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.[1][2] The main hormones involved are estrogen, progesterone and progestin. Some recent therapies include the use of androgens as well.[3]

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.

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 (WHI) was published. That study looked at the effects of hormonal replacement therapy in post-menopausal women. Both age groups had a slightly higher incidence of breast cancer, and both 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. Treatment with unopposed estrogen (the supplementation of endogenous estrogens without a progestogen) 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, a reduced incidence of 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 ages 5059, 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. Subsequent findings 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 0.881.22) in the CEE-alone trial and 1.00 (CI, 0.831.19) 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, 0.510.96) among women ages 50 to 59. This would represent five fewer deaths per 1000 women per 5 years of therapy.

A robust Bayesian meta-analysis from 19 randomized clinical trials reported similar data with a RR of mortality of 0.73 (CI, 0.520.96) 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, 0.871.26) 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. Genetic polymorphism appears to be associated with inter-individual variability in metabolic response to HRT in postmenopausal women.[20][21]

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