This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by JUKIER, L. Articles by PETERSON, R. E. Search for Related Content PubMed PubMed Citation Articles by JUKIER, L. Articles by PETERSON, R. E.

Partial Androgen Resistance Associated with Secondary 5-Reductase Deficiency: Identification of a Novel Qualitative Androgen Receptor Defect and Clinical Implications^*

Division of Endocrinology and Metabolism Montreal General Hospital Cell Genetics Laboratory, Lady Davis Institute for Medical Research Sir Mortimer B. Davis-Jewish General Hospital The Centre for Human Genetics, McGill University Montreal, Quebec H3T 1E2, Canada Division of Endocrinology, Department of Medicine, Cornell University Medical College New York, New York 10021

Address correspondence and requests for reprints to: Dr. L. Pinsky, Lady Davis Institute, 3755 Cote Saint Catherine Road, Montreal, Quebec, Canada H3T 1E2.

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-l, II-2). Their adult levels of plasma testosterone (T) range from 765-2250 ng/dl. The plasma T to 5-dihydrotestosterone (DHT) ratios were 29 (n = 5) in patient II-l, 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-l, 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 5/3-tetrahydrocorticosterone to 5-tetrahydrocorticosterone were 0.98 (n = 2) in patient II-l, 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-l had unusually low 5-reductase (5-R) activity (0.3 pmol/mg protein · 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 h, respectively. The maximum specific DHT receptor-binding activity (B_max) 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 (K_d) for DHT were 1.16 ± 0.28 (n = 4) in II-l, 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 B_max with the synthetic, nonmetabolizable androgen, methyltrienolone (R1881), and the k of Rl881-receptor complexes were normal, but the K_d for R1881 in the GSF of II-l 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 Rl881-binding activity in his cells. We conclude that: (1) two of the brothers (II-l, II-2) have partial peripheral 5-R deficiency in vivo secondary to a mutant androgen receptor (presumed to be shared by all three) that expresses its qualitative defect for both DHT and R1881 kinetically and functionally; (2) secondary 5-R deficiency can modulate the expressivity of a primary partial androgen-receptor defect, as judged from the less severe phenotype of II-5 compared to that of his brothers; and (3) as affirmed by a trial on II-l, DHT rather than T should be used to assess residual androgen sensitivity in subjects with partial, receptor-dependent androgen resistance.

^* This work was supported by the Medical Research Council of Canada Group Grant in Medical Genetics, and by Research Grant HD-09421 from the NIH. Parts of these data were presented in abstract form at the American Federation for Clinical Research, Washington DC (Clin Res 31:273A, 1983).

Received December 2, 1983.

This article has been cited by other articles:

				A. L. M. Boehmer, A. O. Brinkmann, R. M. Nijman, M. C. T. Verleun-Mooijman, P. de Ruiter, M. F. Niermeijer, and S. L. S. Drop Phenotypic Variation in a Family with Partial Androgen Insensitivity Syndrome Explained by Differences in 5{{alpha}} Dihydrotestosterone Availability J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1240 - 1246. [Abstract] [Full Text]