Qualitative receptor defects in families with androgen resistance: Failure of stabilization of the fibroblast cytosol androgen receptor

We describe a new method for detecting the presence of a qualitatively abnormal androgen receptor in skin fibroblasts cultured from patients with androgen resistance. Preparation of normal fibroblast cytosol in the presence of sodium molybdate results in stabilization of a 7-8S dihydrotestosterone-receptor complex on sucrose density gradients. Patients with testicular feminization previously identified as having a qualitatively abnormal androgen receptor, as determined by thermolability of monolayer binding, were shown to have failure of stabilization of the cytosol receptor by molybdate. In light of this, we designed a study to see whether this technique might identify previously unrecognized instances of a qualitatively abnormal androgen receptor. Comparison of the thermolability of monolayer binding and molybdate stabilization of cytosol receptor was thus undertaken in 35 families with androgen resistance due to putative disorders of the androgen receptor. The patients included individuals from 15 families with complete testicular feminization (7 with incomplete testicular feminization, 5 with Reifenstein syndrome, and 8 with the infertile male syndrome). Absent binding was the defect present in 9 families, all with complete testicular feminization. A decreased amount of an apparently normal receptor was detected in 8 families (primarily those with Reifenstein or infertile male syndromes). A qualitatively abnormal receptor was the most frequently encountered receptor defect (14 of 35 families) and was present in some families with each of the 4 clinical syndromes. Since failure of molybdate stabilization was present in all 14 families, but thermolability was demonstrable in only 8 of the 14; it is clear that the former technique is more sensitive. In all 4 families in which more than 1 affected member was studied, the same receptor defect was demonstrable in each sibling. A receptor abnormality could not be identified in 4 families. In these families as well as some of those with a decreased amount of receptor, it is presumed that the qualitative defect is too subtle for detection by present techniques or, alternatively, that a postreceptor defect exists which mimics a receptor abnormality clinically. We conclude that failure of stabilization of the cytosol receptor by sodium molybdate is a more sensitive probe for a qualitatively abnormal receptor than thermolability, and that a qualitatively abnormal androgen receptor is a more common defect than either absent binding or a decreased amount of receptor in patients with androgen resistance.