ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Menopausal hormone therapy: Benefits and risks

Menopausal hormone therapy: Benefits and risks
Literature review current through: May 2024.
This topic last updated: May 24, 2022.

INTRODUCTION — Normal women have menopause at a mean age of 51 years, with 95 percent becoming menopausal between the ages of 45 to 55 years. During the menopause transition and postmenopause, many women experience moderate to severe hot flashes. Systemic estrogen is the most effective treatment available for relief of hot flashes. Postmenopausal women may also experience vulvovaginal symptoms including dyspareunia, which can be effectively treated by local administration of estrogen. An overview of the risks and benefits of menopausal hormone therapy (MHT) will be provided here. The management of women with hot flashes and other menopausal symptoms is reviewed in greater detail separately. (See "Treatment of menopausal symptoms with hormone therapy" and "Menopausal hot flashes" and "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment".)

OVERVIEW

Individualized approach — A clinical practice guideline published by the Endocrine Society presents an individualized approach to treatment based upon calculating a woman's baseline cardiovascular and breast cancer risks prior to initiating therapy (table 1) [1]. Similar to most other guidelines, the Endocrine Society agrees that menopausal hormone therapy (MHT) is indicated for the management of menopausal symptoms but not for the prevention of cardiovascular disease, osteoporosis, or dementia [2-5]. The benefits of MHT appear to outweigh its risks for most symptomatic women who are either under age 60 years or less than 10 years from menopause (figure 1) [1,3,4]. (See "Treatment of menopausal symptoms with hormone therapy".)

Women's Health Initiative (WHI) — In the past, MHT was also often prescribed for prevention of coronary heart disease (CHD) and osteoporosis, based upon epidemiologic data demonstrating a protective effect of estrogen on the heart and bone. However, data from the WHI, a set of two hormone therapy (HT) trials (unopposed estrogen and continuous, combined estrogen-progestin therapy versus placebo) in approximately 27,000 postmenopausal women (mean age 63 years), showed a number of adverse outcomes, including an excess risk of CHD, stroke, venous thromboembolism (VTE), and breast cancer [6-8].

Similar results were noted in a meta-analysis of 22 studies [9] and an updated 2017 United States Preventive Services Task Force (USPSTF) meta-analysis of 18 trials [5,10]. Both included the WHI, and the mean age of subjects was >60 years. In the USPSTF analysis, results were largely based upon the WHI. Based upon their meta-analysis, the USPSTF continues to recommend against the use of both combined estrogen-progestin and unopposed estrogen (for women posthysterectomy) for the prevention of chronic conditions [5,10]. However, they do not address the use of MHT for menopausal symptoms, nor do they present the WHI data showing the low absolute risks of MHT in younger menopausal women [11]. (See 'Estimates of risk in women 50 to 59 years' below.)

Many expert groups do suggest MHT for younger postmenopausal women with moderate to severe symptoms and no contraindications to estrogen use [1,3,4]. In the past, some experts advised that MHT be limited to five years of use. However, hot flashes can last a decade or more in many women. Therefore, some professional societies suggest that longer therapy is reasonable in select women with persistent symptoms. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Follow-up and monitoring'.)

While the WHI clearly demonstrated the adverse effects of MHT in older postmenopausal women (over age 60 years), this is not the age group that presents with new onset of menopausal symptoms. Almost all women who seek medical therapy for menopausal symptoms do so in their late 40s or 50s. (See 'Estimates of risk in women 50 to 59 years' below.)

When counseling women about MHT, the clinician should provide estimates for the absolute risks and benefits for up to five years of treatment in young postmenopausal women (eg, <10 years postmenopausal or ages 50 to 59 years). Women should be reassured that the absolute risk of complications for healthy, young postmenopausal women taking HT for five years is very low (figure 1).

Decline in MHT use — Use of menopausal hormone therapy (MHT) decreased significantly in the decade after publication of the WHI results in 2002. In a report from the National Health and Nutrition Examination Survey (NHANES), use of oral MHT in the United States in women over age 40 decreased from 22 percent in 1999 to 2002 to 12 percent in 2003 to 2004, reaching a low of 4.7 percent in 2009 to 2010 [12]. This continued decline occurred in spite of reassuring data that the benefits of MHT outweigh the risks for most young menopausal women (within 10 years of menopause or under age 60 years). (See 'Younger, postmenopausal women' below.)

Health and economic impact — The decline in use of unopposed estrogen therapy post-WHI appears to have resulted in an increase in health care costs for women in their 50s, the group most likely to seek treatment for menopausal symptoms [13]. In an analysis stratified by age, the decline in estrogen-only therapy use over 13 years was associated with:

A USD $4.1 billion increase in expenditure for excess chronic diseases (37,549 excess events [breast cancer, coronary heart disease, colon cancer, fractures]) among women in their 50s

A USD $1.5 and 4.4 billion decrease in expenditures among women in their 60s and 70s, respectively (women who would not currently be considered candidates for hormone therapy)

The benefits of estrogen for symptom relief (hot flashes) were not included in this analysis as it was not an outcome in the WHI.

In a second analysis of the impact of avoiding unopposed estrogen therapy post-WHI (women posthysterectomy), an important increase in mortality rates in women ages 50 to 59 years was calculated (a minimum of 18,601 and as many as 91,601 additional deaths) [14].

An earlier analysis from WHI investigators reported savings of USD $35 billion dollars in health care costs based upon the decline in combined estrogen-progestin therapy use post-WHI [15]. However, the analysis was not stratified by age and, therefore, does not reflect the potential increase in health care costs experienced when younger women do not take hormone therapy.

ESTIMATES OF RISK IN WOMEN 50 TO 59 YEARS — As noted above, the Women's Health Initiative (WHI) demonstrated adverse effects of menopausal hormone therapy (MHT) in older postmenopausal women (over age 60 years or more than 10 years since menopause); this is not the age group that presents with new onset of menopausal symptoms. Almost all women who seek medical therapy for menopausal symptoms do so in their late 40s or 50s. When counseling symptomatic women considering hormone therapy (HT), the clinician should provide the best estimate of potential risks and benefits for five years of use based upon data from women in their 50s [1].

Although most available HT clinical trial data are from women over age 60 years, estimates of the absolute risks and benefits for women starting MHT in their 50s has been published (figure 1) [1,8,16]. The intervention phase of the WHI was the source of data for the analysis. Data were expressed as the attributable excess risk or benefit for five years of combined estrogen-progestin or unopposed estrogen use in women starting treatment between ages 50 to 59 years. Overall, the risk-benefit profile was more favorable for women ages 50 to 59 compared with older women [8].

Combined estrogen-progestin therapy – Number of cases (additional or fewer) per 1000 women per five years of hormone use when compared with placebo (figure 1):

Coronary heart disease (CHD) – 2.5 additional cases

Invasive breast cancer – 3 additional cases

Stroke – 2.5 additional cases

Pulmonary embolism – 3 additional cases

Colorectal cancer – 0.5 fewer cases

Endometrial cancer – No difference

Hip fracture – 1.5 fewer cases

All-cause mortality – 5 fewer events

Estrogen-alone therapy – Number of cases (additional or fewer) per 1000 women per five years of hormone use when compared with placebo (figure 1):

CHD – 5.5 fewer cases

Invasive breast cancer – 2.5 fewer cases

Stroke – 0.5 fewer cases

Pulmonary embolism – 1.5 additional cases

Colorectal cancer – 0.5 fewer cases

Hip fracture – 1.5 additional cases (of note, there was an overall decrease in all osteoporotic fractures in both the estrogen and combined estrogen-progestin groups)

All-cause mortality – 5.5 fewer events

This analysis highlights that the overall risks of HT in younger postmenopausal women are considerably lower than those for older women (eg, women in the WHI). The major explanation for the difference in absolute excess risk between older and younger postmenopausal women is the lower baseline risk of CHD, stroke, venous thromboembolism (VTE), and breast cancer in younger postmenopausal women [8,16].

A comprehensive overview of findings of the intervention and postintervention phases of the WHI (a total of 13 years of follow-up) highlighted differences in the risk-benefit profiles between combined conjugated estrogen-medroxyprogesterone acetate and unopposed conjugated estrogen therapy, as well as the impact of age on the effects of HT [8]. As summarized throughout this topic, combined therapy was associated with a higher risk of CHD and breast cancer than unopposed estrogen.

CARDIOVASCULAR EFFECTS — The Women's Health Initiative (WHI) reported that many of the apparent benefits of menopausal hormone therapy (MHT) seen in epidemiologic studies were not found in the randomized trials. Rather than a reduction in risk of coronary heart disease (CHD) events, an increase was seen. Possible methodologic explanations for the striking difference in CHD data include "healthy user" bias, older age of the study population, and timing of initiation of therapy [17,18]. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Timing of exposure' and "Estrogen and cognitive function".)

Coronary heart disease — The overall rate of coronary events was increased with combined conjugated equine estrogen-medroxyprogesterone acetate therapy (plus eight additional events per 10,000 person-years, respectively; hazard ratio [HR] 1.23, 95% CI -0.3 to 16.0) [19,20]. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Coronary heart disease'.)

In the unopposed estrogen trial, use of conjugated equine estrogen did not appear to affect the incidence of CHD events over an average follow-up of 6.8 years (HR for conjugated equine estrogen versus placebo 0.96, 95% CI 0.78-1.16 [three fewer events per 10,000 person-years]) [7,19].

Younger, postmenopausal women — Data from a coronary angiographic study [21], a WHI coronary artery calcification study and age-based subgroup analysis [19,22], and a 2006 meta-analysis that included the WHI [23] all suggest that the timing of treatment initiation affects the risk of CHD; in the WHI, women who were <10 years since menopause or between the ages of 50 to 59 years did not have excess risk [19] or possibly had a reduction in risk [23]. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Timing of exposure'.)

Additional reassuring data come from clinical trials in younger postmenopausal women:

A subgroup analysis of a 10-year MHT trial for osteoporosis (Danish Osteoporosis Prevention Study [DOPS]) reported that women taking MHT had a reduced risk of the composite outcome of mortality, heart failure, or myocardial infarction, without an increased risk of stroke, venous thromboembolism (VTE), or cancer [24]. However, there are methodologic concerns about this study, including lack of placebo group [25] and use of a composite outcome that was not described in the original study protocol [26].

The Kronos Early Estrogen Prevention Study (KEEPS), a four-year, randomized, double-blind, placebo-controlled trial (in women ages 45 to 54 years), reported that, when combined with cyclical monthly oral progesterone, oral conjugated estrogen (0.45 mg daily) or transdermal estrogen (50 mcg daily) reduced menopausal symptoms. Surrogate markers of atherosclerosis (coronary artery calcium and carotid intima-media thickness [CIMT]) were not significantly different in the hormone therapy (HT) and placebo groups [27].

In the Early versus Late Intervention Trial with Estradiol (ELITE), 643 postmenopausal women, stratified according to time since menopause (<6 or >10 years; early versus late, respectively), received oral estradiol (with progesterone for women with a uterus) or placebo for a median of five years [28]. Progression of subclinical atherosclerosis (measured as CIMT) was slower than placebo in the early intervention group, while rates of progression were similar to placebo in the late intervention group. Estradiol had no effect on computed tomography (CT) coronary artery calcium in either the early or late intervention group.

A 2015 meta-analysis of 19 trials of oral (including the WHI), but not transdermal, MHT in over 40,000 postmenopausal women performed subgroup analyses in women who started MHT less than 10 years after menopause [29]. Results included the following:

A lower risk of CHD (composite of death from cardiovascular causes and nonfatal myocardial infarction) compared with placebo (relative risk [RR] 0.52, 95% CI 0.29-0.96; eight fewer cases of heart disease per 1000 women treated per year).

A lower mortality rate (RR 0.70, 95% CI 0.52-0.95; six fewer deaths per 1000 women treated per year).

The quality of the evidence for the mortality and CHD meta-analyses was rated as moderate (rated down one level because DOPS, a methodologically flawed trial [24], was included). When DOPS was removed, the analyses were no longer significant.

Estimates of the overall risks and benefits for younger postmenopausal women taking five years of HT are described above. (See 'Estimates of risk in women 50 to 59 years' above.)

Stroke — In the WHI, a 31 percent increase in stroke risk was seen with combined conjugated equine estrogen-medroxyprogesterone acetate use compared with placebo (intention-to-treat HR 1.31, 95% CI 1.02-1.68). The increase in risk is for ischemic but not hemorrhagic stroke [30]. Excess risk was seen in all age groups [19] and was independent of other known risk factors for stroke. In the unopposed estrogen trial, stroke risk was significantly increased with conjugated equine estrogen versus placebo (HR 1.39, 95% CI 1.1-1.77) [7].

In a subgroup analysis that combined data from both trials, the RR of stroke did not vary by patient age. However, the authors calculated an extremely low absolute excess risk of stroke in women ages 50 to 59 years (0.15 versus 0.13 cases per 100 women per year for HT and placebo, respectively) [19].

Stroke risk appears to be lower with transdermal compared with oral estrogen preparations. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Stroke'.)

Estimates of the overall risks and benefits for younger postmenopausal women taking five years of HT are described above. (See 'Estimates of risk in women 50 to 59 years' above.)

Venous thromboembolism — The rate of VTE in the WHI increased with combined conjugated equine estrogen-medroxyprogesterone acetate therapy (34 versus 16 per 10,000 person-years, HR 2.06, unadjusted 95% CI 1.6-2.7) [31]. The increase in risk was similar for both deep vein thrombosis (DVT) and pulmonary embolism (PE) and was also seen in the Heart and Estrogen/Progestin Replacement Study (HERS) trials.

VTE risk was also increased with unopposed conjugated equine estrogen when compared with placebo (HR 1.33, 95% CI 0.99-1.79) [7]. However, only the increased rate of DVT reached statistical significance.

For women ages 50 to 59 years, the group most likely to be taking HT, the estimates of excess VTE risk in one analysis were 4.7 and 1.3 additional cases per 1000 women per five years of combined estrogen-progestin or unopposed estrogen use, respectively [16]. (See 'Estimates of risk in women 50 to 59 years' above.)

The risk of VTE appears to be lower with transdermal compared with oral estrogen preparations. In addition, risk may vary by type of progestin (higher with medroxyprogesterone acetate). This issue is discussed in greater detail elsewhere. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Venous thromboembolism'.)

MORTALITY — Available data suggest that menopausal hormone therapy (MHT) is not associated with an increase in mortality rates when compared with placebo. Younger menopausal women (ages 50 to 59) may actually have a reduction in all-cause mortality with MHT [32]. Early epidemiologic studies reported a reduction in mortality rates with MHT [6,7,19,32,33]. After excess cardiovascular risks were reported in early Women's Health Initiative (WHI) reports, there were concerns that MHT could actually be associated with an increase in cardiovascular mortality. However, this does not appear to be the case.

The best available data come from an 18-year follow-up report from the WHI hormone therapy (HT) trials of unopposed estrogen (median duration seven years) or estrogen-progestin therapy (mean duration five years) versus placebo [32]. All-cause mortality was similar (approximately 27 percent) in women taking MHT or placebo. Cardiovascular and cancer (including breast cancer) mortality rates were also similar for MHT and placebo. When analyzed by 10-year age groups, MHT reduced all-cause mortality in women ages 50 to 59 years during the intervention phase (hazard ratio [HR] 0.61, 95% CI 0.43-0.87) and possibly after 18 years of follow-up, although the reduction was no longer statistically significant (HR 0.87, 95% CI 0.76-1.0).

In an earlier analysis, women ages 50 to 59 years, the group most likely to be taking HT, the estimate of mortality benefit in one analysis was 5.3 and 5 fewer deaths per 1000 per five years of combined estrogen-progestin or unopposed estrogen use, respectively [16]. (See 'Estimates of risk in women 50 to 59 years' above.)

Other evidence for the effect of HT on mortality comes from a meta-analysis of 19 randomized controlled trials in younger postmenopausal women, including age-specific data (women 50 to 59 years) from the two WHI trials and 17 trials with a mean subject age <60 years [34]. In the pooled analysis of approximately 16,000 women (mean age 55 years) followed for an average of 5.1 years, HT reduced mortality by 27 percent when compared with placebo (relative risk [RR] 0.73, 95% CI 0.52-0.96). The absolute reduction in mortality was 0.84 percent (ie, 1 in every 119 women treated with HT did not die at five years compared with untreated patients).

These data provide additional reassurance that HT is a safe option for the treatment of symptoms in younger postmenopausal women [35]. (See 'Estimates of risk in women 50 to 59 years' above and "Treatment of menopausal symptoms with hormone therapy".)

CANCER

Breast cancer — In the Women's Health Initiative (WHI), the risk of invasive breast cancer was significantly increased with combined hormone therapy (HT) at an average follow-up of 5.6 years (hazard ratio [HR] 1.24, unadjusted 95% CI 1.01-1.54) [36].

In contrast to the results of the combined HT trial, a trend towards a slightly lower rate of breast cancer risk was seen in the unopposed estrogen trial (HR 0.77 for unopposed estrogen versus placebo, 95% CI 0.59-1.01) [7]. This comparison narrowly missed statistical significance (p = 0.06). Other issues including mammographic density, breast cancer prognosis, use of HT in breast cancer survivors, and the impact of time since menopause on risk ("gap time") are all reviewed separately. (See "Menopausal hormone therapy and the risk of breast cancer".)

Estimates of the absolute risks of breast cancer in younger postmenopausal women taking five years of HT are described above. (See 'Estimates of risk in women 50 to 59 years' above.)

A 2019 meta-analysis of all available epidemiologic evidence on the association between menopausal hormone therapy (MHT) use and breast cancer risk has been published [37]. The analysis included nearly 145,000 women with breast cancer (51 percent of whom had used MHT) and nearly 425,000 without breast cancer. Their findings included:

Similar to the WHI, estrogen-progestin regimens were associated with excess breast cancer risk. An excess risk was also seen with estrogen-only regimens (a reduction in risk was seen in the WHI). There was no excess risk with vaginal estrogens.

Breast cancer risk increased with the duration of systemic MHT use. Unlike previous studies, obesity was not associated with excess risk; instead, it attenuated risk.

The authors of the study calculated that for women of average weight, five years of MHT use starting at age 50 years would increase their 20-year risk of breast cancer (between the ages of 50 and 69 years) by approximately:

One in every 50 users of estrogen plus daily progestin

One in every 70 users of estrogen plus intermittent progestin

One in every 200 users of estrogen-only regimens

There were important limitations in this study. Unlike the WHI, a set of randomized clinical trials, this meta-analysis included only observational studies. In addition, the majority of women included in the analysis were using conjugated estrogens and medroxyprogesterone acetate. Current MHT regimens typically include lower doses of estrogen as well as a different type and route (eg, transdermal 17-beta estradiol [17-beta-E2]), with micronized progesterone, which is now considered the progestin of choice by most experts [1,3,4]. It is thought that transdermal 17-beta-E2 and micronized progesterone may be associated with lower breast cancer risk than conjugated estrogens and medroxyprogesterone acetate, although data are not yet conclusive. (See "Menopausal hormone therapy and the risk of breast cancer", section on 'Type of progestin'.)

While this meta-analysis has renewed concerns for some about the association between MHT and breast cancer, we continue to suggest an individualized approach when counseling symptomatic postmenopausal women about treatment. This includes putting the potential risk of breast cancer (and cardiovascular disease) in the context of the benefits of MHT (eg, relief of vasomotor symptoms, improved sleep and quality of life, and prevention of bone loss) (figure 1) [1,3,4].

Ovarian cancer — A nonsignificant increase in the risk of ovarian cancer was observed in the WHI with combined estrogen-progestin therapy (HR 1.6, 95% CI 0.8-3.2; 42 versus 27 cases per 100,000 person-years in the hormone and placebo groups, respectively) [38]. The excess risk was not statistically significant and would be approximately 0.75 cases per 1000 women treated for five years [16]. There were no differences in the distributions of tumor grade, stage, or histology. Because of the small number of ovarian cancer cases and the limited precision in estimating effects in the trial, the authors concluded that these results should not affect a woman's decision to take MHT for symptomatic relief.

A meta-analysis of 52 epidemiologic studies including 21,488 postmenopausal women with ovarian cancer suggests that there is a small excess risk of ovarian cancer with MHT use [39]. Ovarian cancer risk was greater in ever-users versus never-users of MHT (relative risk [RR] 1.14, 95% CI 1.10-1.19). Risks were similar for estrogen-only and estrogen-progestin users. The calculated absolute excess risk associated with MHT was very low; five years of MHT use in women ages 50 to 54 years would result in approximately one additional ovarian cancer case per 1000 users and one ovarian cancer death per 1700 users. Age at initiation had little effect on RR, nor did smoking, body mass index, or past use of oral contraceptives.

In one case-control study of 162 matched sets of women with BRCA1 or BRCA2 mutations, postmenopausal HT did not appear to increase the risk of ovarian cancer; odds ratio (OR) with every use of HT was 0.93 (95% CI 0.56-1.56) [40].

We do not consider ovarian cancer to be a major consideration when deciding to take MHT for symptomatic relief, because the absolute risk of ovarian cancer with MHT is very low. The management of menopausal symptoms and other risk factors for ovarian cancer are discussed in detail elsewhere. (See "Treatment of menopausal symptoms with hormone therapy" and "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'Epidemiology and risk factors'.)

Endometrial hyperplasia and carcinoma — Treatment of postmenopausal women with estrogen alone increases the risk of endometrial hyperplasia and carcinoma [41]. Within one year, endometrial hyperplasia can be demonstrated in 20 to 50 percent of women receiving unopposed estrogen [42,43]. Furthermore, multiple case-control and prospective studies have shown an increased incidence of endometrial carcinoma with long-term unopposed estrogen, with the RR ranging from 3.1 to 15 [44-47]. A meta-analysis of clinical trials of HT and endometrial hyperplasia risk is reviewed separately. (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis", section on 'Risk factors'.)

If the absolute risk of endometrial carcinoma in postmenopausal women is approximately 1 in 1000, then the absolute risk in women taking unopposed estrogen increases to approximately 1 in 100 [44]. While the risk of both localized and widespread endometrial cancer is increased with long-term unopposed estrogen [48], the tumors that develop may be less aggressive as survival is better in women with cancers associated with estrogen therapy [49].

The risk of endometrial hyperplasia and cancer with unopposed estrogen therapy is both duration and dose dependent:

In one study, the RR of endometrial cancer increased by 17 percent per year of estrogen therapy to an OR of greater than 8 after 10 years [46]. The excess risk persisted five or more years after cessation of therapy.

In a dose-response study, lower doses of estrogen (esterified estrogens 0.3 mg daily) for two years did not increase the incidence of endometrial hyperplasia compared with no estrogen (1.7 percent in both groups), while doses of 0.625 and 1.25 mg were associated with higher rates of disease, 28 and 53 percent, respectively [49]. However, when a low dose (0.3 mg per day of conjugated equine estrogens) was given for longer than eight years, there was a ninefold increased risk of endometrial cancer [50]. The risk of endometrial hyperplasia was not determined.

Equivalent doses of transdermal and oral estrogen appear to have similar effects on the endometrium. Ultra low-dose transdermal estrogen and placebo result in similarly low rates of endometrial proliferation and endometrial hyperplasia [51].

The risk of endometrial hyperplasia with unopposed estrogen is not reduced by giving it in a cyclic regimen. In one study, for example, in which 25 women were randomly assigned to receive either continuous or cyclic estrogen therapy (without progestin) and followed with serial endometrial biopsies, the incidence of endometrial hyperplasia was almost 50 percent in both groups [43].

Protective effect of progestins — As noted in the WHI, among women treated with estrogen, the excess risk of endometrial hyperplasia and carcinoma can be largely abolished by concurrent therapy with a progestin given in either a cyclic or continuous regimen [38,42,52-54]. In the estrogen-progestin WHI trial, more women in the HT group required endometrial biopsies to assess vaginal bleeding (33 versus 6 percent for placebo), but there was no significant difference in endometrial cancer risk between the two groups (HR 0.81, 95% CI 0.48-1.36) [38].

In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, for example, combined estrogen-progestin therapy led to marked reductions in the incidence of simple (0.8 versus 27.7 percent), complex (0.8 versus 23.7 percent), and atypical hyperplastic (0 versus 11.8 percent) endometrial lesions when compared with unopposed estrogen [53].

In the PEPI trial and in a review from the Cochrane Database, cyclic progestin (when given at least 12 days per month) was as effective as continuous low-dose progestin [53,55]. Shorter-duration progestin therapy (<10 days) may be less protective [46,55-59]. (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis", section on 'Risk factors'.)

In another report, cyclic monthly users of estrogen-progestin had a higher risk of endometrial cancer than continuous estrogen-progestin users [60].

A commonly used combined continuous estrogen-progestin regimen in the United States is low-dose medroxyprogesterone (2.5 or 5 mg daily) given each day with estrogen (conjugated estrogens 0.625 mg or its equivalent). This regimen is associated with a low risk of endometrial hyperplasia [38,42,61] and has the added advantage of inducing amenorrhea in 60 to 75 percent of women after more than six months of treatment [62,63]. (See "Preparations for menopausal hormone therapy".)

Other estrogen-progestin regimens that have been investigated include the following:

Oral micronized progesterone (200 mg/day for 12 days) reduces the risk of hyperplasia to the same degree as medroxyprogesterone acetate (2.5 mg/day continuously or 10 mg/day for 12 days) [53,64].

Medroxyprogesterone (10 mg/day) for 14 days every three months may be associated with higher than normal rates of endometrial hyperplasia and cannot be recommended [57,65,66].

Lower doses of combined estrogen-progestin therapy (conjugated estrogen [0.3 or 0.45 mg/day] with medroxyprogesterone acetate [1.5 or 2.5 mg/day]) also appear to be endometrial protective [67].

Levonorgestrel-releasing intrauterine systems (LNG-IUS) are contraceptive agents that have been used off-label for endometrial protection by some peri- and postmenopausal women taking estrogen. The strategy is to avoid the potential excess risk of cardiovascular disease and breast cancer associated with systemic progestins such as medroxyprogesterone acetate. (See "Preparations for menopausal hormone therapy", section on 'Levonorgestrel-releasing intrauterine device'.)

Endometrial polyps — Limited data suggest that MHT may be associated with an increased risk of endometrial polyps. (See "Endometrial polyps", section on 'Risk factors and prevention'.)

Colorectal cancer — In the WHI, the risk of colorectal cancer was reduced with combined conjugated equine estrogen-medroxyprogesterone acetate use (43 versus 72 cases in the hormone and placebo groups, respectively; HR 0.56, 95% CI 0.38-0.81) (figure 2) [68]. This risk reduction is similar to that seen in epidemiologic studies. In contrast to the results of combined HT, no significant differences were found in rates of colorectal cancer for unopposed conjugated equine estrogen versus placebo use (HR 1.08, 95% CI 0.75-1.55) [7]. This topic is discussed in greater detail separately. (See "Epidemiology and risk factors for colorectal cancer", section on 'Hormone therapy in females'.)

Lung cancer — Women on combined estrogen-progestin therapy who developed non-small cell lung cancer (NSCLC) had a significantly shorter survival compared with those given placebo. (See "Females and lung cancer", section on 'Outcome'.)

COGNITIVE FUNCTION AND DEMENTIA — Although some epidemiologic studies suggested that estrogen may preserve cognitive function and prevent dementia, data from the Women's Health Initiative (WHI) (in women over age 65 years) did not support these observations. The WHI Memory Study (WHIMS), an ancillary study of the WHI, assessed annual cognitive function scores in 4532 postmenopausal women who were over age 65 years and free of probable dementia at baseline.

Both unopposed estrogen and combined estrogen-progestin therapy had no global cognitive benefits in older, nondemented postmenopausal women and led to accelerated cognitive decline. In addition, neither type of menopausal hormone therapy (MHT) prevented dementia in older, nondemented postmenopausal women; to the contrary, it increased risk.

In contrast to the WHI results, some, but not all, epidemiologic studies suggest that women who initiate hormone therapy (HT) soon after menopause have a decreased risk of later dementia, while women who start many years after menopause do not. This topic is discussed in detail separately. (See "Estrogen and cognitive function", section on 'Timing of exposure'.)

The Kronos Early Estrogen Prevention Study (KEEPS), a trial of MHT in younger menopausal women ages 45 to 54 years who underwent extensive cognitive and mood testing, reported that four years of MHT had no overall effect on cognition when compared with placebo [69]. However, oral estrogen appeared to improve mood as women receiving oral conjugated estrogen combined with micronized progesterone had lower depression and anxiety scores than those receiving either transdermal estradiol with micronized progesterone or placebo. (See "Treatment of menopausal symptoms with hormone therapy".)

In the Early versus Late Intervention Trial with Estradiol (ELITE), MHT had no effect on cognitive function when compared with placebo, regardless of whether it was started early or late after menopause. (See "Estrogen and cognitive function", section on 'Trials in younger menopausal females'.)

GALLBLADDER DISEASE — A secondary analysis of data from the Women's Health Initiative (WHI) found a significantly increased risk of biliary tract disease among women using oral estrogen therapy [70]. Both trials showed a greater risk of any gallbladder disease or surgery in the groups randomized to oral estrogen (hazard ratios [HRs] of 1.67 and 1.59 in the estrogen alone and estrogen plus progestin studies, respectively). Women receiving estrogen were more likely to experience an episode of cholecystitis (HR of 1.80 and 1.54, respectively) and were more likely to undergo cholecystectomy (HR of 1.93 and 1.67, respectively).

Similar results were noted in the Heart and Estrogen/Progestin Replacement Study (HERS) trial, in which 2763 postmenopausal women with coronary heart disease (CHD) were randomly assigned to combined estrogen-progestin therapy or placebo [71]. After an average follow-up of four years, there was a marginally significant increase in biliary tract surgery in the treatment group (38 percent). The authors calculated that for every 185 women receiving hormone therapy (HT), one additional woman had biliary tract surgery per year. This topic is discussed in detail elsewhere. (See "Gallstones: Epidemiology, risk factors and prevention", section on 'Medications'.)

In one analysis of the WHI, the attributable excess risk of cholecystitis was calculated to be 9.6 and 14.2 additional cases per 1000 women per five years of combined estrogen-progestin therapy or unopposed estrogen use, respectively [16].

OSTEOPOROTIC FRACTURE — The risk of osteoporotic fracture with combined hormone therapy (HT) versus placebo was reduced at the hip (hazard ratio [HR] 0.67, unadjusted 95% CI 0.47-0.96) and at the vertebrae and wrist (HR 0.65, unadjusted 95% CI 0.46-0.92 and HR 0.71, 95% CI 0.59-0.85, respectively) (figure 3) [72]. Similar risk reductions were seen with unopposed conjugated equine estrogen for hip fracture (HR 0.61, 95% CI 0.41-0.91) and vertebral fracture (HR 0.62, 95% CI 0.42-0.93) [7]. (See "Menopausal hormone therapy in the prevention and treatment of osteoporosis".)

For women ages 50 to 59 years, the group most likely to be taking HT, the estimates of benefit in one analysis were 4.9 and 5.9 fewer fractures per 1000 women per five years of combined estrogen-progestin or unopposed estrogen use, respectively [16]. (See 'Estimates of risk in women 50 to 59 years' above.)

TYPE 2 DIABETES MELLITUS — In a post hoc analysis from the Heart and Estrogen/Progestin Replacement Study (HERS), a secondary prevention of coronary heart disease (CHD) study, 734 of 2783 women were diabetic at baseline; the remaining 2029 women (who were normoglycemic or had impaired glucose tolerance) were followed for the development of type 2 diabetes for an average of four years [73]. Results of the trial were as follows:

The cumulative incidence of type 2 diabetes was 6.2 percent in the hormone therapy (HT) group compared with 9.5 percent in the placebo group (relative hazard [RH] 0.65, 95% CI 0.48-0.89).

Results were still significant after adjustment for variables such as body mass index, weight change, and waist circumference.

The number needed to treat to prevent one case of diabetes was 30 (95% CI 18-103).

Similar results were reported in the Women's Health Initiative (WHI) combined estrogen-progestin trial in which fasting glucose and insulin were measured in a random sample at baseline and at one and three years. After a mean follow-up of 5.6 years, the following results were seen [74]:

The cumulative incidence of treated diabetes was 3.5 percent in the hormone group and 4.2 percent in the placebo group (hazard ratio [HR] 0.79, 95% CI 0.7-0.9). There was little change in the HR after adjustment for changes in body mass index and waist circumference.

Changes in fasting glucose and insulin during the first year of follow-up suggested a decrease in insulin resistance in the hormone group.

Thus, combined HT appears to reduce the risk of type 2 diabetes mellitus, possibly mediated by a decrease in insulin resistance unrelated to body size. However, this effect is insufficient to recommend HT as a diabetes prevention strategy in women with CHD.

For women ages 50 to 59 years, the group most likely to be taking HT, the estimate of benefit in one analysis was 11 fewer cases per 1000 per five years of use (for estrogen-progestin and estrogen use combined) [16]. (See 'Estimates of risk in women 50 to 59 years' above.)

OTHER POSSIBLE BENEFITS

Recurrent urinary tract infection — Estrogen therapy, in particular, vaginal estrogen, is effective for the symptoms of vaginal atrophy (see "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Vaginal estrogen therapy'). Estrogen may also be beneficial for reducing the frequency of recurrent urinary tract infections in postmenopausal women, but the effect appears to be specific to vaginal estrogen, as illustrated by the following studies:

A randomized controlled trial found that vaginal estrogen decreased the risk of recurrence in patients with frequent urinary tract infections (0.5 versus 5.9 episodes per patient-year) (figure 4) [75]. This benefit may be due to normalization of the vaginal flora since the patients treated with estrogen cream had an increase in the prevalence of lactobacilli and decrease in Escherichia coli vaginal colonization.

In a meta-analysis of five estrogen trials (three using the vaginal route of administration and two using the oral route) in 334 postmenopausal women, estrogen therapy significantly reduced the rate of urinary tract infection when compared with placebo [76]. However, when the trials of oral and vaginal estrogen were analyzed separately, vaginal estrogen was beneficial, while oral estrogen was not.

In the Heart and Estrogen/Progestin Replacement Study (HERS), a four-year study of 2763 postmenopausal women, the frequency of urinary tract infections was not decreased in those receiving oral estrogen-progestin therapy compared with placebo [77].

In summary, there is some evidence that vaginal, but not systemic, estrogen therapy may reduce the frequency of recurrent urinary tract infections in postmenopausal women. It has been suggested that vaginal estrogen may be reasonable in postmenopausal women not taking oral estrogen who have three or more recurrent urinary tract infections per year, particularly when antimicrobial resistance to multiple drugs limits the efficacy of antimicrobial prophylaxis [78]. (See "Recurrent simple cystitis in women".)

Health-related quality of life — Estrogen has a variable effect on quality of life in postmenopausal women, depending on the woman's age and the presence of symptoms and/or comorbid conditions. In postmenopausal women with vasomotor flushes, estrogen appears to improve quality of life [79,80].

In the HERS trial, the majority of women did not have vasomotor symptoms at baseline (84.3 percent). In this group, there were greater declines in physical function and energy with estrogen therapy than placebo, while there were no changes in mental health or depressive symptoms in either group. In contrast, in the women with symptoms at baseline, estrogen improved mental health and reduced depressive symptoms, with no effect on physical function or energy level [81,82].

It is possible that the decline in physical function in the asymptomatic group could be due to the increased rates of cardiovascular events in the first two years of the study. In a second study of older women, three years of estrogen therapy, with or without progestin, did not prevent the normal age-related decline in physical functioning [83].

In the Women's Health Initiative (WHI) (an older, asymptomatic population), no significant improvements were seen in quality-of-life measures (including general health, vitality, mental health, depressive symptoms, and sexual satisfaction) [84]. The WHI was not designed to examine the effects of hormone therapy (HT) on vasomotor flushes or other menopausal symptoms. However, 12 percent of the study population did have significant symptoms. In these younger women, HT relieved vasomotor flushes and improved sleep but did not otherwise improve quality of life. In the unopposed estrogen trial, women with moderate to severe vasomotor symptoms at baseline experienced significant improvement in vasomotor flushes when compared with placebo [85]. In the group as a whole, a minimal improvement in sleep disturbance symptoms was seen, but there were no differences in other quality-of-life measures (physical and social functioning, vitality, bodily pain, depressive symptoms, and sexual satisfaction) between the estrogen and placebo groups.

Falls — Problems with balance may play a major role in the incidence of forearm fractures in postmenopausal women [86]. The incidence of Colles fractures increases markedly in women at age 50 years but remains stable in men up to the age of 80 years. A mechanism other than osteoporosis must be invoked to explain this observation because osteoporosis occurs gradually [87]. The fracture is usually caused by falling on an outstretched hand.

Estrogen therapy may improve balance and reduce the tendency to fall, a change that could contribute to the associated decrease in fracture risk. Some studies have noted an improvement in balance with estrogen therapy [88], while others have not [89,90]. In one study of 19 postmenopausal women with vasomotor symptoms, for example, dynamic posturography revealed that the women had improved balance during treatment with estrogen [88]. (See "Menopausal hormone therapy in the prevention and treatment of osteoporosis".)

Skin — Some clinicians believe that estrogen helps to preserve the thickness and the collagen content of skin in postmenopausal women [91-95], but two four-year, randomized trials have reported no differences between menopausal hormone therapy (MHT) and placebo on age-related skin changes (wrinkling and skin rigidity) [96,97].

Although some epidemiologic studies have suggested that MHT is associated with an increased risk of melanoma [98,99], no excess risk of either melanoma or nonmelanoma skin cancer was observed in a post hoc analysis of the WHI (for unopposed estrogen or combined estrogen-progestin therapy) [100].

Eyes — Dry eye disease (DED) is thought to be related in part to estrogen deficiency; rates in women increase after menopause [101]. Administration of menopausal hormone therapy has had beneficial effects on the ocular surface in some [102], but not other studies [103]. However, in a meta-analysis of nine clinical trials in women with DED, improvements were seen in the symptoms of dryness, foreign body sensation, and burning compared with controls [104]. Unopposed estrogen was more effective than combined estrogen-progestin therapy and women under age 55 years appeared to benefit more than those over age 55.

The risk of cataract formation appears to be decreased by long-term estrogen therapy. In the Framingham Heart Study, postmenopausal women who had taken estrogen for 10 years or longer had a 60 percent reduction in risk of nuclear lens opacities compared with control women (odds ratio [OR] 0.4, 95% CI 0.2-1.01) [105]. In a second study, subcapsular as well as nuclear opacities were decreased by 70 and 80 percent, respectively, in women taking estrogen [106]. (See "Cataract in adults".)

MHT may also reduce intraocular pressure [102,107,108] and lower the risk of primary open-angle glaucoma [109], but the absolute reduction in risk is small. In a retrospective analysis of claims data from women over age 50 years, the calculated absolute risks of developing primary open-angle glaucoma (after adjusting for age, ethnicity, and ocular comorbidities) for women taking four years of unopposed estrogen, combined estrogen-progestin, or no HT were 1.6, 1.7, and 2.1 percent, respectively. We do not consider this small reduction in glaucoma risk to be an important consideration in deciding whether to recommend short-term HT for menopausal symptoms.

Other — It has been thought that estrogen may reduce the risk of osteoarthritis. In a cross-sectional study of over 4000 women, those receiving long-term estrogen therapy (≥10 years) had a 40 percent lower risk of hip osteoarthritis than those who had not received estrogen [110]. Similar results were found in a prospective analysis of the Framingham cohort [111]. In the WHI, women who took unopposed estrogen had lower rates of subsequent arthroplasty when compared with those taking placebo [112].

In addition, estrogen preserves teeth [113,114]; the relative risk (RR) for edentia was only 0.6 in postmenopausal women taking estrogen as compared with those who did not, perhaps related to less osteoporosis of the jaw [113].

OTHER POSSIBLE RISKS — Estrogen therapy may be associated with increases in the incidence of gallbladder disease, bronchospasm, ovarian cancer, systemic lupus erythematosus (SLE), and the Raynaud phenomenon. The data are insufficient for epilepsy.

Urinary incontinence — Estrogen may alleviate dyspareunia, recurrent cystitis, and vaginal/urethral atrophy and inflammation in postmenopausal women. However, both the Heart and Estrogen/Progestin Replacement Study (HERS) and Women's Health Initiative (WHI) trials have reported that oral hormone therapy (HT) worsens incontinence. Thus, oral estrogen with or without progestin should not be prescribed for this indication. Of note, extremely low doses of unopposed transdermal estrogen (0.014 mg/day) do not appear to increase the risk of urinary incontinence [115]. (See "Female urinary incontinence: Treatment", section on 'Topical vaginal estrogen'.)

The use of topical vaginal estrogen therapy for urogenital atrophy symptoms is discussed separately. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment".)

Bronchospasm — Estrogen therapy may be associated with the onset of asthma. In the Nurses' Health Study, for example, the relative risk (RR) of new-onset asthma in 36,094 postmenopausal women followed for 10 years was significantly greater in women taking estrogen as compared with those who were not (RR 1.5) [116]. This increased risk was dose related; it was statistically significant only at a dose greater than 0.625 mg/day of conjugated estrogens, probably because of the small numbers of women studied.

Data are conflicting on whether estrogen therapy in postmenopausal asthmatic women causes a worsening of airway function. In one study of 15 postmenopausal women with mild to moderate asthma, the estrogen-treated women had subclinical worsening of disease activity (as measured by peak expiratory flow and spirometry) [117]. In contrast, in a second study of 20 postmenopausal asthmatic women, there were no differences in measures of airway obstruction after stopping and restarting estrogen therapy [118].

Thus, while estrogen is not contraindicated in women with obstructive lung disease, clinicians should be aware of the possibility of worsening bronchospasm. Furthermore, estrogen may be considered as an etiologic factor in women who develop asthma during therapy.

Systemic lupus erythematosus — Estrogen appears to increase the risk of developing SLE [119]. A report from the Nurses' Health Study found a RR of 2.5 for current estrogen therapy and a nonsignificant risk of 1.8 for past estrogen therapy compared with women who had never received estrogen [120]. The risk was related to the duration of estrogen therapy. (See "Epidemiology and pathogenesis of systemic lupus erythematosus".)

Postmenopausal estrogen use may increase the risk of flare in women with established SLE, but these flares tend to be mild to moderate, not severe [121-125]. In a randomized trial including 351 postmenopausal women with SLE, mild to moderate flares were more frequent among those taking menopausal hormone therapy (MHT) compared with placebo (1.14 flares/person-year versus 0.86 flare/person-year) [124]. However, a subsequent trial did not detect a statistically significant change in disease activity when comparing MHT with placebo [125]. Other outcomes of interest included an increase in the risk of thrombosis in the group receiving MHT. Estrogen therapy should be avoided in patients who also have antiphospholipid antibodies because of the increased risk of thromboembolic events. (See "Approach to contraception in women with systemic lupus erythematosus", section on 'Thromboembolic risk and estrogen'.)

Uterine leiomyomas — Use of MHT in the postreproductive years may cause some women with leiomyomas to continue to have symptoms after menopause. The risk of symptoms may depend, in part, on the location of the fibroid (higher if submucosal [126]) and type of estrogen preparation (higher with transdermal estrogen in some studies [127,128] but not others [129]).

A systematic review including five randomized controlled trials found that MHT caused myoma growth, but this typically occurred without clinical symptoms [130]. These findings were confirmed in a subsequent prospective study [131]. Thus, presence of leiomyomas is not a contraindication to MHT nor associated with new symptomatic fibroids in most women.

Epilepsy — In a report of 42 menopausal women with epilepsy, HT was associated with an increase in seizure frequency [132]. Although these data are not sufficient to recommend that women with seizures not be offered HT, the indications for hormone replacement have diminished substantially since publication of the WHI. Women with seizures who are treated should be monitored carefully.

Nephrolithiasis — Menopause may increase urinary calcium excretion, an important risk factor for the development of calcium-containing kidney stones [133]. However, the magnitude of the increase is still unclear. In contrast, exogenous estrogen therapy may decrease urinary calcium excretion. Although one might anticipate an increased risk of nephrolithiasis with menopause and a decreased risk with estrogen therapy, data that address this question have been inconsistent:

In the Nurses' Health Study, a prospective cohort study, natural menopause was not associated with an increased risk of nephrolithiasis [134]. In addition, postmenopausal estrogen users, when compared with nonusers, did not have a lower risk of nephrolithiasis.

Data from the WHI, the only randomized trial to address this question, suggest that estrogen therapy may increase the risk of nephrolithiasis [135]. In a post hoc analysis of the two HT trials, kidney stone data were obtained by patient self-report. After adjusting for age, body mass index, prior HT, and use of coffee or thiazide diuretics, there was a small excess risk of kidney stones in the hormone groups compared with placebo (39 versus 34 per 10,000 person-years; hazard ratio [HR] 1.21).

The reasons for these discrepant findings are unclear. However, the incidence rates of kidney stones in the WHI were nearly three times higher than in the Nurses' Health Study (which included only cases with symptomatic stones) [134]. In addition, women taking estrogen were more likely to develop gallstones [70], and imaging studies to evaluate the gallbladder would identify asymptomatic kidney stones. Given the small absolute risk reported in this study (five additional cases per 10,000 person-years), we do not consider nephrolithiasis to be a major consideration in deciding whether to take short-term HT for menopausal symptoms. (See 'Gallbladder disease' above.)

OTHER ISSUES

Weight — Although women are often concerned that taking menopausal hormone therapy (MHT) will exacerbate the weight gain that occurs in midlife, a meta-analysis of 28 trials in 28,559 women found no evidence of an effect of unopposed estrogen or combined estrogen-progestin on body weight or body mass index [136].

Women with primary ovarian insufficiency (premature ovarian failure) — Data from the Women's Health Initiative (WHI) should not be extrapolated to women with primary ovarian insufficiency (premature ovarian failure; menopause before age 40 years) in whom MHT is generally initiated at a younger age. In otherwise healthy women with primary ovarian insufficiency, we continue their MHT until the average age of menopause, approximately age 50 to 51 years. At that point, the same discussion of potential risks and benefits of MHT should take place.

Androgen therapy — The use of exogenous androgen therapy in peri- and postmenopausal women is reviewed separately. (See "Overview of androgen deficiency and therapy in females" and "Overview of sexual dysfunction in females: Management", section on 'Androgens'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Menopause".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Menopause (The Basics)")

Beyond the Basics topics (see "Patient education: Menopause (Beyond the Basics)" and "Patient education: Menopausal hormone therapy (Beyond the Basics)" and "Patient education: Non-estrogen treatments for menopausal symptoms (Beyond the Basics)" and "Patient education: Vaginal dryness (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

We consider the initiation of menopausal hormone therapy (MHT) to be a safe option for healthy, symptomatic women who are within 10 years of menopause or younger than age 60 years and who do not have contraindications to MHT (such as a history of breast cancer, coronary heart disease [CHD], a previous venous thromboembolic event or stroke, or active liver disease. Estrogen-progestin therapy should be used for women with a uterus and unopposed estrogen for those posthysterectomy. For women with vaginal atrophy symptoms only, we suggest vaginal estrogen (Grade 2B). (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Vaginal estrogen therapy' and "Treatment of menopausal symptoms with hormone therapy", section on 'Is my patient a candidate for MHT?'.)

MHT is effective for the treatment of menopausal hot flashes and vaginal atrophy caused by hypoestrogenism. However, it is not recommended for the prevention of chronic disease such as prevention of cardiovascular or bone disease. (See 'Overview' above.)

In the Women's Health Initiative (WHI) combined hormone therapy (HT) trial, risks included CHD events, stroke, venous thromboembolism (VTE), and breast cancer, while benefits included a reduction of fracture and colorectal cancer risk. Results for stroke, VTE, and fracture risk with unopposed conjugated equine estrogen were similar to those in the combined therapy trial. (See 'Overview' above.)

In contrast, no increase in either CHD or breast cancer risk was seen with unopposed estrogen use; in fact, a possible reduction in breast cancer risk was observed. The discrepancies in CHD and breast cancer risk between the WHI unopposed estrogen trial and the combined estrogen-progestin trial suggest that the progestin played an important role in the increased CHD and breast cancer risk seen with combined therapy. (See 'Overview' above.)

Subsequent analyses suggest that the risk of CHD appears to depend upon the timing of exposure, with no excess risk observed in younger (<60 years of age) menopausal women. In addition, mortality rates appear to be lower in young postmenopausal hormone users compared with nonusers. Thus, for young, symptomatic postmenopausal women, short-term HT is considered to be a reasonable option (figure 1). (See "Menopausal hormone therapy and cardiovascular risk", section on 'Timing of exposure'.)

The risk of endometrial hyperplasia and other possible risks and benefits of MHT are reviewed above. (See 'Endometrial hyperplasia and carcinoma' above and 'Other possible benefits' above and 'Other possible risks' above.)

Recommendations for MHT use are reviewed elsewhere. (See "Treatment of menopausal symptoms with hormone therapy".)

Estimates of risk for women in their 50s taking five years of HT are described above (figure 1). (See 'Estimates of risk in women 50 to 59 years' above.)

  1. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2015; 100:3975.
  2. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. Circulation 2011; 123:1243.
  3. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol 2014; 123:202. Reaffirmed 2018.
  4. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause 2017; 24:728.
  5. US Preventive Services Task Force, Grossman DC, Curry SJ, et al. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: US Preventive Services Task Force Recommendation Statement. JAMA 2017; 318:2224.
  6. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321.
  7. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291:1701.
  8. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA 2013; 310:1353.
  9. Marjoribanks J, Farquhar C, Roberts H, et al. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2017; 1:CD004143.
  10. Gartlehner G, Patel SV, Feltner C, et al. Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2017; 318:2234.
  11. Rossouw JE, Manson JE, Kaunitz AM, Anderson GL. Lessons learned from the Women's Health Initiative trials of menopausal hormone therapy. Obstet Gynecol 2013; 121:172.
  12. Sprague BL, Trentham-Dietz A, Cronin KA. A sustained decline in postmenopausal hormone use: results from the National Health and Nutrition Examination Survey, 1999-2010. Obstet Gynecol 2012; 120:595.
  13. Donneyong MM, Chang TJ, Roth JA, et al. The Women's Health Initiative Estrogen-alone Trial had differential disease and medical expenditure consequences across age groups. Menopause 2020; 27:632.
  14. Sarrel PM, Njike VY, Vinante V, Katz DL. The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59 years. Am J Public Health 2013; 103:1583.
  15. Roth JA, Etzioni R, Waters TM, et al. Economic return from the Women's Health Initiative estrogen plus progestin clinical trial: a modeling study. Ann Intern Med 2014; 160:594.
  16. Santen RJ, Allred DC, Ardoin SP, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010; 95:s1.
  17. Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy. N Engl J Med 2003; 348:645.
  18. Col NF, Pauker SG. The discrepancy between observational studies and randomized trials of menopausal hormone therapy: did expectations shape experience? Ann Intern Med 2003; 139:923.
  19. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297:1465.
  20. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003; 349:523.
  21. Shufelt CL, Johnson BD, Berga SL, et al. Timing of hormone therapy, type of menopause, and coronary disease in women: data from the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation. Menopause 2011; 18:943.
  22. Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007; 356:2591.
  23. Salpeter SR, Walsh JM, Greyber E, Salpeter EE. Brief report: Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med 2006; 21:363.
  24. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345:e6409.
  25. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Trial does not change the conclusions of Cochrane review of long term hormone therapy for perimenopausal and postmenopausal women. BMJ 2012; 345:e8141; author reply e8164.
  26. Rossouw JE, Manson JE, Kaunitz AM, Stefanick ML. Study had insufficient power to investigate safety. BMJ 2012; 345:e8146; author reply e8164.
  27. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014; 161:249.
  28. Hodis HN, Mack WJ, Henderson VW, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med 2016; 374:1221.
  29. Boardman HM, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev 2015; :CD002229.
  30. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA 2003; 289:2673.
  31. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004; 292:1573.
  32. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017; 318:927.
  33. Hulley S, Furberg C, Barrett-Connor E, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:58.
  34. Salpeter SR, Cheng J, Thabane L, et al. Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women. Am J Med 2009; 122:1016.
  35. Martin KA, Manson JE. Approach to the patient with menopausal symptoms. J Clin Endocrinol Metab 2008; 93:4567.
  36. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 2003; 289:3243.
  37. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019; 394:1159.
  38. Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 2003; 290:1739.
  39. Collaborative Group On Epidemiological Studies Of Ovarian Cancer, Beral V, Gaitskell K, et al. Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet 2015; 385:1835.
  40. Kotsopoulos J, Lubinski J, Neuhausen SL, et al. Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Gynecol Oncol 2006; 100:83.
  41. Beral V, Bull D, Reeves G, Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 2005; 365:1543.
  42. Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group. Am J Obstet Gynecol 1994; 170:1213.
  43. Schiff I, Sela HK, Cramer D, et al. Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertil Steril 1982; 37:79.
  44. Henderson BE. The cancer question: an overview of recent epidemiologic and retrospective data. Am J Obstet Gynecol 1989; 161:1859.
  45. Persson I, Adami HO, Bergkvist L, et al. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. BMJ 1989; 298:147.
  46. Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999; 91:1131.
  47. Strom BL, Schinnar R, Weber AL, et al. Case-control study of postmenopausal hormone replacement therapy and endometrial cancer. Am J Epidemiol 2006; 164:775.
  48. Shapiro S, Kelly JP, Rosenberg L, et al. Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med 1985; 313:969.
  49. Chu J, Schweid AI, Weiss NS. Survival among women with endometrial cancer: a comparison of estrogen users and nonusers. Am J Obstet Gynecol 1982; 143:569.
  50. Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med 1997; 157:2609.
  51. Johnson SR, Ettinger B, Macer JL, et al. Uterine and vaginal effects of unopposed ultralow-dose transdermal estradiol. Obstet Gynecol 2005; 105:779.
  52. Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997; 349:458.
  53. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1996; 275:370.
  54. Lacey JV Jr, Leitzmann MF, Chang SC, et al. Endometrial cancer and menopausal hormone therapy in the National Institutes of Health-AARP Diet and Health Study cohort. Cancer 2007; 109:1303.
  55. Furness S, Roberts H, Marjoribanks J, Lethaby A. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. Cochrane Database Syst Rev 2012; :CD000402.
  56. Pike MC, Peters RK, Cozen W, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 1997; 89:1110.
  57. Cerin A, Heldaas K, Moeller B. Adverse endometrial effects of long-cycle estrogen and progestogen replacement therapy. The Scandinavian LongCycle Study Group. N Engl J Med 1996; 334:668.
  58. Whitehead MI, Fraser D. The effects of estrogens and progestogens on the endometrium. Modern approach to treatment. Obstet Gynecol Clin North Am 1987; 14:299.
  59. Whitehead MI, Hillard TC, Crook D. The role and use of progestogens. Obstet Gynecol 1990; 75:59S.
  60. Jaakkola S, Lyytinen H, Pukkala E, Ylikorkala O. Endometrial cancer in postmenopausal women using estradiol-progestin therapy. Obstet Gynecol 2009; 114:1197.
  61. Weinstein L, Bewtra C, Gallagher JC. Evaluation of a continuous combined low-dose regimen of estrogen-progestin for treatment of the menopausal patient. Am J Obstet Gynecol 1990; 162:1534.
  62. Archer DF, Pickar JH, Bottiglioni F. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Menopause Study Group. Obstet Gynecol 1994; 83:686.
  63. Creasman WT, Henderson D, Hinshaw W, Clarke-Pearson DL. Estrogen replacement therapy in the patient treated for endometrial cancer. Obstet Gynecol 1986; 67:326.
  64. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1995; 273:199.
  65. Ettinger B, Selby J, Citron JT, et al. Cyclic hormone replacement therapy using quarterly progestin. Obstet Gynecol 1994; 83:693.
  66. Hirvonen E, Salmi T, Puolakka J, et al. Can progestin be limited to every third month only in postmenopausal women taking estrogen? Maturitas 1995; 21:39.
  67. Pickar JH, Yeh IT, Wheeler JE, et al. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results. Fertil Steril 2003; 80:1234.
  68. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004; 350:991.
  69. Gleason CE, Dowling NM, Wharton W, et al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med 2015; 12:e1001833; discussion e1001833.
  70. Cirillo DJ, Wallace RB, Rodabough RJ, et al. Effect of estrogen therapy on gallbladder disease. JAMA 2005; 293:330.
  71. Simon JA, Hunninghake DB, Agarwal SK, et al. Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2001; 135:493.
  72. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 2003; 290:1729.
  73. Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003; 138:1.
  74. Margolis KL, Bonds DE, Rodabough RJ, et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologia 2004; 47:1175.
  75. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993; 329:753.
  76. Cardozo L, Lose G, McClish D, et al. A systematic review of estrogens for recurrent urinary tract infections: third report of the hormones and urogenital therapy (HUT) committee. Int Urogynecol J Pelvic Floor Dysfunct 2001; 12:15.
  77. Brown JS, Vittinghoff E, Kanaya AM, et al. Urinary tract infections in postmenopausal women: effect of hormone therapy and risk factors. Obstet Gynecol 2001; 98:1045.
  78. Stamm WE. Estrogens and urinary-tract infection. J Infect Dis 2007; 195:623.
  79. MacLennan A, Lester S, Moore V. Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review. Climacteric 2001; 4:58.
  80. Col NF, Weber G, Stiggelbout A, et al. Short-term menopausal hormone therapy for symptom relief: an updated decision model. Arch Intern Med 2004; 164:1634.
  81. Hlatky MA, Boothroyd D, Vittinghoff E, et al. Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial. JAMA 2002; 287:591.
  82. Rexrode KM, Manson JE. Postmenopausal hormone therapy and quality of life: no cause for celebration. JAMA 2002; 287:641.
  83. Greenspan SL, Resnick NM, Parker RA. The effect of hormone replacement on physical performance in community-dwelling elderly women. Am J Med 2005; 118:1232.
  84. Hays J, Ockene JK, Brunner RL, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003; 348:1839.
  85. Brunner RL, Gass M, Aragaki A, et al. Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women's Health Initiative Randomized Clinical Trial. Arch Intern Med 2005; 165:1976.
  86. Ekblad S, Bergendahl A, Enler P, et al. Disturbances in postural balance are common in postmenopausal women with vasomotor symptoms. Climacteric 2000; 3:192.
  87. Crilly RG, Delaquerrière Richardson L, Roth JH, et al. Postural stability and Colles' fracture. Age Ageing 1987; 16:133.
  88. Hammar ML, Lindgren R, Berg GE, et al. Effects of hormonal replacement therapy on the postural balance among postmenopausal women. Obstet Gynecol 1996; 88:955.
  89. Seeley DG, Cauley JA, Grady D, et al. Is postmenopausal estrogen therapy associated with neuromuscular function or falling in elderly women? Study of Osteoporotic Fractures Research Group. Arch Intern Med 1995; 155:293.
  90. Armstrong AL, Oborne J, Coupland CA, et al. Effects of hormone replacement therapy on muscle performance and balance in post-menopausal women. Clin Sci (Lond) 1996; 91:685.
  91. Brincat M, Versi E, Moniz CF, et al. Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy. Obstet Gynecol 1987; 70:123.
  92. Holland EF, Studd JW, Mansell JP, et al. Changes in collagen composition and cross-links in bone and skin of osteoporotic postmenopausal women treated with percutaneous estradiol implants. Obstet Gynecol 1994; 83:180.
  93. Maheux R, Naud F, Rioux M, et al. A randomized, double-blind, placebo-controlled study on the effect of conjugated estrogens on skin thickness. Am J Obstet Gynecol 1994; 170:642.
  94. Ashcroft GS, Dodsworth J, van Boxtel E, et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels. Nat Med 1997; 3:1209.
  95. Wolff EF, Narayan D, Taylor HS. Long-term effects of hormone therapy on skin rigidity and wrinkles. Fertil Steril 2005; 84:285.
  96. Phillips TJ, Symons J, Menon S, HT Study Group. Does hormone therapy improve age-related skin changes in postmenopausal women? A randomized, double-blind, double-dummy, placebo-controlled multicenter study assessing the effects of norethindrone acetate and ethinyl estradiol in the improvement of mild to moderate age-related skin changes in postmenopausal women. J Am Acad Dermatol 2008; 59:397.
  97. Owen CM, Pal L, Mumford SL, et al. Effects of hormones on skin wrinkles and rigidity vary by race/ethnicity: four-year follow-up from the ancillary skin study of the Kronos Early Estrogen Prevention Study. Fertil Steril 2016; 106:1170.
  98. Koomen ER, Joosse A, Herings RM, et al. Estrogens, oral contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma: a population-based case-control study. Ann Oncol 2009; 20:358.
  99. Holly EA, Cress RD, Ahn DK. Cutaneous melanoma in women: ovulatory life, menopause, and use of exogenous estrogens. Cancer Epidemiol Biomarkers Prev 1994; 3:661.
  100. Tang JY, Spaunhurst KM, Chlebowski RT, et al. Menopausal hormone therapy and risks of melanoma and nonmelanoma skin cancers: women's health initiative randomized trials. J Natl Cancer Inst 2011; 103:1469.
  101. Sullivan DA, Rocha EM, Aragona P, et al. TFOS DEWS II Sex, Gender, and Hormones Report. Ocul Surf 2017; 15:284.
  102. Affinito P, Di Spiezio Sardo A, Di Carlo C, et al. Effects of hormone replacement therapy on ocular function in postmenopause. Menopause 2003; 10:482.
  103. Schaumberg DA, Buring JE, Sullivan DA, Dana MR. Hormone replacement therapy and dry eye syndrome. JAMA 2001; 286:2114.
  104. Hao Y, Xiaodan J, Jiarui Y, Xuemin L. The effect of hormone therapy on the ocular surface and intraocular pressure for postmenopausal women: a systematic review and meta-analysis of randomized controlled trials. Menopause 2020; 27:929.
  105. Worzala K, Hiller R, Sperduto RD, et al. Postmenopausal estrogen use, type of menopause, and lens opacities: the Framingham studies. Arch Intern Med 2001; 161:1448.
  106. Freeman EE, Munoz B, Schein OD, West SK. Hormone replacement therapy and lens opacities: the Salisbury Eye Evaluation project. Arch Ophthalmol 2001; 119:1687.
  107. Tint NL, Alexander P, Tint KM, et al. Hormone therapy and intraocular pressure in nonglaucomatous eyes. Menopause 2010; 17:157.
  108. Vajaranant TS, Maki PM, Pasquale LR, et al. Effects of Hormone Therapy on Intraocular Pressure: The Women's Health Initiative-Sight Exam Study. Am J Ophthalmol 2016; 165:115.
  109. Newman-Casey PA, Talwar N, Nan B, et al. The potential association between postmenopausal hormone use and primary open-angle glaucoma. JAMA Ophthalmol 2014; 132:298.
  110. Nevitt MC, Cummings SR, Lane NE, et al. Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 1996; 156:2073.
  111. Zhang Y, McAlindon TE, Hannan MT, et al. Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study. Arthritis Rheum 1998; 41:1867.
  112. Cirillo DJ, Wallace RB, Wu L, Yood RA. Effect of hormone therapy on risk of hip and knee joint replacement in the Women's Health Initiative. Arthritis Rheum 2006; 54:3194.
  113. Paganini-Hill A. The benefits of estrogen replacement therapy on oral health. The Leisure World cohort. Arch Intern Med 1995; 155:2325.
  114. Krall EA, Dawson-Hughes B, Hannan MT, et al. Postmenopausal estrogen replacement and tooth retention. Am J Med 1997; 102:536.
  115. Waetjen LE, Brown JS, Vittinghoff E, et al. The effect of ultralow-dose transdermal estradiol on urinary incontinence in postmenopausal women. Obstet Gynecol 2005; 106:946.
  116. Troisi RJ, Speizer FE, Willett WC, et al. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. A prospective cohort study. Am J Respir Crit Care Med 1995; 152:1183.
  117. Lieberman D, Kopernik G, Porath A, et al. Sub-clinical worsening of bronchial asthma during estrogen replacement therapy in asthmatic post-menopausal women. Maturitas 1995; 21:153.
  118. Hepburn MJ, Dooley DP, Morris MJ. The effects of estrogen replacement therapy on airway function in postmenopausal, asthmatic women. Arch Intern Med 2001; 161:2717.
  119. Meier CR, Sturkenboom MC, Cohen AS, Jick H. Postmenopausal estrogen replacement therapy and the risk of developing systemic lupus erythematosus or discoid lupus. J Rheumatol 1998; 25:1515.
  120. Sánchez-Guerrero J, Liang MH, Karlson EW, et al. Postmenopausal estrogen therapy and the risk for developing systemic lupus erythematosus. Ann Intern Med 1995; 122:430.
  121. Arden NK, Lloyd ME, Spector TD, Hughes GR. Safety of hormone replacement therapy (HRT) in systemic lupus erythematosus (SLE). Lupus 1994; 3:11.
  122. Kreidstein S, Urowitz MB, Gladman DD, Gough J. Hormone replacement therapy in systemic lupus erythematosus. J Rheumatol 1997; 24:2149.
  123. Greenstein B. Hormonal aspects of lupus: therapeutic possibilities. Lupus 1993; 2:349.
  124. Buyon JP, Petri MA, Kim MY, et al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med 2005; 142:953.
  125. Sánchez-Guerrero J, González-Pérez M, Durand-Carbajal M, et al. Menopause hormonal therapy in women with systemic lupus erythematosus. Arthritis Rheum 2007; 56:3070.
  126. Akkad AA, Habiba MA, Ismail N, et al. Abnormal uterine bleeding on hormone replacement: the importance of intrauterine structural abnormalities. Obstet Gynecol 1995; 86:330.
  127. Sener AB, Seçkin NC, Ozmen S, et al. The effects of hormone replacement therapy on uterine fibroids in postmenopausal women. Fertil Steril 1996; 65:354.
  128. Polatti F, Viazzo F, Colleoni R, Nappi RE. Uterine myoma in postmenopause: a comparison between two therapeutic schedules of HRT. Maturitas 2000; 37:27.
  129. Palomba S, Sena T, Noia R, et al. Transdermal hormone replacement therapy in postmenopausal women with uterine leiomyomas. Obstet Gynecol 2001; 98:1053.
  130. Ang WC, Farrell E, Vollenhoven B. Effect of hormone replacement therapies and selective estrogen receptor modulators in postmenopausal women with uterine leiomyomas: a literature review. Climacteric 2001; 4:284.
  131. Yang CH, Lee JN, Hsu SC, et al. Effect of hormone replacement therapy on uterine fibroids in postmenopausal women--a 3-year study. Maturitas 2002; 43:35.
  132. Harden CL, Pulver MC, Ravdin L, Jacobs AR. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia 1999; 40:1402.
  133. Nordin BE, Need AG, Morris HA, et al. Evidence for a renal calcium leak in postmenopausal women. J Clin Endocrinol Metab 1991; 72:401.
  134. Mattix Kramer HJ, Grodstein F, Stampfer MJ, Curhan GC. Menopause and postmenopausal hormone use and risk of incident kidney stones. J Am Soc Nephrol 2003; 14:1272.
  135. Maalouf NM, Sato AH, Welch BJ, et al. Postmenopausal hormone use and the risk of nephrolithiasis: results from the Women's Health Initiative hormone therapy trials. Arch Intern Med 2010; 170:1678.
  136. Norman RJ, Flight IH, Rees MC. Oestrogen and progestogen hormone replacement therapy for peri-menopausal and post-menopausal women: weight and body fat distribution. Cochrane Database Syst Rev 2000; :CD001018.
Topic 7427 Version 42.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟