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Androgens act within target cells by mechanisms similar to those of other hormones of the steroid-thyroid-retinoid class. The hormone combines with a receptor protein, and the androgen-receptor complex interacts with other proteins to form transcription regulatory complexes that control the formation of messenger RNA. However, androgen action differs from that of other steroid hormones in two important ways. First, testosterone, the major circulating androgen, must be converted to dihydrotestosterone before exerting many of its actions. Second, during embryogenesis, androgens act to convert the undifferentiated urogenital tract into the male phenotype. In this manner, androgens promote differentiation of the organs that serve as major target tissues for the hormone in later life.
Inherited defects that impede androgen action cause resistance to the action of the hormone and produce manifestations that range from undervirilized or infertile men to individuals with ambiguous genitalia to phenotypic women. In molecular terms, these disorders can be classified on the basis of the step in androgen action that is impeded by the individual mutations.
Steroid 5α-reductase 2 deficiency (MIM 264600) is an autosomal recessive disorder that impairs the conversion of testosterone to dihydrotestosterone. In affected males, the internal urogenital tract virilizes normally, but formation of the male external genitalia is variably impaired and is usually female in character. In affected 46,XY males raised as women, this disorder is commonly associated with a change to male gender role behavior after the time of expected puberty.
Mutations of the receptor that mediates the action of both testosterone and dihydrotestosterone cause at least four syndromes in 46,XY individuals: women with complete and incomplete testicular feminization, the Reifenstein syndrome, and the undervirilized or infertile male (MIM 300068, 312300, 308370). Most of the defects are due to point mutations that result in premature termination codons or amino acid substitutions in the hormone- or DNA-binding domains of the receptor; partial or complete deletions of the coding sequence and splicing abnormalities are less common.
The fact that mutations of the androgen receptor are more common than mutations in all other receptors of this class is due to three factors. First, the gene that encodes the androgen receptor is located on the X chromosome, and hence mutations are always expressed in males. Second, normal androgen action is essential for reproduction but not for the life of individuals, so the total absence of receptor function is compatible with life. Third, even slight abnormalities in androgen action can cause anatomic or functional abnormalities (and hence usually come to the attention of physicians). As a consequence, the androgen resistance syndromes have provided a remarkable opportunity to use mutations for the analysis of normal hormone action and of abnormal sexual development.
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The fact that endocrine disease can result from resistance to hormone action at the cellular level was first recognized by Albright and colleagues, who deduced that pseudohypoparathyroidism is caused by peripheral resistance to the action of parathyroid hormone.1 The ...