Syndromes of androgen resistance

Androgen resistance can be divided into two broad categories: deficiency in 5 alpha-reductase and defects in the androgen receptor. Studies of these two disorders have provided insight into both the normal pathway of androgen action and into the pathogenesis of abnormal sexual development. 5 alpha-Reductase deficiency is a rare autosomal recessive disorder involving the 5 alpha-reductase 2 enzyme; affected males exhibit a defect in virilization most evident as impairment of the virilization of the external genitalia and urogenital sinus. Disorders of the androgen receptor in genetic males cause a spectrum of developmental abnormalities that vary from phenotypic females to men with mild defects in virilization. On functional grounds we have divided these defects into absence of receptor function, qualitatively abnormal receptors, quantitative defects in receptor amount, and apparently normal receptor. Cloning of the cDNA for the receptor and application of the polymerase chain reaction techniques for sequencing of mutants made it possible to analyze these defects at the molecular level. It is now apparent that the functional categorization underestimated the complexity of the mutations. Indeed, major gene deletions and/or rearrangements, single amino acid substitutions, and premature termination codons all can cause variably severe functional abnormalities.