Testicular feminization associated with a thermolabile androgen receptor in culutred human fibroblasts.

Evidence for a qualitative abnormality in the androgen receptor was obtained by studies of temperature sensitivity. The binding of [(3)H]dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one) was studied in monolayers of cultured genital skin fibroblasts from genetic males with abnormal sexual differentiation resulting from androgen resistance. Binding in cells from eight patients with a female phenotype (complete and incomplete testicular feminization) fell from half-normal levels at the usual assay temperature of 37 degrees C to levels <20% of normal when cells were incubated at 42 degrees C. This thermal inactivation was rapidly reversed when the assay temperature was lowered to 37 degrees C, was not associated with altered dihydrotestosterone metabolism, and was also demonstrable with [(3)H]methyltrienolone as the binding ligand. Binding increased to overlap the normal range when the assay temperature was lowered to 26 degrees C. The patients with receptor-deficient testicular feminization include three pairs of siblings; the pedigrees in two of these families are compatible with X-linkage. Only minor changes in the amount of binding at elevated temperatures were observed in cells from 10 control subjects and from 2 male pseudohermaphrodites with normal levels of androgen receptors. In 10 patients with androgen resistance and partial receptor deficiency associated with a predominantly male phenotype (Reifenstein syndrome and infertile men), dihydrotestosterone binding also did not change consistently with elevated temperature. Binding was approximately half-normal at 37 degrees C and either increased or decreased slightly at 42 degrees C. The thermal instability in receptor-deficient testicular feminization represents a new molecular defect associated with hereditary male pseudohermaphroditism that appears to be caused by an alteration in the tertiary structure of the androgen receptor protein.