Menopausal hormone therapy: Benefits and risks

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 5^th to 6^th 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 10^th to 12^th 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.)