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HRT in Women
Low-dose intravaginal estrogens appear to be a safe and effective treatment for symptoms of GSM
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<blockquote data-quote="madman" data-source="post: 224319" data-attributes="member: 13851"><p><strong>PART 2: <u>SYSTEMIC TESTOSTERONE </u></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Introduction </strong></p><p></p><p><em><strong>Testosterone is the most abundant biologically active hormone in women.76 It is produced in the ovaries and adrenal gland and from precursors at the cellular level where it interacts with the androgen receptor.76 It is also the precursor hormone for estradiol and has an indirect effect on the estrogen receptor via aromatization.76 </strong>Testosterone levels decline with age, particularly within the early reproductive years,77,78, and symptoms of androgen deficiency can occur as early as the mid-30s for some women.76 Premature ovarian insufficiency or iatrogenic menopause causes an earlier and more profound decline.79 <strong>Symptoms of testosterone deficiency can include sexual problems (particularly desire), fatigue, depression, headaches, cognitive problems, osteoporosis, sarcopenia, and reduced quality of life.79</strong> But despite these symptoms, in all countries other than Australia, there are no licensed testosterone products for female use, and instead, <strong>a fractionated dose of an approved transdermal male formulation (prescribed off-license) that approximates physiological testosterone levels in premenopausal women is often recommended.79</strong></em></p><p></p><p></p><p></p><p></p><p><strong>*<u>Testosterone Benefits</u> </strong></p><p></p><p><em>There has been very few adequately powered prospective, randomized, placebo-controlled clinical trials looking specifically at the benefits of testosterone therapy in women, mainly because most studies involve small numbers or include women taking concurrent estrogen therapy.78 <strong>However, from the available data, studies do suggest androgens are important for bone density, muscle mass, mood, energy, and cognitive function,80–85 and robust trials have been undertaken surrounding testosterone therapy and sexual function in postmenopausal women,78 particularly evaluating its benefits for low sexual desire.</strong> <strong>Improvements in sexual desire, arousal, orgasmic function, pleasure, and sexual responsiveness together with a reduction in sexual concerns have been demonstrated among placebo-controlled RCTs in women with hypoactive sexual desire disorder.78 <u>Suggested reasons for this include an increased dopamine release in the central nervous system79 and/or an amplified activation of brain areas involved with sexual arousal (such as the limbic system)</u>.86 <u>It is also possible that there is a direct vasodilatory effect of testosterone on vaginal tissue, causing increased blood flow to this area</u>.87,88 <u>Lastly, testosterone may also have beneficial effects on lower urinary tract function</u>. </strong>A recent analysis of data from the National Health and Nutrition Examination Survey found that women with low serum testosterone were significantly more likely to have stress or mixed urinary incontinence.89 A suggested reason for this was an anabolic effect of androgens on skeletal muscle and the role of pelvic musculature in maintaining urethral support.89</em></p><p></p><p></p><p></p><p></p><p><strong>*<u>Role of Testosterone on GSM</u> </strong></p><p></p><p><em><strong>Androgens appear to have a role in maintaining genitourinary tissue structure and function,90,91 and the effects of testosterone on vaginal health appear not to always require its conversion to estradiol by aromatase first. </strong>This was demonstrated in a small study of women with breast cancer taking aromatase inhibitors.92 In this study, intravaginal application of testosterone at a dose of either 150 or 300 μg for 4 weeks was shown to reduce signs and symptoms of GSM.</em></p><p><em></em></p><p><em><strong>There is a distinct regulation of androgen receptors in different tissue layers of the genital tract. Compared with human vaginal epithelium, there is greater immunostaining for androgen receptors and less immunostaining for estrogen receptors in labial skin.93 </strong>This may have clinical implications, for example, with conditions such as vestibulodynia. In a small study of premenopausal women, those who developed vestibulodynia were more likely to have longer CAG (cytosine-adenine-guanine) repeats in their androgen receptor gene.9</em></p><p></p><p></p><p></p><p></p><p><strong>*<u>Risks and Association for Cancer Development </u></strong></p><p></p><p><em><strong>Most of the safety data for testosterone use at physiological doses is limited to 24 months of treatment duration,78 and there is a need for longer-term follow-up studies. However, the available data does suggest a good safety profile with transdermal use.78,95,96</strong></em></p><p></p><p></p><p></p><p></p><p><strong>*<u>Cardiovascular</u></strong></p><p></p><p><em><strong>Transdermal and other nonoral testosterone delivery are not associated with changes in serum lipids, blood pressure, or carbohydrate metabolism95,97; nor has it been associated with more frequent reporting of myocardial infarction, stroke, venous thromboembolism, or cardiovascular death95,98; however, <u>long-term randomized clinical trial data in populations at risk have not been completed to date</u>.</strong> <strong>There is even some evidence that it may have favorable cardiovascular effects</strong>. Results from 1 small study show that transdermal testosterone replacement improves functional capacity and insulin resistance in women with chronic heart failure.83 This is interesting because approximately 25% of men with chronic heart failure have biochemical evidence of testosterone deficiency, and low levels have been related to disease progression in men.99 Another small study reported an enhancement of brachial artery dilation following treatment with testosterone implants in postmenopausal women using long-term estrogen therapy.100 Thus, nonoral testosterone may improve endothelial function. It should be mentioned that, unlike the transdermal route, oral testosterone negatively affects high-density lipoprotein cholesterol and low-density lipoprotein cholesterol and is not recommended at this time given available formulations.78,95</em></p><p></p><p></p><p></p><p></p><p><strong>*<u>Breast and Endometrium</u> </strong></p><p></p><p><em><strong>Transdermal testosterone does not appear to stimulate the endometrium101–103; nor does it appear to increase mammographic breast density95,104,105 or elevate breast cancer risk.78,96,98 Because testosterone aromatizes to estradiol, there have been some concerns that it could have secondary stimulatory effects on the estrogen receptor.</strong> However, in a large 10-year prospective cohort study, there was a 39% lower incidence of invasive breast cancer in users of subcutaneous testosterone implants compared with the age-matched expected incidence, and the authors concluded that, although not novel, testosterone therapy should be investigated as breast cancer prevention.106 <strong>There are increasing data demonstrating antiproliferative, proapoptotic, and antiestrogenic stimulatory effects of testosterone in the breast.76,107–111</strong></em></p><p><em><strong></strong></em></p><p><em><strong>For women with a history of estrogen-positive breast cancer taking an aromatase inhibitor, transdermal testosterone might help to improve some menopausal symptoms without increasing estradiol levels112,113; however, this finding is limited by small sample sizes and short duration of treatment.</strong> An in vitro study reports that the antiproliferative effects of anastrozole on human breast cancer cells are significantly enhanced by combined treatment with testosterone,114 and another case study has concluded that a higher letrozole dose enables a greater inhibitory effect of testosterone at the breast.115<strong> There is also some evidence that testosterone may be beneficial in women with metastatic breast cancer who become refractory to treatment with other endocrine therapies.116</strong></em></p><p></p><p></p><p></p><p></p><p><strong>*<u>Androgenic Adverse Effects</u> </strong></p><p><strong></strong></p><p><strong><em>When administered at <u>physiological doses</u>, systemic testosterone has been associated with mild or no androgenic effects only. These may include acne and hair growth at the site of application but not alopecia, facial hair, voice change, or clitoromegaly.95,117 </em></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>*<u>Prescribing Testosterone in the Absence of Approved Therapy for Females </u></strong></p><p><strong></strong></p><p><strong><em>There is currently no Food and Drug Administration– or European Medicines Agency–approved dosage form for testosterone. <u>A recent publication from the International Society for the Study of Women's Sexual Health provides standards for safely prescribing testosterone to women</u>. <u>It details the identification of appropriate patients, dosing, and monitoring</u>.118</em></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Conclusion</strong></p><p><strong></strong></p><p><strong><em><u>The evidence available suggests a positive safety profile for transdermal testosterone treatment when delivered at physiological concentrations</u>. The best-documented use of testosterone in menopausal women is to increase sexual desire and downstream benefits on arousal, orgasm, sexual self-esteem, and so on. Specifically, there is no evidence that transdermal testosterone significantly increases the risk of breast cancer, myocardial infarction, stroke, thromboembolism, or adverse cardiovascular events. <u>Recent reviews and a global consensus are available</u>.78,95 For those women being treated with aromatase inhibitors, testosterone is unlikely to have a negative impact on their risk of recurrent breast cancer; however, further research is required to confirm this tentative conclusion.</em></strong></p></blockquote><p></p>
[QUOTE="madman, post: 224319, member: 13851"] [B]PART 2: [U]SYSTEMIC TESTOSTERONE [/U] Introduction [/B] [I][B]Testosterone is the most abundant biologically active hormone in women.76 It is produced in the ovaries and adrenal gland and from precursors at the cellular level where it interacts with the androgen receptor.76 It is also the precursor hormone for estradiol and has an indirect effect on the estrogen receptor via aromatization.76 [/B]Testosterone levels decline with age, particularly within the early reproductive years,77,78, and symptoms of androgen deficiency can occur as early as the mid-30s for some women.76 Premature ovarian insufficiency or iatrogenic menopause causes an earlier and more profound decline.79 [B]Symptoms of testosterone deficiency can include sexual problems (particularly desire), fatigue, depression, headaches, cognitive problems, osteoporosis, sarcopenia, and reduced quality of life.79[/B] But despite these symptoms, in all countries other than Australia, there are no licensed testosterone products for female use, and instead, [B]a fractionated dose of an approved transdermal male formulation (prescribed off-license) that approximates physiological testosterone levels in premenopausal women is often recommended.79[/B][/I] [B]*[U]Testosterone Benefits[/U] [/B] [I]There has been very few adequately powered prospective, randomized, placebo-controlled clinical trials looking specifically at the benefits of testosterone therapy in women, mainly because most studies involve small numbers or include women taking concurrent estrogen therapy.78 [B]However, from the available data, studies do suggest androgens are important for bone density, muscle mass, mood, energy, and cognitive function,80–85 and robust trials have been undertaken surrounding testosterone therapy and sexual function in postmenopausal women,78 particularly evaluating its benefits for low sexual desire.[/B] [B]Improvements in sexual desire, arousal, orgasmic function, pleasure, and sexual responsiveness together with a reduction in sexual concerns have been demonstrated among placebo-controlled RCTs in women with hypoactive sexual desire disorder.78 [U]Suggested reasons for this include an increased dopamine release in the central nervous system79 and/or an amplified activation of brain areas involved with sexual arousal (such as the limbic system)[/U].86 [U]It is also possible that there is a direct vasodilatory effect of testosterone on vaginal tissue, causing increased blood flow to this area[/U].87,88 [U]Lastly, testosterone may also have beneficial effects on lower urinary tract function[/U]. [/B]A recent analysis of data from the National Health and Nutrition Examination Survey found that women with low serum testosterone were significantly more likely to have stress or mixed urinary incontinence.89 A suggested reason for this was an anabolic effect of androgens on skeletal muscle and the role of pelvic musculature in maintaining urethral support.89[/I] [B]*[U]Role of Testosterone on GSM[/U] [/B] [I][B]Androgens appear to have a role in maintaining genitourinary tissue structure and function,90,91 and the effects of testosterone on vaginal health appear not to always require its conversion to estradiol by aromatase first. [/B]This was demonstrated in a small study of women with breast cancer taking aromatase inhibitors.92 In this study, intravaginal application of testosterone at a dose of either 150 or 300 μg for 4 weeks was shown to reduce signs and symptoms of GSM. [B]There is a distinct regulation of androgen receptors in different tissue layers of the genital tract. Compared with human vaginal epithelium, there is greater immunostaining for androgen receptors and less immunostaining for estrogen receptors in labial skin.93 [/B]This may have clinical implications, for example, with conditions such as vestibulodynia. In a small study of premenopausal women, those who developed vestibulodynia were more likely to have longer CAG (cytosine-adenine-guanine) repeats in their androgen receptor gene.9[/I] [B]*[U]Risks and Association for Cancer Development [/U][/B] [I][B]Most of the safety data for testosterone use at physiological doses is limited to 24 months of treatment duration,78 and there is a need for longer-term follow-up studies. However, the available data does suggest a good safety profile with transdermal use.78,95,96[/B][/I] [B]*[U]Cardiovascular[/U][/B] [I][B]Transdermal and other nonoral testosterone delivery are not associated with changes in serum lipids, blood pressure, or carbohydrate metabolism95,97; nor has it been associated with more frequent reporting of myocardial infarction, stroke, venous thromboembolism, or cardiovascular death95,98; however, [U]long-term randomized clinical trial data in populations at risk have not been completed to date[/U].[/B] [B]There is even some evidence that it may have favorable cardiovascular effects[/B]. Results from 1 small study show that transdermal testosterone replacement improves functional capacity and insulin resistance in women with chronic heart failure.83 This is interesting because approximately 25% of men with chronic heart failure have biochemical evidence of testosterone deficiency, and low levels have been related to disease progression in men.99 Another small study reported an enhancement of brachial artery dilation following treatment with testosterone implants in postmenopausal women using long-term estrogen therapy.100 Thus, nonoral testosterone may improve endothelial function. It should be mentioned that, unlike the transdermal route, oral testosterone negatively affects high-density lipoprotein cholesterol and low-density lipoprotein cholesterol and is not recommended at this time given available formulations.78,95[/I] [B]*[U]Breast and Endometrium[/U] [/B] [I][B]Transdermal testosterone does not appear to stimulate the endometrium101–103; nor does it appear to increase mammographic breast density95,104,105 or elevate breast cancer risk.78,96,98 Because testosterone aromatizes to estradiol, there have been some concerns that it could have secondary stimulatory effects on the estrogen receptor.[/B] However, in a large 10-year prospective cohort study, there was a 39% lower incidence of invasive breast cancer in users of subcutaneous testosterone implants compared with the age-matched expected incidence, and the authors concluded that, although not novel, testosterone therapy should be investigated as breast cancer prevention.106 [B]There are increasing data demonstrating antiproliferative, proapoptotic, and antiestrogenic stimulatory effects of testosterone in the breast.76,107–111 For women with a history of estrogen-positive breast cancer taking an aromatase inhibitor, transdermal testosterone might help to improve some menopausal symptoms without increasing estradiol levels112,113; however, this finding is limited by small sample sizes and short duration of treatment.[/B] An in vitro study reports that the antiproliferative effects of anastrozole on human breast cancer cells are significantly enhanced by combined treatment with testosterone,114 and another case study has concluded that a higher letrozole dose enables a greater inhibitory effect of testosterone at the breast.115[B] There is also some evidence that testosterone may be beneficial in women with metastatic breast cancer who become refractory to treatment with other endocrine therapies.116[/B][/I] [B]*[U]Androgenic Adverse Effects[/U] [I]When administered at [U]physiological doses[/U], systemic testosterone has been associated with mild or no androgenic effects only. These may include acne and hair growth at the site of application but not alopecia, facial hair, voice change, or clitoromegaly.95,117 [/I] *[U]Prescribing Testosterone in the Absence of Approved Therapy for Females [/U] [I]There is currently no Food and Drug Administration– or European Medicines Agency–approved dosage form for testosterone. [U]A recent publication from the International Society for the Study of Women's Sexual Health provides standards for safely prescribing testosterone to women[/U]. [U]It details the identification of appropriate patients, dosing, and monitoring[/U].118[/I] Conclusion [I][U]The evidence available suggests a positive safety profile for transdermal testosterone treatment when delivered at physiological concentrations[/U]. The best-documented use of testosterone in menopausal women is to increase sexual desire and downstream benefits on arousal, orgasm, sexual self-esteem, and so on. Specifically, there is no evidence that transdermal testosterone significantly increases the risk of breast cancer, myocardial infarction, stroke, thromboembolism, or adverse cardiovascular events. [U]Recent reviews and a global consensus are available[/U].78,95 For those women being treated with aromatase inhibitors, testosterone is unlikely to have a negative impact on their risk of recurrent breast cancer; however, further research is required to confirm this tentative conclusion.[/I][/B] [/QUOTE]
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HRT in Women
Low-dose intravaginal estrogens appear to be a safe and effective treatment for symptoms of GSM
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