THE ADENOVIRUS-MEDIATED DELIVERY OF A REPORTER GENE PERMITS THE ASSESSMENT OF ANDROGEN RECEPTOR FUNCTION IN GENITAL SKIN FIBROBLAST-CULTURES

Defects in the androgen receptor cause a spectrum of abnormalities in genetic males ranging from phenotypic women with testicular feminizati on to men with minor defects in fertility and/or virilization. The dia gnosis of androgen resistance can be quite cumbersome, including analy sis of the family history, karyotyping, endocrine studies, measurement of androgen binding in genital skin fibroblasts, and, in some instanc es, sequencing of mutant cDNAs. Furthermore, androgen-binding studies may be normal in patients with qualitative receptor abnormalities or m utations in the DNA-binding domain of the receptor. To circumvent thes e difficulties, we have used a recombinant adenovirus to deliver an an drogen-responsive reporter gene (mouse mammary tumor virusluciferase) to fibroblasts cultured from genital skin from 12 normal controls and from eight individuals with complete testicular feminization. Followin g incubation with androgen (2 nM mibolerone) for 72 h, luciferase acti vity in normal fibroblasts increased >10-fold (range 11-200-fold) in a manner that corresponded with the level of androgen receptor detected in ligand-binding assays. By contrast, luciferase activity increased negligibly in fibroblasts from individuals with testicular feminizatio n (average = 1.2-fold increase). This assay permits a direct assessmen t of endogenous androgen receptor function in cells and should be a po werful aid in the diagnosis of androgen resistance.