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" The data from 180 patients were abstracted for this table from Quigley, C. A., DeBellis, A., Marschke, K. B., El-Awady, M. K., Wilson, E. M., and French, F. S. (1995). Androgen receptor defects: Historical clinical and molecular perspectives. Endocr. Rev. 16, 271-321.

" The data from 180 patients were abstracted for this table from Quigley, C. A., DeBellis, A., Marschke, K. B., El-Awady, M. K., Wilson, E. M., and French, F. S. (1995). Androgen receptor defects: Historical clinical and molecular perspectives. Endocr. Rev. 16, 271-321.

An extensive evaluation of mutations in the androgen receptor has been carried out (see Table 12-8). More than 50 different naturally occurring mutations have been identified and documented as to the change in the nucleotide sequence. The presence of a mutation in the AR gene can result in a dysfunction at any level in the receptor-mediated steps of androgen action, including androgen production and secretion, androgen binding to its receptor, nuclear localization of the AR, and binding of the AR to promoters of regulated genes. Collectively these defects lead to clinical disorders categorized as the androgen-insensitivity syndrome (AIS), which are all related to the condition of male pseudohermaphroditism.2 At the functional level, two categories of AIS have been linked to the AR: (a) abnormalities of binding of androgen to the AR and (b) abnormalities of binding of the AR to the HRE on gene promoters. Clearly either of these defects will disrupt the normal transcriptional activity of the AR and lead to the onset of the clinical condition.

The detailed evaluation of the AR and its correlation with AIS represent a modern triumph of molecular biology application to clinical endocrinology.

2. Antiandrogen Compounds

Some synthetic analogs of testosterone compete for binding to the AR, but do not generate androgenic effects; such analogs are termed antiandrogens. The principal antiandrogen compounds available include cyproterone acetate, a,a,a-trifluoro-2-methyl-4'-nitro-m-propionotoluide (flutamide), and 6a-bromo-17a - methyl -17/3 - hydroxy - 4 - oxa - 5a - androstan -3 - one (BOMT) (see Figure 12-13). The biological actions of these steroids result from their blocking active androgens from interacting with their target organ intracellular receptors.

Estrogens are also capable of generating antiandro-genic responses; these effects are largely mediated either by (1) inhibition of testicular androgen secretion via blocking the secretion of LH or (2) direct suppression of testosterone synthesis by Leydig cells.

3. Anabolic Steroids

Anabolic steroids are analogs of testosterone that mediate an array of responses in the skin, skeleton, and muscle, including nitrogen, potassium, and inorganic phosphorus retention, as well as increased skeletal muscle mass. Chemically it has been possible to produce compounds that maximize the anabolic activity and minimize androgenicity. The examples of nandro-lone decanoate, oxandrolone, and stanozolol are given in Figure 12-13. The biochemical basis for their actions in muscle and skeleton is not known. Although these

2 A pseudohermaphrodite is an individual with the genetic composition and gonads of one sex and the genitalia of the other. Thus, male pseudohermaphroditism results in the appearance in the male of female external genitalia in genetic 46 XY males.

Antiandrogens

Antiandrogens

Cyproterone acetate

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