Menopause is defined as the cessation of a person’s menstrual cycle. It is defined retrospectively, 12 months after the final menstrual period.¹ Perimenopause, or the menopausal transition, is the few-year time period preceding a person’s final menstrual period and is characterized by increasing menstrual cycle length variability and periods of amenorrhea, and often symptoms such as vasomotor dysfunction.² Natural menopause occurs at a median age of 51.3 years.³ The prevalence and incidence of most chronic diseases (e.g., cardiovascular disease, cancer, osteoporosis, and fracture) increase with age, and the average U.S. person who reaches menopause is expected to live more than another 30 years.⁴ However, the excess risk for chronic conditions that can be attributed to menopause alone is uncertain.

The U.S. Preventive Services Task Force (USPSTF) concludes with moderate certainty that the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons with an intact uterus has no net benefit.

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

See the Table for more information on the USPSTF recommendation rationale and assessment. For more details on the methods the USPSTF uses to determine the net benefit, see the USPSTF Procedure Manual.⁵

Patient Population Under Consideration

This recommendation statement applies to asymptomatic, postmenopausal persons who are considering hormone therapy for the primary prevention of chronic medical conditions. It does not apply to persons who are considering hormone therapy for the management of perimenopausal symptoms, such as hot flashes or vaginal dryness. It also does not apply to persons who have had premature menopause (primary ovarian insufficiency) or surgical menopause.

The trials that provided evidence on the benefits and harms of menopausal hormone therapy for this recommendation generally used the term “women” to describe participants, although it is likely that these trials enrolled participants on the basis of sex, not gender identity.

Intervention

Menopausal hormone therapy refers to the use of combined estrogen and progestin in persons with an intact uterus, or estrogen alone in persons who have had a hysterectomy, taken at or after the time of menopause. For this recommendation, the USPSTF considered evidence on the benefits and harms of systemic (i.e., oral or transdermal) menopausal hormone therapy but not local formulations of hormone therapy, because these are not generally used for the primary prevention of chronic conditions.

Indications for hormone therapy approved by the U.S. Food and Drug Administration in menopausal persons are limited to the treatment of menopausal symptoms and the prevention of postmenopausal osteoporosis.⁶ Several different formulations of menopausal hormone therapy are approved by the U.S. Food and Drug Administration for use in the United States; the specific formulation used in the Women’s Health Initiative (WHI), the largest trial reviewed by the USPSTF, was 0.625 mg/day of oral conjugated equine estrogen, with or without 2.5 mg/day of medroxyprogesterone acetate.⁷ Currently, evidence 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 is limited.⁸

Other Related USPSTF Recommendations

The USPSTF has made several recommendations related to the prevention of cardiovascular disease and other chronic conditions in adults, including aspirin use for the prevention of cardiovascular disease, which is currently being updated,⁹ screening for high blood pressure,¹⁰ screening for prediabetes and type 2 diabetes,¹¹ behavioral counseling to promote a healthful diet and physical activity for cardiovascular disease prevention in adults (with and without cardiovascular risk factors),^12,13 and screening for osteoporosis.¹⁴ The USPSTF has also made recommendations on screening for breast cancer¹⁵ and screening for colorectal cancer.¹⁶

When final, this recommendation will replace the 2017 USPSTF recommendation on hormone therapy for the primary prevention of chronic conditions in postmenopausal women. The current draft recommendation is consistent with the 2017 USPSTF recommendation. In 2017, the USPSTF recommended against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal women and against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal women who have had a hysterectomy.¹⁷

Scope of Review

To update its 2017 recommendation statement, the USPSTF commissioned a systematic review of the evidence on the benefits and harms of systemic (i.e., oral or transdermal) hormone therapy for the prevention of chronic conditions in postmenopausal persons and whether outcomes vary by age or by timing of intervention after menopause.⁸ The use of hormone therapy for the treatment of menopausal symptoms (e.g., vasomotor hot flashes or vulvovaginal symptoms) or for other indications is outside the scope of this recommendation.

Benefits and Harms of Preventive Medication

The USPSTF found 20 randomized, controlled trials that compared the effects of estrogen, either alone or in combination with progestin, vs. placebo for the prevention of chronic conditions.⁸ Of these studies, the WHI trials were the only studies powered to assess the effectiveness of hormone therapy for the primary prevention of various chronic conditions. The WHI trials enrolled postmenopausal persons ages 50 to 79 years and compared 0.625 mg/day of oral conjugated equine estrogen, with or without 2.5 mg/day of medroxyprogesterone acetate, with placebo. Evidence on other types, doses, or modes of delivery of hormone therapy was limited. The WHI also had the longest durations of followup, with a median intervention of 7.2 years for the estrogen-only trial and 5.6 years for the estrogen plus progestin trial, as well as long-term followup of up to 20.4 years.^7,18 In the section that follows, the USPSTF focuses on coronary heart disease outcomes, all-cause mortality, and outcomes for which it assessed the evidence as adequate or convincing for benefit or harms. Other outcomes and more details are available in the accompanying systematic evidence review.⁸

Coronary Heart Disease

Observational evidence has suggested that there might be a protective effect of menopausal hormone therapy on coronary heart disease; however, the WHI and other trials of menopausal hormone therapy have not demonstrated such an effect. A pooled analysis of three trials (n=18,085) showed no significant difference in risk of coronary heart disease events in persons treated with estrogen plus progestin compared with placebo (2.8% vs. 2.6%; relative risk [RR], 1.12 [95% CI, 0.94 to 1.33]) during a mean followup of 4 years. Similarly, a pooled analysis of three trials (n=11,310) found no difference in coronary events between persons taking estrogen alone and those taking placebo (RR, 0.95 [95% CI, 0.79 to 1.14]) during a mean followup of 4.1 years.⁸

Breast Cancer

Because estrogen generally stimulates breast cell proliferation, trials of menopausal hormone therapy have reported on the risk of breast cancer as one of the primary adverse outcomes of treatment.

In the WHI (n=16,608), persons randomized to estrogen plus progestin had a significantly increased risk of invasive breast cancer compared with those taking placebo (2.4% vs. 1.9%; hazard ratio [HR], 1.24 [95% CI, 1.01 to 1.53]),⁷ which persisted during postintervention followup.¹⁹ Other trials either reported few cases of breast cancer or were generally consistent with the WHI findings in direction of effect. In the WHI, during 20.3 years of followup, the risk of breast cancer mortality was higher for women in the estrogen plus progestin group than in the placebo group, although the difference did not reach statistical significance (HR, 1.35 [95% CI, 0.94 to 1.95]).¹⁸  

Four trials reported on the effects of estrogen alone on breast cancer; however, only the WHI followed participants for more than 3 years. At 20.7 years of followup, the WHI reported a lower risk of invasive breast cancer among persons assigned to estrogen alone compared with placebo (HR, 0.78 [95% CI, 0.65 to 0.93]),¹⁹ although the risk of breast cancer was not significantly lower during the study’s 7.2-year intervention phase.^7,20 The other trials reported very few cases of breast cancer.⁸ The WHI also reported on breast cancer mortality. At 20.7 years of followup, persons who received estrogen alone during the intervention phase had a lower risk of breast cancer mortality than those who were in the placebo group (HR, 0.60 [95% CI, 0.37 to 0.97]).¹⁸ 

Fractures

Five trials reported on fracture risk in persons randomized to estrogen plus progestin compared with placebo. A pooled analysis of these trials (N=20,499) found a statistically significantly reduction of fractures in persons taking estrogen plus progestin (8.7% vs 10.9%; RR, 0.79 [95% CI, 0.66 to 0.94]).⁸

The WHI (N=10,739) also found a lower risk of total fractures in persons taking estrogen alone compared with placebo during the intervention phase (1.53% annualized vs. 2.14% annualized; HR, 0.72 [95% CI, 0.64 to 0.80]),⁷ which persisted during 4.3 years of postintervention followup.²¹ A smaller trial found fewer fractures at all sites in the estrogen-alone arm, although the difference was not statistically significant.²²

Diabetes

Two trials reported on the effects of menopausal hormone therapy on incident diabetes. In the WHI (n=15,874), fewer persons randomized to estrogen plus progestin reported a new diagnosis of diabetes compared with those taking placebo (HR, 0.81 [95% CI, 0.70 to 0.94]).^7,23 A smaller trial also found a reduced risk of incident diabetes, although this was a post-hoc analysis.²⁴ 

In the WHI (n=9,917), fewer persons taking estrogen alone reported a new diagnosis of diabetes compared with those taking placebo (1.34% annualized vs. 1.55% annualized; HR, 0.86 [95% CI, 0.76 to 0.98]).⁷

Colorectal Cancer

Four trials reported on the incidence of colorectal cancer in persons randomized to estrogen plus progestin therapy. In the WHI estrogen plus progestin trial (n=16,608), persons randomized to estrogen plus progestin had a lower risk of colorectal cancer than those in the placebo group (0.59% vs 0.93%; HR, 0.62 [95% CI, 0.43 to 0.89]) over a median followup of 5.6 years.⁷ The other trials either reported few cases of colorectal cancer or were generally consistent with the WHI findings in direction of effect.⁸

The WHI estrogen-alone trial (n=10,739) reported no difference in the risk of colorectal cancer between persons randomized to estrogen alone and those taking placebo (1.2% vs  1.1%; HR, 1.15 [95% CI, 0.81 to 1.64]) during 7.2 years.⁷

Thromboembolic Events

Five trials reported on risk of thromboembolism. In the WHI (n=16,608), persons randomized to estrogen plus progestin had an increased risk of venous thrombosis (1.96% vs. 0.94%; HR, 2.06 [95% CI, 1.57 to 2.70]), deep vein thrombosis (1.4% vs. 0.8%; HR, 1.87 [95% CI, 1.37 to 2.54]), and pulmonary embolism (1.0% vs. 0.5%; HR, 1.98 [95% CI, 1.36 to 2.87]) compared with those in the placebo group.^7,25 Other trials either reported few thromboembolic events or were consistent with the WHI findings.⁸

In the WHI (n=10,739), persons randomized to estrogen alone had an increased risk of deep vein thrombosis (1.6% vs. 1.0%; HR, 1.48 [95% CI, 1.06 to 2.07]); the risk of pulmonary embolism was higher in the estrogen group than in the placebo group, but results were not statistically significant, although the confidence interval was wide (0.98% vs. 0.72%; HR, 1.35 [95% CI, 0.89 to 2.05]).⁷

Stroke

The WHI found an increased risk of stroke with both estrogen plus progestin and estrogen-alone therapy. Stroke risk was significantly higher in persons randomized to estrogen plus progestin compared with placebo (1.9% vs. 1.3%; HR, 1.37 [95% CI, 1.07 to 1.76]).⁷ Similarly, persons receiving estrogen alone had a statistically significantly higher risk of stroke compared with those receiving placebo (3.2% vs. 2.4%; HR, 1.35 [95% CI, 1.07 to 1.70]).⁷ A smaller trial reported that stroke risk was similar in estrogen plus progestin and placebo groups, although the confidence interval was quite wide.²⁶

Dementia

The Women’s Health Initiative Memory Study (WHIMS) was a substudy of the WHI, evaluating the risk of dementia in persons randomized to estrogen plus progestin or estrogen alone compared with placebo. This study found that persons randomized to estrogen plus progestin (n=4,523) had a higher risk of probable dementia than those taking placebo (1.8% vs. 0.9%; HR, 2.05 [95% CI, 1.21 to 3.48]).²⁷ No significant increase in risk of probable dementia was found in persons taking estrogen alone (n=2,947).²⁸

Gallbladder Disease

Two trials reported on the risk of gallbladder disease in persons taking menopausal hormone therapy. The WHI (n=14,203) reported a significantly higher risk of gallbladder disease in persons randomized to estrogen plus progestin treatment compared with placebo (1.31% annualized vs. 0.84% annualized; HR, 1.57 [95% CI, 1.36 to 1.80]) and in persons randomized to estrogen alone (n=8,376; 1.64% annualized vs.  1.06% annualized; HR, 1.55 [95% CI, 1.34 to 1.79]).⁷ A smaller trial reported few cases of gallbladder disease.²⁹

Urinary Incontinence

Two trials reported on incident urinary incontinence (self-reported) in persons taking estrogen plus progestin; both found increased risk. In the WHI (n=10,073), 16.6% (annualized) of persons taking estrogen plus progestin reported incident incontinence after 1 year of treatment compared with 11.1% (annualized) of those taking placebo (HR, 1.49 [95% CI, 1.36 to 1.63]).⁷ A smaller trial also reported increased risk.³⁰ Similarly, in persons randomized to estrogen alone, the WHI found a higher risk of urinary incontinence at 1 year (22.6% annualized vs. 14.0% annualized; HR, 1.61 [95% CI, 1.46 to 1.79]) and 6.6 years after stopping treatment (28.6% annualized vs. 23.1% annualized; HR, 1.24 [95% CI, 1.13 to 1.35]).⁷

All-Cause Mortality

A pooled analysis of three trials (n=19,580) showed no difference in all-cause mortality between persons taking estrogen and progestin therapy and those taking placebo (RR, 1.01 [95% CI, 0.88 to 1.16]) during 3.2 to 5.6 years of followup. Similarly, a pooled analysis of three trials (n=11,587) showed no difference in all-cause mortality between persons receiving estrogen alone and those receiving placebo (RR, 1.04 [95% CI, 0.89 to 1.21]) during a mean followup of 7.1 years.⁸

Effects on Outcomes by Age or Timing of Intervention

It has been hypothesized that the benefits and harms of menopausal hormone therapy might differ based on participant’s age or timing of initiation of therapy with respect to menopause. Accordingly, the WHI trials reported on outcomes stratified by decade of age and by time since menopause. Of note, the analyses of outcomes by time since menopause were post hoc. For most outcomes, there were no differences based on these parameters.⁷ The WHI reported no statistically significant differences in risk of coronary heart disease based on age or time since menopause.⁷ One analysis of the WHI estrogen plus progestin trial reported a statistically significant trend for risk of myocardial infarction (a secondary trial outcome) by time since menopause, with significantly higher risk in persons 20 or more years after menopause,⁷ while a second analysis found no difference in coronary risk between early (<5 years) vs. late (≥5 years) initiation of hormone therapy with respect to menopause.³¹

The WHI estrogen-alone trial reported statistically significant trends by decade of age for the outcomes of myocardial infarction, colorectal cancer, and all-cause mortality, with lower risk in younger persons and higher risk in older persons, although the confidence intervals in all age groups included the null, with the exception of colorectal cancer, for which risk was significantly increased in 70- to 79-year-olds.⁷ Importantly, these findings are all limited by the multiplicity of outcomes and subgroup comparisons conducted (in these analyses, p-values were not adjusted for the large number of tests conducted), the relatively small number of events that occurred for several of these outcomes, and the post-hoc nature of the time since menopause analyses. Other studies have reported on the effect of timing on the benefits and harms of menopausal hormone therapy, but they are limited by study quality or other issues as well.⁸

More research is needed that addresses the following.

• Whether age or the timing of initiation of hormone therapy with respect to menopause affects health outcomes.
• Whether the benefits and harms of menopausal hormone therapy might vary across population groups. Because people who experience systemic racism, poverty, or other socioeconomic barriers can be at higher risk for certain chronic conditions (e.g., type 2 diabetes or stroke), it would be important to understand whether hormone therapy might have a different magnitude (or balance) of harms or benefits across racial and ethnic groups. Combining individual patient data from previously conducted trials to conduct an individual patient data meta-analysis might provide this information.
• The comparative benefits and harms of different formulations and treatment durations of menopausal hormone therapy.

The American College of Obstetricians and Gynecologists recommends against the use of menopausal hormone therapy for primary and secondary prevention of coronary heart disease.³² It also notes that evidence suggests that women in early menopause who are in good cardiovascular health and at low risk of adverse cardiovascular outcomes should be considered candidates for the use of estrogen therapy or conjugated equine estrogen plus a progestin for relief of menopausal symptoms, and that menopausal hormone therapy is approved for use in women with an increased risk of osteoporosis and fracture.³³ The North American Menopause Society recommends that hormone therapy should not be prescribed for chronic disease prevention. It also notes that extended duration of hormone therapy use might be appropriate in symptomatic women or for the prevention of osteoporosis, if alternative therapies are not tolerated, based on a careful assessment of individual benefits and risks.³⁴ The American Academy of Family Physicians endorses the previous USPSTF recommendation on hormone therapy in postmenopausal persons.³⁵

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