Familial external genital ambiguity due to a transformation defect of androgen-receptor complexes that is expressed with 5 alpha-dihydrotestosterone and the synthetic androgen methyltrienolone.
We have studied various properties of the binding of 5 alpha-dihydrotestosterone (DHT) or the synthetic, nonmetabolizable androgen methyltrienolone (R1881; 17 beta-hydroxy-17 alpha-methylestra-4,9,11-trien-3-one) to the androgen receptor of genital skin fibroblasts (GSF) from controls and a subject with familial, receptor-positive, partial androgen insensitivity. The mutant cells form R1881-receptor complexes that dissociate 7 times more rapidly than normal at 30 degrees C, and they do not increase their specific R1881-receptor activity in response to a 72-hr period of incubation with R1881, whereas the cells from normal individuals do so two- to three-fold. As previously reported [Pinsky et al, 1981; Kaufman et al, 1981], the mutant cells have similar abnormalities with DHT as with R1881. When the patient's cells are incubated for 120 min with varying concentrations (0.05-3 nM) of R1881 or DHT, Scatchard analysis shows that their androgen-receptor activity has an apparent equilibrium dissociation constant (Kd) for each ligand that is six-fold greater than that of normal cells (approximately 0.2 nM). Normal GSF have higher, more variable values of Kd (0.3-1.8 nM) for either ligand after 30 compared to 120 min of incubation, and the 60-min values are intermediate. This explains why we previously reported that the patient's cells had a 30-min Kd for DHT in the normal range [Pinsky et al, 1981]. Sucrose gradient centrifugation of mutant GSF cytosol incubated with DHT in the presence of 10 mM sodium molybdate yields a normal 6.5-8S peak of DHT-receptor complexes. From these data we conclude that normal GSF form initial, low-affinity androgen-receptor complexes that are transformed into one (or more) higher-affinity (? activated) states by a process that depends on time and initial concentration of androgen; the subject's GSF can form low-affinity androgen-receptor complexes but cannot generate the normal high-affinity state of the complexes, and this lack precludes augmentation of their androgen-receptor activity in response to prolonged incubation with either androgen; and failure of molybdate to stabilize the androgen-receptor activity in GSF cytosol is not a more sensitive indicator of structurally altered androgen-receptor proteins than are other qualities described heretofore.
D000293:Adolescent; D002648:Child; D013196:Dihydrotestosterone / Q000378:metabolism*; D012734:Disorders of Sex Development / Q000188:drug therapy / Q000235:genetics*; D004963:Estrenes / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D006177:Gynecomastia / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008297:Male; D015741:Metribolone; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics*; D013739:Testosterone / Q000031:analogs & derivatives / Q000627:therapeutic use
D004963:Estrenes; D011944:Receptors, Androgen; D011987:Receptors, Steroid; D013196:Dihydrotestosterone; D015741:Metribolone; D013739:Testosterone; C004648:testosterone enanthate