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Human Complete Androgen Insensitivity with Normal Dihydrotestosterone Receptor Binding Capacity in Cultured Genital Skin Fibroblasts: Evidence for a Qualitative Abnormality of the Receptor^*

TERRY R. BROWN, MARC MAES, STEPHEN W. ROTHWELL and CLAUDE J. MIGEON

Department of Pediatrics, Division ofPediatric Endocrinology, The Johns Hopkins University School of Medicine Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Dr. Terry R. Brown, Department of Pediatrics, Division of Pediatric Endocrinology, CMSC 3-110, The Johns Hopkins Hospital, Baltimore, Maryland 21205.

Complete androgen insensitivity syndrome (CAIS), or so-called testicular feminization, results from the lack of androgen action on target organs. Within this syndrome, two major variants have been described. In the first variant, the specific intracellular androgen receptors are undetectable (CAIS, AR), whereas normal levels of androgen receptors are measured in the second variant (CAIS, AR+). From studies with cultured labial skin fibroblasts of three CAIS, AR+ patients from the same family, we have demonstrated that their androgen receptors present qualitative differences when compared to normal receptors: 1) the apparent affinity constant (K_d) of 5dihydrotestosterone for the receptor is higher than normal; 2) the in vitro dissociation rate of the receptor-steroid complex is faster than normal: 3) the cellular androgen receptor is more thermolabile than normal when cells are exposed to superphysiological temperatures; and 4) the relative binding affinity of the androgen receptor for progesterone is greater than normal. These findings suggest the presence of a structural abnormality of the androgen receptor in patients with CAIS, AR+. However, these changes (e.g. slightly decreased affinity of the receptor for 5a-dihydrotestosterone) probably do not explain the total lack of androgen action in these patients. Finally, the present data from this family along with those from the literature suggest the presence of heterogeneity as to the cause of the defect in CAIS, AR+.

^* This work was supported by USPHS Research Grant AM-00180, Traineeship Grant T32-AM-07116, and Research Career Award 5-KO6- AM-21855 (to C.J.M.). Presented in part at the 63rd Annual Meeting The Endocrine Society, Cincinnati, OH, June 17-19,1981.

Present address: Cliniques Universitaires Saint-Luc, Department de Pediatrie, 1200 Bruxelles, Belgique.

Received November 9, 1981.

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