Testicular Feminization Associated with a Thermolabile Androgen Receptor in Cultured Human Fibroblasts

James E. Griffin

doi:10.1172/JCI109624

Published December 1, 1979 - More info

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Abstract

Evidence for a qualitative abnormality in the androgen receptor was obtained by studies of temperature sensitivity. The binding of [³H]dihydrotestosterone (17β-hydroxy-5α-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°C to levels <20% of normal when cells were incubated at 42°C. This thermal inactivation was rapidly reversed when the assay temperature was lowered to 37°C, was not associated with altered dihydrotestosterone metabolism, and was also demonstrable with [³H]methyltrienolone as the binding ligand. Binding increased to overlap the normal range when the assay temperature was lowered to 26°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°C and either increased or decreased slightly at 42°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.