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You are here: HomePublic Comments and NominationsOpportunity for Public CommentDraft Recommendation Statement : Draft Recommendation Statement

Draft Recommendation Statement

Menopausal Hormone Therapy: Primary Prevention of Chronic Conditions

This opportunity for public comment expires on June 12, 2017 at 8:00 PM EST

Note: This is a Draft Recommendation Statement. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. The final Recommendation Statement will be developed after careful consideration of the feedback received and will include both the Research Plan and Evidence Review as a basis.

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Draft: Recommendation Summary

PopulationRecommendationGrade
(What's This?)
Postmenopausal women

The USPSTF recommends against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women.

D
Postmenopausal women who have had a hysterectomy

The USPSTF recommends against the use of estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy.

D

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In an effort to maintain a high level of transparency in our methods, we open our draft Recommendation Statements to a public comment period before we publish the final version.

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Draft: Preface

The US Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without obvious related signs or symptoms.

It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

Draft: Rationale

Importance

Menopause occurs at a median age of 51.3 years, and the average U.S. woman who reaches menopause is expected to live another 30 years. The prevalence and incidence of most chronic conditions, such as coronary heart disease, dementia, stroke, fractures, and breast cancer, increase with age; however, the excess risk for these conditions that can be attributed to menopause alone is uncertain. Since the publication of the Women’s Health Initiative (WHI) findings that hormone therapy use is associated with serious adverse health effects, use of menopausal hormone therapy has declined, from 44% of U.S. women using or having used hormone therapy in 1988–1994 to 4.7% of women in 2010.

Benefits of Preventive Medication

Combined Estrogen and Progestin

Many health outcomes potentially associated with the use of hormone therapy in postmenopausal women have been examined. The USPSTF found convincing evidence that combined estrogen and progestin therapy is of moderate benefit in reducing the risk for fractures in postmenopausal women and adequate evidence that combined estrogen and progestin therapy is of small benefit in reducing the risk for diabetes.

Estrogen Alone

The use of estrogen without progestin has generally been restricted to women who have had a hysterectomy because unopposed estrogen use increases the risk for endometrial cancer in women with an intact uterus. The USPSTF found convincing evidence that estrogen is of moderate benefit in reducing the incidence of fractures in postmenopausal women. The USPSTF found adequate evidence that the use of estrogen alone is of moderate benefit in reducing the risk for developing or dying of invasive breast cancer and is of small benefit in reducing the risk for diabetes. The USPSTF found convincing evidence that estrogen does not have a beneficial effect on coronary heart disease.

Harms of Preventive Medication

Combined Estrogen and Progestin

The USPSTF found convincing evidence that use of combined estrogen and progestin is associated with moderate harms, including an increase in the risk for invasive breast cancer and venous thromboembolism, and a small to moderate harm of increased risk for coronary heart disease. The USPSTF also found adequate evidence of moderate harms, such as increased risk for stroke, dementia, gallbladder disease, and urinary incontinence.

Estrogen Alone

The USPSTF found adequate evidence that estrogen use alone is associated with moderate harms, including an increase in the risk for stroke, dementia, gallbladder disease, urinary incontinence, and venous thromboembolism.

USPSTF Assessment

The USPSTF concludes with moderate certainty that the use of combined estrogen and progestin has no net benefit for the prevention of chronic conditions in most postmenopausal women.

The USPSTF concludes with moderate certainty that the use of estrogen alone has no net benefit for the prevention of chronic conditions in most postmenopausal women who have had a hysterectomy.

Draft: Clinical Considerations

Patient Population Under Consideration

This recommendation applies to postmenopausal women who are considering hormone therapy for the primary prevention of chronic medical conditions. It does not apply to women who are considering hormone therapy for the management of menopausal symptoms, such as hot flashes or vaginal dryness. It also does not apply to women younger than age 50 years who have had premature menopause or surgical menopause.

Assessment of Risk

This recommendation applies to the average-risk population. Risk factors for a specific chronic condition or individual characteristics that affect the likelihood of having a specific therapy-associated adverse event may cause a woman’s net balance of benefits and harms to differ from that of the average population.

Treatment and Intervention

Menopausal hormone therapy refers to the use of estrogen and progestin in women with an intact uterus, or estrogen alone in women who have had a hysterectomy, taken at or after the time of menopause. Several different formulations of menopausal hormone therapy are approved by the U.S. Food and Drug Administration (FDA) for use in the United States. Currently, evidence is limited to determine whether different types, doses, or modes of delivery of hormone therapy affect its benefit-to-harm profile for the prevention of chronic conditions.1

FDA–approved indications for hormone therapy in menopausal women are limited to the treatment of menopausal symptoms and the prevention of postmenopausal osteoporosis. A black box warning indicates that estrogen therapy, with or without progestin, should be prescribed at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.2

The use of menopausal hormone therapy results in some benefits but also some significant harms. Combined estrogen and progestin therapy is associated with a decreased risk of fractures, diabetes, and colorectal cancer; however, it is also associated with an increased risk of invasive breast cancer, coronary heart disease, thromboembolic events, stroke, dementia, gallbladder disease, and self-reported urinary incontinence. Estrogen alone is associated with a decreased risk of fractures, invasive breast cancer, and diabetes; however, it is also associated with an increased risk of thromboembolic events, stroke, dementia, gallbladder disease, and self-reported urinary incontinence. The reason for the discordant effect of estrogen alone compared with combined estrogen and progestin therapy on the risk of invasive breast cancer is unclear.

Other Approaches to Prevention

Several interventions and preventive medications to reduce the risk of chronic conditions in women have been studied. The use of medications such as tamoxifen and raloxifene in women at increased risk for breast cancer, who do not have contraindications and are at low risk for adverse medication effects, is a potential strategy to decrease risk of breast cancer.3 The USPSTF recommends behavioral counseling interventions to promote a healthful diet and physical activity for the prevention of cardiovascular disease in adults who are overweight or obese and have additional cardiovascular disease risk factors.4 The USPSTF also recommends daily low-dose aspirin use to decrease the risk of colorectal cancer and cardiovascular disease in appropriate candidates.5

Draft: Other Considerations

Research Needs and Gaps

Evidence about whether the benefits and harms of menopausal hormone therapy vary by age, race/ethnicity, or time since menopause is limited. In the WHI trial, there was a trend toward lower all-cause mortality in younger women (ages 50 to 59 years at randomization) randomized to estrogen alone but not combination therapy. There is no evidence that women of different races/ethnicities experience a different balance of benefits and harms with menopausal hormone therapy; however, the majority (approximately 80%) of women in the largest trial (WHI) where white, so these analyses may be underpowered to detect such differences. Data regarding whether the timing of initiation of menopausal hormone therapy since menopause affects the balance of benefits and harms are conflicting. An individual participant data meta-analysis may be helpful to determine whether the balance of benefits and harms of menopausal hormone therapy is different in any of these subgroups.

Draft: Discussion

Burden of Disease

Natural menopause occurs at a median age of 51.3 years.6 The prevalence and incidence of most chronic conditions increase with age, and the average U.S. woman who reaches menopause is expected to live another 30 years.7 However, the excess risk for these conditions that can be attributed to menopause alone is uncertain. The evidence supporting menopause as a risk factor for chronic disease is strongest for cardiovascular disease and osteoporosis. According to the National Center for Health Statistics, heart disease is the leading cause of death among women in the United States. In 2013, 289,758 women died of coronary heart disease.8 In 2014, there were more than 267,000 hospitalizations for hip fractures among persons age 65 years and older, and overall, 69% of hip fractures occur in women.9 It is estimated that by 2025, the annual incidence and costs of fractures in the United States will increase by 50%.10

Scope of Review

To update its 2012 recommendation, the USPSTF reviewed evidence about the benefits and harms of hormone therapy for the prevention of chronic conditions and whether outcomes vary among women in different subgroups or by timing of intervention since menopause. The use of hormone therapy for the treatment of menopausal symptoms, such as vasomotor hot flashes or vulvovaginal complaints, or for other indications is outside the scope of this recommendation.

The USPSTF found 18 fair- or good-quality trials comparing the effects of combined estrogen and progestin or estrogen alone versus placebo on the prevention of chronic conditions in postmenopausal women.1 Of these trials, the WHI trial was the largest, and was the only trial designed and sufficiently powered to evaluate the effectiveness of hormone therapy for primary prevention of the multiple conditions that are the focus of this recommendation statement. The WHI trial provided most of the estimates of the benefits and harms of menopausal hormone therapy. Including the posttrial phases, the WHI trial had up to 13 years of followup to assess how risks for chronic conditions changed after women stopped hormone therapy.

Benefits and Harms of Preventive Medication

Coronary Heart Disease

Observational evidence suggested that there might be a protective effect of menopausal hormone therapy on coronary heart disease; however, the WHI and other trials have not demonstrated such an effect. Pooled results of three trials that reported on the risk of coronary heart disease in women randomized to combined estrogen and progestin compared with placebo (N=18,081) showed a statistically significantly higher risk of coronary events in women who took hormone therapy (relative risk [RR], 1.23 [95% confidence interval (CI), 1.00 to 1.52]) during a mean followup of 5 years.1

Postintervention followup of women in the WHI trial showed that 2.4 years after stopping combined estrogen and progestin, risk of coronary heart disease was similar between women who took hormone therapy during the trial and those who received placebo (hazard ratio [HR], 1.04 [95% CI, 0.89 to 1.21]).11

Pooled results of three trials that reported on the risk of coronary heart disease in women randomized to estrogen alone compared with placebo (N=11,310) showed no statistically significant difference in risk of coronary events between women who took estrogen therapy or placebo (RR, 0.95 [95% CI, 0.79 to 1.14]).1

Postintervention followup of women in the WHI trial showed that 3.9 years after stopping estrogen alone, risk of coronary heart disease was similar between women who took hormone therapy during the trial and those who received placebo (HR, 0.97 [95% CI, 0.75 to 1.25]).12

Breast Cancer

Because estrogen has a generally trophic effect on breast tissue, trials of menopausal hormone therapy have reported on the risk of breast cancer as one of the primary adverse outcomes of treatment. Six trials comparing combined estrogen and progestin with placebo reported on breast cancer incidence. However, only two of these trials followed women for more than 4 years, and only the WHI trial reported on the risk of invasive breast cancer (vs. any breast cancer).

During the intervention phase of the WHI trial (median duration, 5.6 years), women assigned to combined estrogen and progestin had a significantly increased risk of invasive breast cancer compared with women assigned to placebo (HR, 1.24 [95% CI, 1.01 to 1.53]). The risk remained significantly increased compared with placebo during a median postintervention followup of 8.2 years (HR, 1.32 [95% CI, 1.08 to 1.61]).13 In the Heart and Estrogen/Progestin Replacement Study (HERS), more women randomized to combined estrogen and progestin developed breast cancer during the 4.1-year intervention phase than did women who received placebo, but the results were not statistically significant (HR, 1.38 [95% CI, 0.82 to 2.31]).14

In three smaller trials (the Estrogen Replacement and Atherosclerosis [ERA],15 Postmenopausal Estrogen/Progestin Interventions [PEPI],16 and Estonian Postmenopausal Hormone Therapy [EPHT]17 trials), the risk of breast cancer incidence was similar between women randomized to combined estrogen and progestin and those randomized to placebo over 3 to 4 years; however, few cases occurred overall. The fourth trial, the Women’s International Study of Long Duration Oestrogen After Menopause (WISDOM), was stopped after 1 year because of the WHI results indicating excess breast cancer risk in women receiving combined estrogen and progestin; breast cancer incidence was similar between groups at 1 year.18

Five trials comparing estrogen alone with placebo reported on breast cancer incidence; however, only the WHI trial reported on risk of invasive breast cancer. In the WHI trial, women assigned to estrogen alone had a nonsignificant decrease in risk of invasive breast cancer compared with women assigned to placebo during the median 7.2-year intervention phase (HR, 0.79 [95% CI, 0.61 to 1.02]).12, 13 The risk remained lower during the median 6.6-year postintervention phase after the trial had been stopped. The difference between groups was statistically significant during cumulative followup (trial and postintervention phase; median duration, 13 years) (HR, 0.79 [95% CI, 0.65 to 0.97]).13

In the Estrogen for the Prevention of Re-Infarction Trial (ESPRIT), the risk of breast cancer was similar between women randomized to estrogen only or placebo during the 2-year intervention period (RR, 0.98 [95% CI, 0.25 to 3.91]).19 In the ERA trial,15 PEPI trial,16 and Estrogen in the Prevention of Atherosclerosis Trial (EPAT),20 there were few cases of breast cancer, and the results were inconclusive.

Thromboembolic Events

In the WHI trial, women randomized to combined estrogen and progestin had an increased risk of pulmonary embolism (HR, 1.98 [95% CI, 1.36 to 2.87]) and deep vein thrombosis (HR, 1.87 [95% CI, 1.37 to 2.54]) compared with women randomized to placebo over a median followup of 5.6 years.13 There was no difference between groups in risk of deep vein thrombosis or pulmonary embolism during the 2.4-year postintervention period.11 Women randomized to estrogen alone had an increased risk of deep vein thrombosis during the mean 7.1-year intervention phase (HR, 1.48 [95% CI, 1.06 to 2.07]); the risk of pulmonary embolism was not significantly higher than in the placebo group (HR, 1.35 [95% CI, 0.89 to 2.05]).13 There was no difference between groups in risk of deep vein thrombosis or pulmonary embolism during the 3.9-year postintervention period.12

In three smaller trials (ERA,15 EPHT,17 and the Estrogen Memory Study [EMS]21) of combined estrogen and progestin, which varied in study duration and outcome measures, there was no difference in risk of venous thromboembolism among women randomized to hormone therapy or placebo over 2 to 3 years; however, the number of events was small. One trial of estrogen alone (EPAT20) reported no venous thromboembolic events in the treatment or placebo group during 2 years of followup.

Stroke

In the WHI trial, women who took combined estrogen and progestin had a significantly higher risk of stroke compared with those who received placebo during the intervention phase (median duration, 5.6 years; HR, 1.37 [95% CI, 1.07 to 1.76]); during postintervention followup, stroke risk was similar between the two groups (HR, 1.04 [95% CI, 0.86 to 1.26]). Cumulatively, stroke risk was higher in the combined estrogen and progestin group than in the placebo group (HR, 1.16 [95% CI, 1.00 to 1.35]).13

Two other trials comparing combined estrogen and progestin with placebo reported on the incidence of various cerebrovascular events as harms of treatment. In the EPHT trial, women randomized to combined estrogen and progestin had an increased risk of any cerebrovascular event compared with those randomized to placebo (HR, 2.46 [95% CI, 1.14 to 5.34]).17 In EMS, few events occurred over 2 years, and the results were inconclusive.21

In the WHI trial, women who took estrogen alone had a statistically significantly higher risk of stroke compared with those who received placebo during the intervention phase (median duration, 7.2 years; HR, 1.35 [95% CI, 1.07 to 1.70]). During the postintervention period, the risk became similar again between the two treatment groups; cumulatively, at 10.7 years of followup, women in in the estrogen-alone group had a higher risk of stroke compared with the placebo group (HR, 1.15 [95% CI, 0.97 to 1.37]).12, 13 In the smaller EPAT20 and the ERA15 trial, few events occurred, and results were inconclusive.

Cognitive Impairment

Observational evidence had suggested that menopausal hormone therapy might protect against dementia or cognitive impairment; however, the WHI Memory Study (WHIMS) did not confirm this. WHIMS and the WHIMS estrogen-alone trial evaluated the risk of probable dementia or mild cognitive impairment among women taking estrogen plus progestin or estrogen alone compared with placebo. Both studies were subsets of the WHI trial and were limited to women ages 65 to 79 years at baseline who were free of probable dementia. Women who took estrogen plus progestin had a higher risk of probable dementia than those who received placebo (HR, 2.05 [95% CI, 1.21 to 3.48]) but not mild cognitive impairment.22 Women who took estrogen alone had a higher risk of the composite outcome measure (probable dementia or mild cognitive impairment) (HR, 1.38 [95% CI, 1.01 to 1.89]) but not probable dementia alone.23

Gallbladder Disease

In the WHI trial, women randomized to combined estrogen and progestin or estrogen alone had an increased risk of gallbladder disease (HR, 1.59 [95% CI, 1.28 to 1.97] and HR, 1.67 [95% CI, 1.35 to 2.06], respectively).24 Risk for gallbladder disease in the combined estrogen and progestin group decreased postintervention but continued to favor placebo over combined estrogen and progestin therapy (median duration, 8.2 years postintervention; HR, 1.24 [95% CI, 1.01 to 1.52]); risk of gallbladder disease neutralized 6.6 years postintervention in the estrogen-alone group (HR, 0.98 [95% CI, 0.68 to 1.41]).13

Fractures

Pooled results of five trials (N=20,499) showed a significantly reduced risk of fractures in women randomized to combined estrogen and progestin compared with placebo (RR, 0.80 [95% CI, 0.68 to 0.94]).1

The WHI trial showed a significantly reduced risk of total osteoporotic fractures in women randomized to estrogen alone compared with placebo (HR, 0.72 [95% CI, 0.64 to 0.80]).13 The difference was no longer statistically significant in the postintervention phase (through 10.7 years), though this study reported only on hip fractures.12 The ERA trial found fewer fractures at all anatomical sites in women who took estrogen alone compared with placebo, but the relative risk was not statistically significant (RR, 0.42 [95% CI, 0.17 to 1.04]).15

Diabetes

Two trials provided information about the risk of developing diabetes with combined estrogen and progestin therapy among 17,903 women without diabetes or not receiving treatment for diabetes at baseline. Combined estrogen and progestin therapy reduced the risk of incident diabetes in HERS (mean followup, 4.1 years; HR, 0.65 [95% CI, 0.48 to 0.89])25 and self-reported incident diabetes in the WHI trial (mean followup, 5.6 years; HR, 0.81 [95% CI, 0.70 to 0.94]). This reduction in diabetes risk was no longer observed 8.2 years postintervention in the WHI trial (HR, 1.19 [95% CI, 1.05 to 1.34]).13

The WHI trial was the only one to provide information about the risk of self-reported incident diabetes with estrogen-alone therapy. During a median followup of 7.2 years, fewer women who took estrogen alone compared with placebo reported a new diabetes diagnosis (HR, 0.86 [95% CI, 0.76 to 0.98]). The overall reduction in diabetes risk was no longer observed 6.6 years postintervention (HR, 1.07 [95% CI, 0.92 to 1.25]).13

Urinary Incontinence

Both the WHI trial and HERS showed a consistently higher risk of self-reported incident urinary incontinence at all time points in women who took combined estrogen and progestin compared with placebo. In the WHI trial, women who took combined estrogen and progestin had a higher risk of incontinence at 1 year (RR, 1.39 [95% CI, 1.27 to 1.52]) and at 3 years (RR, 1.81 [95% CI, 1.16 to 2.84]).26 In HERS, women who took combined estrogen and progestin had a higher risk of incontinence at the 4.2-year followup (odds ratio, 1.6 [95% CI, 1.3 to 1.9]).27

Two trials, WHI26 and Ultra Low Dose Transdermal Estrogen Assessment (ULTRA),28 provided data on self-reported incident urinary incontinence in women who took estrogen alone versus placebo. In the WHI trial, women who took estrogen had an increased risk of urinary incontinence compared with those who received placebo at 1 year (RR, 1.53 [95% CI, 1.37 to 1.71]); results drawing on smaller samples at 2 years (ULTRA) and 3 years (WHI) of treatment did not show any significant differences in incident urinary incontinence.

Colorectal Cancer

Four trials reported on the incidence of colorectal cancer in women receiving combined estrogen and progestin versus placebo. In the WHI intervention phase, women who received combined estrogen and progestin were less likely to develop colorectal cancer (HR, 0.62 [95% CI, 0.43 to 0.89]). Over the median 13.2-year cumulative followup period, the risk of colorectal cancer remained lower in the hormone therapy arm (HR, 0.80 [95% CI, 0.63 to 1.01]).13 In HERS, there was a decrease in the risk of colorectal cancer with combined estrogen and progestin use (HR, 0.69 [95% CI, 0.32 to 1.49]) over a mean duration of 4.1 years.14 EMS21 and the WISDOM18 trial reported no statistically significant differences in risk of colorectal cancer. Event rates in these studies, however, were low, and the length of followup was short (<2 years), which precluded these studies from being combined with the WHI trial and HERS in a meta-analysis.

The WHI trial reported no difference in the incidence of colorectal cancer between women randomized to estrogen alone versus placebo during the intervention phase (HR, 1.15 [95% CI, 0.81 to 1.64]) or during the cumulative followup period (HR, 1.13 [95% CI 0.85 to 1.51]).13

Other Cancer

Both the WHI trial13 and HERS14 showed no difference in the incidence of lung cancer in women who received combined estrogen and progestin compared with placebo during the intervention phase and postintervention followup. EMS21 reported only 1 case of lung cancer, in the hormone therapy arm, and its short trial period precluded it from being combined with the WHI trial and HERS in a meta-analysis.

The WHI trial reported no difference in lung cancer incidence between women who received estrogen alone and women who received placebo both during the intervention phase and during postintervention followup.13

In the WHI trial13 and HERS,14 the incidence of endometrial cancer during the intervention phase did not differ significantly between women who received combined estrogen and progestin therapy or placebo. During the WHI postintervention period, statistically significantly fewer women who were randomized to hormone therapy during the trial phase developed endometrial cancer (HR, 0.58 [95% CI, 0.40 to 0.86]) compared with women who received placebo.13 Two additional trials, ERA15 and PEPI,16 reported no cases of endometrial cancer; however, the trials were too short in duration to combine in a meta-analysis with the WHI trial and HERS.

In the WHI trial, there was no significant difference in the incidence of invasive ovarian cancer between women who received either combined estrogen and progestin or placebo, both during the intervention phase and postintervention followup.13

ESPRIT29 reported no difference in the incidence of ovarian cancer between women who received estrogen alone or placebo during long-term followup (which included both a 2-year intervention phase and a posttrial observational phase, for an average of 12.6 years).

There was no difference in the incidence of cervical cancer among women with an intact uterus who received either combined estrogen and progestin or placebo in the WHI trial.30

Subgroups

Subgroups of interest for this recommendation statement included: race/ethnicity; age; duration of hormone therapy use; type, dose, and mode of delivery of hormone therapy; and comorbid conditions.

Trials did not report results for most of these subgroups. Subgroup analyses of trial results based on these characteristics were restricted to race/ethnicity, age, and a limited number of comorbid conditions or risk factors. For most outcomes, there were no statistically significant subgroup effects; however, studies may have been underpowered to detect such effects.

Age did appear to influence the effects of estrogen-alone therapy on risk of myocardial infarction, all-cause mortality, and colorectal cancer. In the WHI trial, younger women (ages 50 to 59 years) who took estrogen alone had lower risk of myocardial infarction, though not total coronary heart disease events,13 and a reduced risk of all-cause mortality.12 However, the small number of events that occurred in the estrogen-alone trial limits the strength of these findings. Older women (ages 70 to 79 years) who took estrogen alone had a higher risk of colorectal cancer in the WHI trial (HR, 2.24 [95% CI, 1.16 to 4.30]).13

To date, evidence to determine whether different types, doses, and modes of delivery of hormone therapy have a different balance of benefits and harms is limited.

Timing of Preventive Medication

The timing hypothesis posits that hormone therapy initiated closer to the time of menopause may have a more beneficial, or less deleterious, effect on risk of coronary heart disease than hormone therapy initiated later. Subgroup analyses of the WHI trial regarding the effect of timing of hormone therapy on risk of coronary events provide conflicting findings. In one subgroup analysis, women randomized to combined estrogen and progestin therapy within 10 years of menopause did not have the increased risk of coronary heart disease seen in those randomized to hormone therapy more than 20 years postmenopause; however, there was also no beneficial effect in the former group. In contrast, a second subgroup analysis that considered prior hormone therapy use (i.e., before trial enrollment), which therefore provides a more accurate assessment of the time between menopause and initiation of hormone therapy, found no difference in coronary risk between early (<5 years) and late (>5 years) initiation of hormone therapy.

To date, no good-quality randomized trials have prospectively evaluated the effect of timing of hormone therapy initiation relative to the onset of menopause on associated benefits and harms.

Estimate of Magnitude of Net Benefit

Although the use of hormone therapy to prevent chronic conditions in postmenopausal women is associated with some benefits, there are also well-documented harms. The USPSTF determined that the magnitude of both the benefits and the harms of postmenopausal hormone therapy is small to moderate. Therefore, the USPSTF concludes with moderate certainty that combined estrogen and progestin therapy has no net benefit for the prevention of chronic conditions in most postmenopausal women, and that estrogen alone has no net benefit for the prevention of chronic conditions in most postmenopausal women who have had a hysterectomy.

How Does Evidence Fit With Biological Understanding?

Estrogen has traditionally been viewed as having cardioprotective effects. The incidence of coronary heart disease in premenopausal women is lower than in men of the same age; this difference decreases as women age past menopause. Estrogen decreases low-density lipoprotein cholesterol levels, increases high-density lipoprotein cholesterol levels, and has a vasodilator effect. Despite these observations, data from randomized, controlled trials show a lack of benefit, or even a harmful effect, of postmenopausal hormone therapy on risk of coronary heart disease. Several potential factors, including timing of administration of hormone therapy with respect to menopause, older age, and presence of atheroma have been proposed to account for these discrepant findings. Nonetheless, the underlying causes of this lack of benefit are uncertain.

Another discrepant finding is that combined estrogen and progestin therapy is associated with a small increase in the risk of breast cancer, while estrogen alone appears to slightly reduce this risk. While estrogen generally stimulates breast cell proliferation, some preclinical studies have shown that estrogen can induce breast cell apoptosis if given under conditions of estrogen deprivation, and that progestin can stimulate breast cell proliferation and angiogenesis. These findings have been proposed as a possible explanation for the apparent discrepant effects of combined estrogen and progestin therapy and estrogen alone on breast cancer risk.31

Draft: Update of Previous USPSTF Recommendation

As in its 2012 recommendation on the use of menopausal hormone therapy for the primary prevention of chronic conditions, the USPSTF continues to recommend against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women and against the use of estrogen alone for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy.

Draft: Recommendations of Others

The American Heart Association32 and the American College of Obstetricians and Gynecologists33 recommend against the use of hormone therapy for the primary or secondary prevention of heart disease, and most clinical guidelines, including those of the Canadian Task Force on Preventive Health Care34 and the American Academy of Family Physicians,35 recommend against the use of hormone therapy for prevention of any chronic conditions. The American Association of Clinical Endocrinologists36 notes that hormone therapy is approved by the FDA for use in women at increased risk of osteoporosis and fractures. The American College of Obstetricians and Gynecologists mentions the possibility that the effect of hormone therapy on risk of cardiovascular disease may differ based on early versus late initiation of hormone therapy with respect to onset of menopause. The North American Menopause Society37 focuses primarily on considerations for women with symptoms; it notes that the balance of potential health benefits and risks should be weighed individually for each woman. 

References:

1. Gartlehner G, Patel S, Viswanathan M, Feltner C, Palmieri Weber R, Lee R, et al. Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: An Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 155. AHRQ Publication No. 15-05227-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2017.
2. Pfizer Inc. Premarin package insert. 2014. http://labeling.pfizer.com/showlabeling.aspx?id=131. Accessed April 26, 2017.
3. U.S. Preventive Services Task Force. Medications for risk reduction of primary breast cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(10):698-708.
4. U.S. Preventive Services Task Force. Behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults with cardiovascular risk factors: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;161(8):587-93.
5. U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164(12):836-45.
6. McKinlay SM. The normal menopause transition: an overview. Maturitas. 1996;23(2):137-45.
7. Social Security Administration. Actuarial life table: period life table, 2013. https://www.ssa.gov/oact/STATS/table4c6.html. Accessed April 26, 2017.
8. Xu JQ, Murphy SL, Kochanek KD, Bastian BA. Deaths: final data for 2013. Natl Vital Stat Rep. 2016;64(2):1-119.
9. Healthcare Cost and Utilization Project. Total number of discharges by age group, by sex, for CCS principal diagnosis category 226, fracture of neck of femur. 2014. https://hcupnet.ahrq.gov/. Accessed February 14, 2017.
10. Ensrud KE. Epidemiology of fracture risk with advancing age. J Gerontol A Biol Sci Med Sci. 2013;68(10):1236-42.
11. Heiss G, Wallace R, Anderson GL, Aragaki A, Beresford SA, Brzyski R, et al; WHI Investigators. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299(9):1036-45.
12. LaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, et al; WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305(13):1305-14.
13. Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, 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(13):1353-68.
14. Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, et al; HERS Research Group. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002;288(1):58-66.
15. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000;343(8):522-9.
16. Miller VT, LaRosa J, Barnabei V, Kessler C, Levin G, Smith-Roth A, et al. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA. 1995;273(3):199-208.
17. Veerus P, Hovi SL, Fischer K, Rahu M, Hakama M, Hemminki E. Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757]. Maturitas. 2006;55(2):162-73.
18. Vickers MR, MacLennan AH, Lawton B, Ford D, Martin J, Meredith SK, et al; WISDOM Group. Main morbidities recorded in the Women's International Study of long Duration Oestrogen after Menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ. 2007;335(7613):239.
19. Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H, et al; ESPRIT Team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet. 2002;360(9350):2001-8.
20. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, et al; Estrogen in the Prevention of Atherosclerosis Trial Research Group. Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135(11):939-53.
21. Tierney MC, Oh P, Moineddin R, Greenblatt EM, Snow WG, Fisher RH, et al. A randomized double-blind trial of the effects of hormone therapy on delayed verbal recall in older women. Psychoneuroendocrinology. 2009;34(7):1065-74.
22. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al; WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003;289(20):2651-62.
23. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, et al; Women's Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004;291(24):2947-58.
24. Cirillo DJ, Wallace RB, Rodabough RJ, Greenland P, LaCroix AZ, Limacher MC et al. Effect of estrogen therapy on gallbladder disease. JAMA. 2005;293:330-9.
25. Kanaya AM, Herrington D, Vittinghoff E, Lin F, Grady D, Bittner V, et al; Heart and Estrogen/progestin Replacement Study. 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):1-9.
26. Hendrix SL, Cochrane BB, Nygaard IE, Handa VL, Barnabei VM, Iglesia C, et al. Effects of estrogen with and without progestin on urinary incontinence. JAMA. 2005;293(8):935-48.
27. Steinauer JE, Waetjen LE, Vittinghoff E, Subak LL, Hulley SB, Grady D, et al. Postmenopausal hormone therapy: does it cause incontinence? Obstet Gynecol. 2005;106(5 Pt 1):940-5.
28. Waetjen LE, Brown JS, Vittinghoff E, Ensrud KE, Pinkerton J, Wallace R, et al. The effect of ultralow-dose transdermal estradiol on urinary incontinence in postmenopausal women. Obstet Gynecol. 2005;106(5 Pt 1):946-52.
29. Cherry N, McNamee R, Heagerty A, Kitchener H, Hannaford P. Long-term safety of unopposed estrogen used by women surviving myocardial infarction: 14-year follow-up of the ESPRIT randomised controlled trial. BJOG. 2014;121(6):700-5.
30. Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, et al; Women's Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA. 2003;290(13):1739-48.
31. Chlebowski RT, Anderson GL. Changing concepts: menopausal hormone therapy and breast cancer. J Natl Cancer Inst. 2012:104(7):517-27.
32. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM, et al; American Heart Association. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the American Heart Association. Circulation. 2011;123(11):1243-62.
33. American College of Obstetricians and Gynecologists. ACOG committee opinion no. 565: hormone therapy and heart disease. Obstet Gynecol. 2013;121(6):1407-10.
34. Wathen CN, Feig DS, Feightner JW, Abramson BL, Cheung AM; Canadian Task Force on Preventive Health Care. Hormone replacement therapy for the primary prevention of chronic diseases: recommendation statement from the Canadian Task Force on Preventive Health Care. CMAJ. 2004;170(10):1535-7.
35. American Academy of Family Physicians. Clinical preventive service recommendation: hormone replacement therapy. 2012 http://www.aafp.org/patient-care/clinical-recommendations/all/hrt.html. Accessed April 26, 2017.
36. Goodman NF, Cobin RH, Ginzburg SB, Katz IA, Woode DE; American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of menopause. Endocr Pract. 2011;17(Suppl 6):1-25.
37. North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause. 2012;19(3):257-71.

Current as of: May 2017

Internet Citation: Draft Recommendation Statement: Menopausal Hormone Therapy: Primary Prevention of Chronic Conditions . U.S. Preventive Services Task Force. May 2017.
https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/menopausal-hormone-therapy-preventive-medication1

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