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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 3 of 11 The DNA-binding domain, a region highly conserved among all members of this superfamily, is comprised of 68 amino acids. This region folds into a tertiary structure resulting in the formation of two distinct zinc fingers that bind to the DNA in the major groove. The first zinc finger confers specificity, while the second zinc finger contributes to an increased binding affinity for DNA.2-6 The AR binds to the palindromic ARE in a dimer form and in a cooperative manner, which is suited to interaction with the ARE half-sites of the palindromic response elements.3Several other regions of the AR protein contribute to stabilization of the dimer molecule, among which include the ligand-binding domain and the loop of the second zinc finger.2-6 Considerable homology exists between the DNA-binding domain of AR and that of progesterone, glucocorticoid, and mineralocorticoid receptors. Hence, regulation of gene expression by these proteins involves a complex mechanism that requires interaction of the transactivation domains with other accessory factors such as transcriptional factors, coactivators and corepressors.2-7 The transactivational functional domain (TAF1) of the AR is localized in the amino terminal region of which unique sequences within this region interact with transcription factors and other accessory coactivators and corepressors3 A second transactivation functional domain (TAF2) is localized to the hormone-binding region. Consequently, regulation of gene expression by the AR and the physiological response to androgens which is observed in various target tissues may be modulated by one or all of the following factors: binding of a specific ligand (T versus DHT) to the AR, tissue-specific expression of the AR, differential binding of AR to AREs, or tissue- and cell-specific expression of accessory transcriptional factors (coactivators and corepressors) necessary for interactions with the transactivation domain of the AR.3 E. Effect of age on androgen status Advancing age has a much larger impact on androgen status than menopause. Several studies have examined androgen changes across the menopausal transition. Total testosterone does not change appreciably until women are much older (71-95 years of age), while androstenedione levels decrease much earlier.13 Mean 24-hour levels of testosterone decrease in women from age 20 to age 50, however this decline reflects aging, in that the ratio of DHEAS/T is constant over this time span.14 DHEA and DHEAS concentrations begin to decline in the second decade of life, and by the age of 80, serum levels are approximately 20% to 30% of peak levels.15 Data from a large longitudinal study demonstrate a 13% decline in mean DHEAS and a 46% decline in mean T levels between ages 42 and 50.16 These data confirm that although aging affects levels of testosterone, these levels are not much different before and after the menopause transition, and the small reduction in ovarian production is thought to result from declines in androstenedione.13 F. Androgen function in the postmenopausal ovary Androgens are produced by ovarian theca lutein cells, are present in ovarian follicular fluid, and are the principal sex steroid of growing follicles. AR are found in the normal surface epithelium of the ovaries, suggesting that androgens are active in the organ. It is currently believed that after menopause, the ovaries are a major site of androgen production.17-22 In the postmenopausal ovary, the loss of ovarian follicles and granulosa cells eliminates its estrogen-producing ability.23 However, secondary interstitial cells and hilar cells may persist in the postmenopausal ovary;24 which for many years were thought to remain continuously activated by the high levels of circulating LH, and thus remained steroidogenically active.19 Furthermore, one of the most convincing data which suggested an important contribution of the postmenopausal ovary to steroidogenesis came from the analysis of ovarian and peripheral vein hormone levels.25 However, postmenopausal ovaries are atrophic with limited blood flow. Hence ovarian vein sampling may be difficult and cross-contamination of adrenal venous blood can occur at the sampling site. Thus, herein lies the difficulty in assessing true hormonal activity in the postmenopausal population.26 |
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| Last Updated ( Monday, 26 March 2007 ) | |||||||||||||
