Hormone replacement therapy (HRT) in menopause is medical treatment in surgically menopausal, perimenopausal and postmenopausal women.
Its goal is to mitigate discomfort caused by diminished circulating estrogen and progesterone hormones in menopause. Combination HRT is often recommended as it decreases the amount of endometrial hyperplasia and cancer associated with unopposed estrogen therapy.
The main hormones involved are estrogen, progesterone and progestin. Some recent therapies include the use of androgens as well.
The 2002 Women's Health Initiative of the National Institutes of Health found disparate results for all cause mortality with hormone replacement, finding it to be lower when HRT was begun earlier, between age 50-59, but higher when begun after age 60. In older patients, there was an increased incidence of breast cancer, heart attacks and stroke, although a reduced incidence of colorectal cancer and bone fracture.[4] Some of the WHI findings were again found in a larger national study done in the UK, known as The Million Women Study. As a result of these findings, the number of women taking hormone treatment dropped precipitously.[5] The Women's Health Initiative recommended that women with non-surgical menopause take the lowest feasible dose of HRT for the shortest possible time to minimize associated risks.[4]
The current indications for use from the U.S. Food and Drug Administration include short-term treatment of menopausal symptoms, such as vasomotor hot flashes or urogenital atrophy, and prevention of osteoporosis.[6] In 2012, the United States Preventive Task Force concluded that the harmful effects of combined estrogen and progestin are likely to exceed the chronic disease prevention benefits in most women.[7][8] A consensus expert opinion published by the The Endocrine Society stated that when taken during perimenopause, or the initial years of menopause, hormonal therapy carries significantly fewer risks than previously published, and reduces all cause mortality in most patient scenarios.[9] The American Association of Clinical Endocrinology also released a position statement in 2009 that approved of HRT in appropriate clinical scenarios.
These recommendations have not held up with further data analysis however. Later studies released by the WHI showed that all cause mortality was not dramatically different between the groups receiving conjugated equine estrogen (CEE), those receiving estrogen and progesterone, and those not on HRT at all. Specifically, the relative risk for all-cause mortality was 1.04 (confidence interval 0.88–1.22) in the CEE-alone trial and 1.00 (CI, 0.83–1.19) in the estrogen plus progesterone trial.[12] Further, in analysis pooling data from both trials, post-menopausal HRT was associated with a significant reduction in mortality (RR, 0.70; CI, 0.51–0.96) among women ages 50 to 59 yr. This would represent five fewer deaths per 1000 women per 5 yr of therapy.
A robust Bayesian meta-analysis from 19 randomized clinical trials reported similar data with a RR of mortality of 0.73 (CI, 0.52–0.96) in women younger than age 60.[13] However, MHT had minimal effect among those between 60 and 69 years of age (RR, 1.05; CI, 0.87–1.26) and was associated with a borderline significant increase in mortality in those between 70 to 79 years of age (RR, 1.14; CI, 0.94 –1.37; P for trend < 0.06).[14] Similarly, in the HERS trial, with participants having a mean age of 66.7 yr, MHT did not reduce in total mortality (RR, 1.08; CI, 0.84 –1.38).[15] A 2003 meta-analysis of 30 randomized trials of menopausal HRT in relation to mortality showed that it was associated with a nearly 40% reduction in mortality in trials in which participants had a mean age of less than 60 yr or were within 10 yr of menopause onset but was unrelated to mortality in the other trials.[16] The findings in the younger age groups were similar to those in the observational Nurses' Health Study (RR for mortality, 0.63; CI, 0.56 – 0.70).[9][17]
The beneficial potential of HRT was bolstered in a consensus expert opinion published by the The Endocrine Society, which stated that when taken during perimenopause, or the initial years of menopause, hormonal therapy carries significantly fewer risks than previously published, and reduces all cause mortality in most patient scenarios.[9] The American Association of Clinical Endocrinology released a position statement in 2009 that approved of HRT in the appropriate clinical scenario.
Proprietary mixtures of progestins and conjugated equine estrogens are a commonly prescribed form of HRT. As the most common and longest-prescribed type of estrogen used in HRT, most studies of HRT involve CEE. More recently developed forms of drug delivery include suppositories, subdermal implants, skin patches and gels. They have more local effect, lower doses, fewer side effects and constant rather than cyclical serum hormone levels.[18]
The data published by the WHI suggested supplemental estrogen increased risk of venous emboli and breast cancer but was protective against osteoporosis and colorectal cancer, while the impact on cardiovascular disease was mixed.[19] These results were later confirmed in trials from the United Kingdom, but not in more recent studies from France and China.
Data from numerous studies have consistently found that HRT leads to improvements in aspects of post-menopausal sexual dysfunction.[3] Sexuality is a critical aspect of quality of life for the large majority of menopausal women; therefore, any features of the menopausal transition that can negatively affect a woman’s sexuality have the ability to significantly alter her quality of life. The most prevalent of female sexual dysfunctions liked to menopause include lack of desire and low libido, both of which can be explained by changes in hormonal physiology.[2]
Improvements in sexual pain, vaginal lubrication and orgasm are found to be statistically different from those using HRT.[2] Estrogens have positive effects of mood, sexual function, target end organs, and cognitive function. It has also been shown to prevent amyloid plaque formation, oxiadative stress, or deterioration of the cholinergic neurotransmitter system, all of which contribute to the etiology of Alzheimer’s Disease.[20] There are several options of HRTs for women. These can include the use of estrogens alone (ERT), a combination of estrogens with one of several progestins as HRT, or the combination of estrogens, progestins, and androgens as HRT.
The impact of hormone replacement on cardiovascular morbidity is a subject of much controversy in the medical literature. The reduced risk of cardiovascular diseases associated with hormone replacement therapy (HRT), reported in observational studies, has not been subsequently confirmed in randomized clinical trials. The increased risk of cardiovascular disease in the WHI was not statistically significant, and only found in the oldest women, and those who started HRT late after menopause began.[24] The increase in risks of coronary heart disease in the treatment arm of the study varied according to age and years since onset of menopause. Women aged 50 to 59 using HRT showed a trend towards lower risk of coronary heart disease,[25] as did women who were within five years of the onset of menopause.[26]
The adverse cardiovascular outcomes may only apply to oral dosing with the progestin and equine estrogens in oral systemic therapy, while topical estradiol and estriol may not produce the same risks, due to the absence of anabolic effects of hepatic vitamin K dependent clotting factors.[22]
Another recent randomized controlled trial found HRT may reduces development of heart disease and reduce the incidence of heart attack in women between 50 and 59, although not in women past the age of 60. The mechanism may have something to do with the contradictory effects of increasing propensity for clotting, versus positive effect on the lipid profile.[23] Follow-up studies are being performed which are intended to confirm these findings. The increased risk of breast cancer remains.
Firstly, if one is to decrease testosterone in MtF transsexuals, it is likely that sexual desire and arousal would be inhibited; alternatively, if high doses of estrogen negatively impact sexual desire, which has been found in some research with natal women, it is hypothesized that combining androgens with high levels of estrogen would intensify this outcome.[50] Unfortunately, to date there haven’t been any randomized clinical trials looking at the relationship between type and dose of cross-sex hormone therapy, so the relationship between them remains unclear.[50] Typically, the estrogens given to MtF transsexuals were 2-3 times higher than the recommended dose for HRT in postmenopausal women.[49] While pharmokinetic studies indicate that by taking these increased doses it may lead to a higher boost in plasma estradiol levels; however, since the long-term side effects haven’t been studied, the safety of this route is unclear.[49]
As with any pharmacological or hormone treatment, there are potential side effects, which in the case of hormone therapy include changes in sexual functioning. These have the ability to significantly impact sexual functioning, either directly or indirectly through the various side effects, such as cerebrovascular disorders, obesity, and mood fluctuations.[50] In addition, some research has found an onset of diabetes following feminizing hormone therapy, which impairs sexual response. Whatever route an individual and his or her doctor choose to take, it is important to consider both the medical risks of hormone therapy as well as the psychological needs of the patient.
Its goal is to mitigate discomfort caused by diminished circulating estrogen and progesterone hormones in menopause. Combination HRT is often recommended as it decreases the amount of endometrial hyperplasia and cancer associated with unopposed estrogen therapy.
The main hormones involved are estrogen, progesterone and progestin. Some recent therapies include the use of androgens as well.
The 2002 Women's Health Initiative of the National Institutes of Health found disparate results for all cause mortality with hormone replacement, finding it to be lower when HRT was begun earlier, between age 50-59, but higher when begun after age 60. In older patients, there was an increased incidence of breast cancer, heart attacks and stroke, although a reduced incidence of colorectal cancer and bone fracture.[4] Some of the WHI findings were again found in a larger national study done in the UK, known as The Million Women Study. As a result of these findings, the number of women taking hormone treatment dropped precipitously.[5] The Women's Health Initiative recommended that women with non-surgical menopause take the lowest feasible dose of HRT for the shortest possible time to minimize associated risks.[4]
The current indications for use from the U.S. Food and Drug Administration include short-term treatment of menopausal symptoms, such as vasomotor hot flashes or urogenital atrophy, and prevention of osteoporosis.[6] In 2012, the United States Preventive Task Force concluded that the harmful effects of combined estrogen and progestin are likely to exceed the chronic disease prevention benefits in most women.[7][8] A consensus expert opinion published by the The Endocrine Society stated that when taken during perimenopause, or the initial years of menopause, hormonal therapy carries significantly fewer risks than previously published, and reduces all cause mortality in most patient scenarios.[9] The American Association of Clinical Endocrinology also released a position statement in 2009 that approved of HRT in appropriate clinical scenarios.
Health effects
There have been a number of large scale cross sectional and cohort studies on the effects of hormone replacement in menopause, the largest being in the United States, the United Kingdom and China. Demographically, the vast majority of data available is in post-menopausal American women with concurrent pre-existing conditions, and with a mean age of over 60 years.[10] In 2002 the Women's Health Initiative was published looking at the effects of hormonal replacement therapy in post-menopausal women. Both age groups had a slightly higher incidence of breast cancer; heart attack and stroke were increased in older patients, although not in younger participants. Progesterone is the major anabolic hormone for breast tissue, and accordingly breast cancer was not increased in patients who were on estrogen therapy alone after hysterectomy. Sole therapy with estrogen is contraindicated if the uterus is still present due its proliferative effect on the endometrium. The WHI also found a reduced incidence of colorectal cancer when estrogen and progesterone were used together, and most importantly, bone fractures. Ultimately, the study found disparate results for all cause mortality with hormone replacement, finding it to be lower when HRT was begun during the fifth decade of life, but higher when begun after age 60.[4] Some findings of the WHI were reconfirmed in a larger national study done in the UK, known as The Million Women Study. Coverage of the WHI findings led to a reduction in the number of post-menopausal women on hormone replacement therapy.[11] The authors of the study recommended that women with non-surgical menopause take the lowest feasible dose of HRT, and for the shortest possible time, to minimize risk.[4]These recommendations have not held up with further data analysis however. Later studies released by the WHI showed that all cause mortality was not dramatically different between the groups receiving conjugated equine estrogen (CEE), those receiving estrogen and progesterone, and those not on HRT at all. Specifically, the relative risk for all-cause mortality was 1.04 (confidence interval 0.88–1.22) in the CEE-alone trial and 1.00 (CI, 0.83–1.19) in the estrogen plus progesterone trial.[12] Further, in analysis pooling data from both trials, post-menopausal HRT was associated with a significant reduction in mortality (RR, 0.70; CI, 0.51–0.96) among women ages 50 to 59 yr. This would represent five fewer deaths per 1000 women per 5 yr of therapy.
A robust Bayesian meta-analysis from 19 randomized clinical trials reported similar data with a RR of mortality of 0.73 (CI, 0.52–0.96) in women younger than age 60.[13] However, MHT had minimal effect among those between 60 and 69 years of age (RR, 1.05; CI, 0.87–1.26) and was associated with a borderline significant increase in mortality in those between 70 to 79 years of age (RR, 1.14; CI, 0.94 –1.37; P for trend < 0.06).[14] Similarly, in the HERS trial, with participants having a mean age of 66.7 yr, MHT did not reduce in total mortality (RR, 1.08; CI, 0.84 –1.38).[15] A 2003 meta-analysis of 30 randomized trials of menopausal HRT in relation to mortality showed that it was associated with a nearly 40% reduction in mortality in trials in which participants had a mean age of less than 60 yr or were within 10 yr of menopause onset but was unrelated to mortality in the other trials.[16] The findings in the younger age groups were similar to those in the observational Nurses' Health Study (RR for mortality, 0.63; CI, 0.56 – 0.70).[9][17]
The beneficial potential of HRT was bolstered in a consensus expert opinion published by the The Endocrine Society, which stated that when taken during perimenopause, or the initial years of menopause, hormonal therapy carries significantly fewer risks than previously published, and reduces all cause mortality in most patient scenarios.[9] The American Association of Clinical Endocrinology released a position statement in 2009 that approved of HRT in the appropriate clinical scenario.
Proprietary mixtures of progestins and conjugated equine estrogens are a commonly prescribed form of HRT. As the most common and longest-prescribed type of estrogen used in HRT, most studies of HRT involve CEE. More recently developed forms of drug delivery include suppositories, subdermal implants, skin patches and gels. They have more local effect, lower doses, fewer side effects and constant rather than cyclical serum hormone levels.[18]
The data published by the WHI suggested supplemental estrogen increased risk of venous emboli and breast cancer but was protective against osteoporosis and colorectal cancer, while the impact on cardiovascular disease was mixed.[19] These results were later confirmed in trials from the United Kingdom, but not in more recent studies from France and China.
Management of sexual dysfunction
Hormone replacement therapy's goal is to mitigate discomfort caused by diminished circulating estrogen and progesterone hormones in menopause. In those with premature or surgically induced menopause, a combination HRT is often recommended, as it may also prolong life and may decrease a woman's chances of developing endometrial cancers associated with unopposed estrogen therapy, as well by decreasing the incidence of dementia.[1][2] The main hormones involved are estrogen, progesterone and progestin. Some recent therapies include the use of androgens as well.[3]Data from numerous studies have consistently found that HRT leads to improvements in aspects of post-menopausal sexual dysfunction.[3] Sexuality is a critical aspect of quality of life for the large majority of menopausal women; therefore, any features of the menopausal transition that can negatively affect a woman’s sexuality have the ability to significantly alter her quality of life. The most prevalent of female sexual dysfunctions liked to menopause include lack of desire and low libido, both of which can be explained by changes in hormonal physiology.[2]
Improvements in sexual pain, vaginal lubrication and orgasm are found to be statistically different from those using HRT.[2] Estrogens have positive effects of mood, sexual function, target end organs, and cognitive function. It has also been shown to prevent amyloid plaque formation, oxiadative stress, or deterioration of the cholinergic neurotransmitter system, all of which contribute to the etiology of Alzheimer’s Disease.[20] There are several options of HRTs for women. These can include the use of estrogens alone (ERT), a combination of estrogens with one of several progestins as HRT, or the combination of estrogens, progestins, and androgens as HRT.
Cardiovascular effects
At the time of menopause, there are predictable effects on the lipid profile. Specifically, HDL decreases, while LDL, triglycerides and lipoprotein a increase. Supplemental estrogen improves the lipid profile by reversing each of these effects. Beyond this, it improves cardiac contractility, coronary artery blood flow, metabolism of carbohydrates, and decreases platelet aggregation and plaque formation. At the molecular level HRT may promote reverse cholesterol transport (RCT) via the induction of cholesterol ABC transporters.[23]The impact of hormone replacement on cardiovascular morbidity is a subject of much controversy in the medical literature. The reduced risk of cardiovascular diseases associated with hormone replacement therapy (HRT), reported in observational studies, has not been subsequently confirmed in randomized clinical trials. The increased risk of cardiovascular disease in the WHI was not statistically significant, and only found in the oldest women, and those who started HRT late after menopause began.[24] The increase in risks of coronary heart disease in the treatment arm of the study varied according to age and years since onset of menopause. Women aged 50 to 59 using HRT showed a trend towards lower risk of coronary heart disease,[25] as did women who were within five years of the onset of menopause.[26]
The adverse cardiovascular outcomes may only apply to oral dosing with the progestin and equine estrogens in oral systemic therapy, while topical estradiol and estriol may not produce the same risks, due to the absence of anabolic effects of hepatic vitamin K dependent clotting factors.[22]
Another recent randomized controlled trial found HRT may reduces development of heart disease and reduce the incidence of heart attack in women between 50 and 59, although not in women past the age of 60. The mechanism may have something to do with the contradictory effects of increasing propensity for clotting, versus positive effect on the lipid profile.[23] Follow-up studies are being performed which are intended to confirm these findings. The increased risk of breast cancer remains.
Effects on sexuality in transsexuals
Cross-sex hormone treatment is an integral component in the medical treatment of transsexuals, as the hormones can lead to decreasing the dichotomy between an individual's body and their gender identity.[49] Managing long-term hormonal regimens have not been studied and are difficult to estimate because research on the long-term use of hormonal therapy has not been noted.[49] However, it is possible to speculate the outcomes of these therapies on transsexual people based on the knowledge of the current effects of gonadal hormones on sexual functioning in cisgender men and women.[50]Firstly, if one is to decrease testosterone in MtF transsexuals, it is likely that sexual desire and arousal would be inhibited; alternatively, if high doses of estrogen negatively impact sexual desire, which has been found in some research with natal women, it is hypothesized that combining androgens with high levels of estrogen would intensify this outcome.[50] Unfortunately, to date there haven’t been any randomized clinical trials looking at the relationship between type and dose of cross-sex hormone therapy, so the relationship between them remains unclear.[50] Typically, the estrogens given to MtF transsexuals were 2-3 times higher than the recommended dose for HRT in postmenopausal women.[49] While pharmokinetic studies indicate that by taking these increased doses it may lead to a higher boost in plasma estradiol levels; however, since the long-term side effects haven’t been studied, the safety of this route is unclear.[49]
As with any pharmacological or hormone treatment, there are potential side effects, which in the case of hormone therapy include changes in sexual functioning. These have the ability to significantly impact sexual functioning, either directly or indirectly through the various side effects, such as cerebrovascular disorders, obesity, and mood fluctuations.[50] In addition, some research has found an onset of diabetes following feminizing hormone therapy, which impairs sexual response. Whatever route an individual and his or her doctor choose to take, it is important to consider both the medical risks of hormone therapy as well as the psychological needs of the patient.
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