Androgen resistance associated with a qualitative abnormality of the androgen receptor and responsive to high dose androgen therapy.

A 46,XY infant with perineoscrotal hypospadias and microphallus was identified in a family in which seven individuals have severe hypospadias that is inherited in a pattern compatible with an X-linked defect. The infant had small testes that were palpable in the labioscrotal folds, the proximal urethra was male in character, and there was no vagina. Serum testosterone rose from 0.5 to 5.1 nmol/L in response to hCG, and there was a negligible clinical response to a short term course of testosterone enanthate. A clinical diagnosis of male pseudohermaphroditism due to androgen resistance was made. Studies in cultured genital skin fibroblasts disclosed normal 5 alpha-reductase activity, a normal amount of high affinity dihydrotestosterone binding, and normal up-regulation of androgen receptors when monolayers were incubated with dihydrotestosterone or mibolerone. Fibroblast cytosol preparations contained a normal 7-8S sedimenting peak of androgen binding. However, androgen binding in monolayers decreased 60% when the assay temperature was raised from 30 to 41 C, and the dissociation rate of ligand from the receptor was enhanced 5-fold compared to the control value, establishing the diagnosis of androgen resistance due to a qualitative abnormality of the androgen receptor. Because of parental decision to raise the patient as a male, he was given two courses of high dose testosterone cypionate when he was 2.5 and 3.5 yr old (100 mg every 2 weeks for six doses). This treatment produced significant phallic growth, making it possible to undertake surgical correction of the hypospadias. We postulate that the impairment of androgen receptor function was overcome in part by the large dose of androgen.