Abstract. Dihydrotestosterone-receptor com-plexes formed in human fibroblast cytosol prepared at 00C in the presence of sodium molybdate can be readily transformed to the DNA-binding state by heating at 250C. Under these conditions 50-70% of dihydrotestosteronereceptor complexes bind to DNA. We describe here studies of the transformation process in cytosols derived from normal cells and from fibroblasts propagated from subjects with syndromes ofandrogen resistance. In contrast to the situation with dihydrotestosterone, normal testosteronereceptor complexes are unstable under in vitro transforming conditions. Although equal amounts ofhormonereceptor complex are formed at 00C, only 15% of testosterone-receptor complexes remain stable and acquire DNA-binding capacity after warming. This instability is not reversible upon lowering the temperature and is corrected by low concentrations (0.25 gM) of the protease inhibitor leupeptin. We have also identified two cousins with androgen resistance whose androgen-receptor complexes exhibit similar in vitro transformation lability with both dihydrotestosterone and testosterone. Phenotypic evidence in these subjects indicates that dihydrotestosterone-mediated processes are more completely impaired than are testosterone-mediated events. These findings This work has been published in abstract form (Clin. Res. 31:471, 1983 suggest that dihydrotestosterone may amplify the androgenic signal at its targets not only by its higher affinity for the receptor but also by its more efficient conversion to the DNA-binding state and that such amplification may be less critical in target tissues in which testosterone suffices for androgenic effect. This offers one possible explanation of how a mutation that affects a single receptor protein may differentially impair the actions of two binding ligands of the receptor.

Impaired virilization of genetic males with testes (male pseudohermaphroditism) can result either from deficiency in androgen production or defects in androgen action, the latter most commonly involving an abnormal androgen receptor. We report here two maternal cousins with male pseudohermaphroditism and clinical features characteristic of the Lubs phenotype, namely apparent females with sufficient fusion of the labioscrotal folds so that a single urogenital sinus orifice is present. Testosterone levels in these genetic males rose appropriately after administration of human chorionic gonadotropin. The amount (maximal binding capacity of 24 to 30 fmol/mg protein) and hormone binding affinity (half‐maximal saturation of 0.2 nM) of the androgen receptor in cultured skin fibroblasts was normal, but the receptor was qualitatively abnormal as evidenced by instability on sucrose density gradient centrifugation. The pattern of inheritance in this family is compatible with X‐linkage. These findings, together with previous studies, indicate that the spectrum of abnormalities that result from defects of the androgen receptor in genetic men can encompass the entire spectrum between male and female phenotypes.