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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 9 of 11 L. Androgen receptor expression in breast cancer Numerous studies indicate that 70-80% of primary breast tumors express AR, as well as 75% of breast cancer metastases, and it is the sole sex steroid receptor expressed in approximately 25% of metastatic disease.63 However it is unknown at this time whether there is any relationship between exogenous androgen therapy and the incidence of breast cancer, as epidemiological studies have shown both positive and negative associations between endogenous androgen levels and breast cancer risk.8, 64 For instance, experimental data suggest that conventional estrogen treatment regimens, as oral contraceptives or hormone replacement therapy, may upset the normal estrogen-androgen balance and promote unopposed estrogenic stimulation of mammary epithelial proliferation which may potentiate breast cancer risk.8 In addition, endogenous androgen activity may be suppressed as oral estrogen therapy reduces free androgens by stimulating hepatic production of SHBG and suppressing LH, thereby inhibiting ovarian androgen production.8 A recent study found that a low-dose oral contraceptive induced robust mammary epithelial proliferation in rats but addition of methyltestosterone to the therapy significantly suppressed the proliferation.8 In addition, testosterone added to estrogen therapy significantly inhibits estrogen-induced mammary epithelial proliferation in ovariectomized rhesus monkeys.8 There is also the theoretical risk of aromatization of androgens into estrogens in target tissue which may have potential deleterious impact on women with a history of breast cancer or any estrogen-dependent neoplasia. Androgens have been shown in vitro to have either inhibitory or stimulatory effects on the growth of human breast cancer cells, and androgens either up- or downregulate AR mRNA expression in breast cancer cell lines.65 AR have also been associated with longer survival in women with operable breast cancer and a favorable response to hormone treatment in advanced disease.66, 67 Although androgens have not been used as a primary hormonal treatment for breast cancer since the 1960s due to their masculinizing side-effects (i.e., hirsutism, acne), androgens such as fluoxymesterone have a therapeutic efficacy comparable to current hormonal therapies such as tamoxifen.68 In fact, clinical observations and experimental data indicate that androgens inhibit mammary growth and have been used with success similar to that of tamoxifen to treat breast cancer. 8 In vivo studies using the hormone-dependent DMBA rat mammary tumor model have shown that treatment with testosterone results in tumor regression and a concomitant reduction in estrogen receptor (ER) levels.65 One possible mechanism for this decrease in ER levels in the tumors is that androgen directly regulates ER expression. An alternative explanation is that pharmacological doses of testosterone may be aromatized to estrogen resulting in autologous down-regulation of ER. Thirdly, androgens bind with a low affinity to ER, which may result in an apparent reduction in ER levels following treatment with high doses of testosterone propionate due to interference with ligand binding in biochemical assays for ER.65 Further studies are needed to evaluate the efficacy of supplementing hormone therapy with androgens and ensuing breast cancer risk. Furthermore, as current forms of estrogen in oral contraceptives and oral estrogen replacement therapy suppress endogenous androgen activity, there is a need for future studies on the efficacy of supplementing both oral contraceptive and estrogen replacement therapy with physiological replacement androgen, in a nonaromatizable form, to maintain the natural estrogen-androgen ratios typical of normal women. M. Androgen receptor expression in bone Sex steroids are directly involved in bone remodeling. Androgens, acting either directly or via aromatization to estrogen, have profound impact on the physiology and preservation of bone mineral density in women. Androgens also increase muscle mass and strength and induce mechanical factors that alter the balance between bone resorption and formation in favor of formation, with the net result an increase in bone mass and strength.69 ARs are found in all three bone cells: osteoblasts, osteoclasts, and osteocytes. However ARs are predominantly expressed in active osteoblasts and to a greater degree in cortical rather than cancellous bone at the site of bone formation. ARs are also found in bone marrow cells that regulate osteoclastogenesis. Osteoclast function is regulated by estrogen primarily, although indirect aromatization of T to estrogen can also occur. ARs can also be found embedded in osteocytes within the bone matrix.69 |
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| Last Updated ( Monday, 26 March 2007 ) | |||||||||||||
