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Pathogenesis and clinical manifestations of disorders of androgen action

Olaf Hiort, MD
Section Editors
Peter J Snyder, MD
Alvin M Matsumoto, MD
Deputy Editor
Kathryn A Martin, MD


Loss of function mutations of the gene that encodes the androgen receptor (AR) result in androgen insensitivity syndrome (AIS) in 46,XY individuals with functional testes and unhindered testosterone formation. AIS encompasses a clinical continuum of decreased to absent androgen effects, varying from a completely female phenotype to a male phenotype with undervirilization or infertility. In contrast to the variability in phenotypic expression, the disorders have similar endocrine, pathophysiologic, and genetic features [1]. The pathophysiology will be reviewed here, while diagnosis and therapy are discussed separately. (See "Diagnosis and treatment of disorders of the androgen receptor".)


Recognition that patients with complete androgen insensitivity syndrome (CAIS) have profound resistance to the action of androgen came from studies in which affected women were found to be resistant to the virilizing action of exogenous androgen [2].

This hormone resistance was found to be due to defects in androgen receptor (AR) function as a result of studies of women with CAIS who had no detectable AR binding [3-5], qualitatively abnormal AR binding [6-8], or decreased amounts of qualitatively normal receptor binding [6,9]. Similar findings were described in patients with the less severe phenotypes [9].

Involvement of the AR in these disorders was confirmed when the encoding gene was cloned and specific molecular defects were defined. The AR gene is located on chromosome Xq11-12. X-linkage of the AR gene was established when the human cDNA was cloned from an X-chromosome library [10,11].

The AR is a member of the steroid-thyroid-retinoid superfamily of nuclear receptors with a C-terminal region containing hormone-binding and DNA-binding domains and an N-terminal region important in transactivation (figure 1). Specific mutations of the AR gene have been identified in many patients with androgen insensitivity syndromes (AIS). Most mutations today have been localized in the hormone-binding domain and, to a lesser extent, in the DNA-binding domain and the transactivation domain [12]. Mutations in the 5' untranslated region of the AR gene have also been described, which impair AR function by reducing AR protein levels [13].

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Literature review current through: Nov 2017. | This topic last updated: Apr 21, 2017.
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