Inherited impairment of nuclear androgen uptake as a cause of familial androgen insensitivity.

The endocrine and biochemical characteristics of four related 46,XY pseudohermaphrodite patients with the Reifenstein Syndrome are presented. All of them (6 and 9 years old, first generation, and 9 and 12 months old, second generation) exhibited ambiguity of external genitalia and a family pedigree characteristic of an X-linked pattern of inheritance. Serum basal levels of LH, FSH, testosterone (T), androstenedione and 5 alpha-dihydrotestosterone (DHT) were within normal limits. Administration of hCG induced a normal response in terms of serum T in three of the patients, with a concomitant increase in serum DHT. However, an abnormally elevated T: DHT ratio was found in two of these subjects on the day of maximal T response (T: DHT ratio, 24 and 27; normal range, 4-21). Genital skin-derived fibroblasts from all patients were studied for [3H]DHT uptake in a whole-cell monolayer assay. Three of the mutant strains exhibited values of [3H]DHT uptake at 37 degrees C within the lower limits of normality (39.4-47.05 fmol/mg protein/h; normal strains, 36-101 fmol/mg protein/h), whereas fibroblasts from the remaining patient presented a slightly decreased uptake (31.66 fmol/mg protein); when studied at 42 degrees C, all mutant strains behaved as the normal controls. The existence of a specific 4.6 S cytosol androgen receptor was clearly seen in the two mutant strains when analysed by sucrose gradient centrifugation. Nevertheless, in one of the mutant strains, a significantly low maximal nuclear [3H]DHT uptake was detected (173.6 fmol/mg DNA; control strain, 301.6 fmol/mg DNA). The overall data were interpreted as demonstrating the existence of an impaired uptake of the androgen-receptor complex at the nuclear levels as the cause of the incomplete phenotypic expression of androgen action in this family. In this setting, the presence of low peripheral 5 alpha-reductase activity may be considered as a secondary manifestation of the androgen insensitivity.