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

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 tho...

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Published in:The journal of clinical endocrinology and metabolism 2004-11, Vol.89 (11), p.5815-5822
Main Authors: Hannema, Sabine E, Scott, Ian S, Hodapp, John, Martin, Howard, Coleman, Nick, Schwabe, John W, Hughes, Ieuan A
Format: Article
Language:English
Subjects:
Adolescent
Adult
Androgen-Insensitivity Syndrome - physiopathology
Animals
Binding Sites
Biological and medical sciences
Child
Child, Preschool
COS Cells
DNA - metabolism
Endocrinopathies
Female
Fundamental and applied biological sciences. Psychology
Humans
Infant
Male
Medical sciences
Mutation
Protein Structure, Secondary
Receptors, Androgen - chemistry
Receptors, Androgen - genetics
Receptors, Androgen - physiology
Vertebrates: endocrinology
Wolffian Ducts - growth & development
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Summary: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.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2004-0709