insensitivity, the molecular basis of this genetic disorder has not been elucidated. In the present report a rodent model for testicular feminization is described. The Stanley-Gumbreck pseudohermaphroditic rat has an inherited disorder characterized by a female phenotype, a male genotype and tissue insensitivity to androgens. Even though male differentiation does not occur when these animals are treated with physiologic doses of testosterone, some androgen dependent growth is evident when 100-fold larger doses of testosterone are given. Studies of androgen metabolism in the psuedohermaphroditic animals indicate that testosterone transport and metabolism to dihydrotestosterone are normal. However, intranuclear retention of dihydrotestosterone is defective. These findings suggest that the androgen insensitivity of the pseudohermaphroditic rat is due to an inherited abnormality of a regulatory protein which renders the nucleus of the cell incapable of concentrating androgens at their proposed intracellular site of action. The pseudohermaphroditic rats also have a defect of testicular and adrenal steroid synthesis in addition to the androgen insensitivity. The relation of these two abnormalities in rat and in man are discussed.