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| Vibrance Newsletter | ||
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| Androgen Receptor Expression in Women and its Relationship to Sexual Function |
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| Written by Jennifer Berman, MD | |||||||||||||
Page 2 of 11 C. Biochemical mechanism of androgen action Androgens enter target and nontarget cells by passive diffusion, and once inside the cell, the biologically active androgens (T, DHT) bind to a specific, soluble intracellular receptor protein molecule localized in the cytoplasm or in the nucleus.2-5 The binding energy of the hormone to its receptor results in physiochemical changes in the receptor complex, converting the receptor from a biologically inactive form to a biologically active state.2-5 These reactions initiated by hormone binding lead to interaction of the hormone receptor complex with unique and specific DNA enhancer elements referred to as androgen response elements (AREs).3, 6 The interaction of the activated androgen receptor complex with the AREs results in recruitment and binding of transcriptional factors, coactivators, or corepressors into the transcriptional complex and regulation of androgen-dependent gene transcription.3, 7 D. Structural and functional domains of the androgen receptor Androgens exert their effects by first binding to androgen receptors (AR). The AR gene is located on the X chromosome with no corresponding allele on the Y, so it functions solely as a single-copy gene, as shown by the complete loss of androgen effect in XY individuals with an inactivating mutation of the AR.8 The AR, comprised of 918 amino acids, with an estimated molecular weight of 110 kDa 3, is a ligand-dependent nuclear transactivating factor and a member of the steroid-thyroid hormone-retinoic acid nuclear receptor superfamily.2, 4-7 The members of this superfamily are characterized by distinct functional domains comprised within a unique protein structure which includes: the hormone-binding domain, DNA-binding domain, and amino terminal domain encompassing a transactivation function, the nuclear localization domain, and the dimerization domain.3 The hormone-binding domain is located near the carboxyl terminal region and is comprised of a hydrophobic region, which forms the hormone-binding site.3 The two predominant and naturally occurring androgens that bind to the AR are T and DHT. In vivo and in vitro studies have demonstrated that DHT binds with greater affinity to the AR than T and is more potent in inducing biological responses.9, 10 The higher potency of DHT is attributed to DHT binding to the AR with greater affinity and thereby dissociating more slowly, and the AR-DHT complex being more stable.11 The AR gene shares significant homology with both the estrogen receptor and progesterone receptor genes. Two isoforms of the AR have been identified in a variety of human tissues and are similar in structure to the isoforms of the progesterone receptor. Despite the differences in structure and abundance the two AR isoforms do not appear to differ in their regulation or in their ability to bind with ligands and activate target genes.12 Recent studies have suggested that different genes may be activated by different ligands and that this may be reconciled by the presence of cell-specific and limiting transcription factors and coactivators. In addition, the local concentration of the androgen hormone depends on the expression and activity of steroid-converting enzymes such as dehydrogenases and reductases; the latter of which play important roles in the peripheral conversion of androgens to active or inactive metabolites. Furthermore, the tissue- and cell-specific expression of different coactivators or corepressors in different target cells plays an important role in specific gene expression by androgens in various target tissues. The conformational changes in the hormone receptor complex are induced by ligand binding of T versus DHT. The energy of binding and the conformational changes in the protein determine which transcriptional factors, coactivators, and corepressors are to be assembled in the transcription complex and determine which genes are regulated by androgens and therefore act as a discriminatory mechanism of gene activation.3 |
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| Last Updated ( Monday, 26 March 2007 ) | |||||||||||||
