Prevalence of androgen receptor abnormalities in patients with male pseudohermaphroditism and normal testosterone synthesis

To determine the prevalence of androgen receptor defects, we measured the androgen receptor in genital skin fibroblasts from 15 patients with male pseudohermaphroditism, one week to 14 years of age. All of the patients had a 46, XY karyotype and normal testes. A normal rise in serum testosterone and dihydrotestosterone levels in response to stimulation with human chorionic gonadotropin was documented in 14 of 15 patients tested. In one pubertal patient random serum testosterone was in the normal adult range. The amount of high affinity androgen receptor binding was nearly undetectable (< 4 fmol/mg protein) in all patients with a normal female phenotype. In 9 patients with ambiguous genitalia, the androgen receptor was reduced in one, qualitatively abnormal in 2 and normal in the other 6. Thus, in one-third of our patients with ambiguous external genitalia a receptor abnormality was identified. The etiology for the incomplete virilization in the remaining 6 patients is unclear. Subtle, unrecognized defects of the androgen receptor, post-receptor abnormalities, or factors interfering with testosterone production or action in utero could be responsible for the abnormal sexual differentiation. The results of this study indicate that although the diagnosis of androgen resistence can be confirmed by the findings of an abnormal androgen receptor, the diagnosis cannot be excluded by the failure to detect such an abnormality. Until more refined techniques are developed for assessing receptor function and identifying post-receptor abnormalities, the decision for sex assignment in 46, XY infants with ambiguous genitalia, normal testosterone and dihydro testosterone formation, and uninformative family histories must still be based upon the appearance of the external genitalia.