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Residual Activity of Mutant Androgen Receptors Explains Wolffian Duct Development in the Complete Androgen Insensitivity Syndrome

Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital (S.E.H., J.H., H.M., I.A.H.), Cambridge, United Kingdom CB2 2QQ; Medical Research Council Cancer Cell Unit, Hutchison/Medical Research Council Research Center (I.S.S., N.C.), Cambridge, United Kingdom CB2 2XZ; and Medical Research Council Laboratory of Molecular Biology (J.W.S.), Cambridge, United Kingdom CB2 2QH

Address all correspondence and requests for reprints to: Prof. I. A. Hughes, Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge, United Kingdom CB2 2QQ. E-mail: iah1000{at}cam.ac.uk.

Development of the Wolffian ducts (WD) into epididymides and vasa deferentia is dependent on testosterone. Patients with the complete androgen insensitivity syndrome (CAIS) are therefore not expected to develop these structures. However, WD derivatives have been described in cases of CAIS. It is thought that these may be remnants. This study assesses the degree of WD development in 33 patients with CAIS and investigates whether this development was androgen dependent. Epididymides and vasa deferentia were identified in 70% of patients with substitution mutations in the androgen receptor ligand-binding domain. They were more developed than epididymides and vasa deferentia from 16- to 20-wk-old male fetuses, suggesting that the WD had been stimulated to grow, rather than failed to regress. Receptors with substitutions in the ligand-binding domain were normally expressed and showed residual response to androgens in transactivation assays. Patients with premature stop codons or frameshift mutations, which prevented androgen receptor expression, or DNA-binding domain mutations that abolished transcriptional activity did not have epididymides or vasa deferentia. We hypothesize that mutant receptors with residual activity in vitro respond to high local testosterone concentrations in vivo, thereby stimulating WD development. The classification of androgen insensitivity in such patients should be considered severe rather than complete.

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