Partial androgen resistance associated with secondary 5 alpha-reductase deficiency: identification of a novel qualitative androgen receptor defect and clinical implications.
We studied a family in which three brothers were born with ambiguous genitalia and had poor virilization at puberty. One patient (II-5) required less surgery to repair his hypospadias and is lean, muscular, and hairy compared to his brothers (II-1, II-2). Their adult levels of plasma testosterone (T) range from 765-2250 ng/dl. The plasma T to 5 alpha-dihydrotestosterone (DHT) ratios were 29 (n = 5) in patient II-1, 25 (n = 2) in patient II-2, and 14 (n = 2) in patient II-5, compared to 12 +/- 3 (SD) in normal men. The mean urinary etiocholanolone to androsterone ratios were 1.9 (n = 2) in patient II-1, 2.0 in patient II-2, and 1.3 in patient II-5, compared to 0.87 +/- 0.34 in normal men. The mean urinary ratios of 5 beta-tetrahydrocorticosterone to 5 alpha-tetrahydrocorticosterone were 0.98 (n = 2) in patient II-1, 1.25 in patient II-2, and 0.71 in patient II-5, compared to 0.53 +/- 0.22 in normal men. Genital skin fibroblasts (GSF) from patient II-1 had unusually low 5 alpha-reductase (5 alpha-R) activity (0.3 pmol/mg protein X h; n = 6), but those of patient II-5, a normal brother (II-3), and a sister (II-4; with impaired development of sexual hair) had normal values of 6.5 (n = 2), 9 (n = 3), and 9 (n = 2) pmol/mg protein X h, respectively. The maximum specific DHT receptor-binding activity (Bmax) and the rate constant of dissociation (k) of DHT-receptor complexes in the GSF from each of these individuals were normal, but the apparent equilibrium dissociation constants (Kd) for DHT were 1.16 +/- 0.28 (n = 4) in II-1, 0.39 +/- 0.20 (n = 6) in the sister, and it was 0.19 +/- 0.09 (n = 3) in the unaffected brother and 0.22 +/- 0.09 nM (n = 26) in normal men. The Bmax with the synthetic, nonmetabolizable androgen, methyltrienolone (R1881), and the k of R1881-receptor complexes were normal, but the Kd for R1881 in the GSF of II-1 was 1.4 nM (n = 2), compared to 0.16 +/- 0.05 (n = 8) in normal men, and prolonged exposure to R1881 failed to augment (up-regulate) the basal R1881-binding activity in his cells.(ABSTRACT TRUNCATED AT 400 WORDS)
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D000328:Adult; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005835:Genitalia / Q000378:metabolism; D006177:Gynecomastia / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007021:Hypospadias / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010088:Oxidoreductases / Q000172:deficiency*; D011944:Receptors, Androgen / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D013256:Steroids / Q000097:blood / Q000652:urine; D013739:Testosterone / Q000097:blood
D011944:Receptors, Androgen; D011987:Receptors, Steroid; D013256:Steroids; D013739:Testosterone; D010088:Oxidoreductases; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase