This is the current release of the guideline.

This release updates a previously published guideline: Postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. Ann Intern Med 2002 Nov 19;137(10):834-9.

Chronic conditions including:

• Osteoporosis and fractures
• Colorectal cancer
• Breast cancer
• Coronary heart disease
• Stroke
• Venous thromboembolism (deep vein thrombosis and pulmonary embolism)
• Cognition and dementia
• Endometrial and ovarian cancer
• Cholecystitis

Prevention

Family Practice
Internal Medicine
Obstetrics and Gynecology
Preventive Medicine

Advanced Practice Nurses
Allied Health Personnel
Health Care Providers
Nurses
Physician Assistants
Physicians

• To summarize the U.S. Preventive Services Task Force (USPSTF) recommendations on hormone therapy for the prevention of chronic conditions in postmenopausal women and the supporting scientific evidence
• To update the USPSTF 2002 recommendations on hormone replacement therapy

Postmenopausal women

Hormone replacement therapy (HRT)

• Combined estrogen and progestin (considered, but not recommended)
• Unopposed estrogen (considered, but not recommended)

The use of postmenopausal hormone replacement therapy (HRT) and:

• Coronary heart disease and stroke incidence and/or mortality
• Risk of venous thromboembolism, including deep venous thrombosis (DVT), pulmonary embolism, or both
• Bone mineral density (BMD) and risk of fracture
• Cognitive function, including verbal memory, vigilance, reasoning, and motor speed
• Breast cancer incidence, mortality, or both
• Colon, endometrial, and ovarian cancer incidence and/or mortality
• Risk of cholecystitis and rate of biliary tract surgery

Searches of Electronic Databases

Not stated

Not stated

Weighting According to a Rating Scheme (Scheme Given)

The U.S. Preventive Services Task Force (USPSTF) grades the quality of the overall evidence on a 3-point scale (good, fair, or poor).

Good

Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes.

Fair

Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies; generalizability to routine practice; or indirect nature of evidence on health outcomes.

Poor

Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.

Review of Published Meta-Analyses
Systematic Review

Not stated

Balance Sheets
Expert Consensus

When the overall quality of the evidence is judged to be good or fair, the U.S. Preventive Services Task Force (USPSTF) proceeds to consider the magnitude of net benefit to be expected from implementation of the preventive service. Determining net benefit requires assessing both the magnitude of benefits and the magnitude of harms and weighing the two.

The USPSTF classifies benefits, harms, and net benefits on a 4-point scale: "substantial," "moderate," "small," and "zero/negative."

"Outcomes tables" (similar to 'balance sheets') are the USPSTF's standard resource for estimating the magnitude of benefit. These tables, prepared by the topic teams for use at USPSTF meetings, compare the condition specific outcomes expected for a hypothetical primary care population with and without use of the preventive service. These comparisons may be extended to consider only people of specified age or risk groups or other aspects of implementation. Thus, outcomes tables allow the USPSTF to examine directly how the preventive services affect benefits for various groups.

When evidence on harms is available, the topic teams assess its quality in a manner like that for benefits and include adverse events in the outcomes tables. When few harms data are available, the USPSTF does not assume that harms are small or nonexistent. It recognizes a responsibility to consider which harms are likely and judge their potential frequency and the severity that might ensue from implementing the service. It uses whatever evidence exists to construct a general confidence interval on the 4-point scale (e.g., substantial, moderate, small, and zero/negative).

Value judgments are involved in using the information in an outcomes table to rate either benefits or harms on the USPSTF's 4-point scale. Value judgments are also needed to weigh benefits against harms to arrive a rating of net benefit.

In making its determinations of net benefit, the USPSTF strives to consider what it believes are the general values of most people. It does this with greater confidence for certain outcomes (e.g., death) about which there is little disagreement about undesirability, but it recognizes that the degree of risk people are willing to accept to avert other outcomes (e.g., cataracts) can vary considerably. When the USPSTF perceives that preferences among individuals vary greatly, and that these variations are sufficient to make trade-off of benefits and harms a "close-call," then it will often assign a C recommendation (see the "Recommendation Rating Scheme" field). This recommendation indicates the decision is likely to be sensitive to individual patient preferences.

The USPSTF uses its assessment of the evidence and magnitude of net benefit to make recommendations. The general principles the USPSTF follows in making recommendations are outlined in Table 5 of the companion document cited below. The USPSTF liaisons on the topic team compose the first drafts of the recommendations and rationale statements, which the full panel then reviews and edits. Recommendations are based on formal voting procedures that include explicit rules for determining the views of the majority.

From: Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow, CD, Teutsch SM, Atkins D. Current methods of the U.S. Preventive Services Task Force: a review of the process. Methods Work Group, Third U.S. Preventive Services Task Force. Am J Prev Med 2001 Apr;20(3S):21-35.

The U.S. Preventive Services Task Force (USPSTF) grades its recommendations according to one of five classifications (A, B, C, D, or I), reflecting the strength of evidence and magnitude of net benefit (benefits minus harms).

A

The U.S. Preventive Services Task Force (USPSTF) strongly recommends that clinicians provide [the service] to eligible patients. The USPSTF found good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms.

B

The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians provide [the service] to eligible patients. The USPSTF found at least fair evidence that [the service] improves health outcomes and concludes that benefits outweigh harms.

C

The U.S. Preventive Services Task Force (USPSTF) makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms it too close to justify a general recommendation.

D

The U.S. Preventive Services Task Force (USPSTF) recommends against routinely providing [the service] to asymptomatic patients. The USPSTF found at least fair evidence that [the service] is ineffective or that harms outweigh benefits.

I

The U.S. Preventive Services Task Force (USPSTF) concludes that the evidence is insufficient to recommend for or against routinely providing [the service]. Evidence that [the service] is effective is lacking, of poor quality, or conflicting and the balance of benefits and harms cannot be determined.

A formal cost analysis was not performed and published cost analyses were not reviewed.

Comparison with Guidelines from Other Groups
External Peer Review
Internal Peer Review

Peer Review. Before the U.S. Preventive Services Task Force makes its final determinations about recommendations on a given preventive service, the Evidence-based Practice Center and the Agency for Healthcare Research and Quality send a draft systematic evidence review to 4 to 6 external experts and to federal agencies and professional and disease-based health organizations with interests in the topic. They ask the experts to examine the review critically for accuracy and completeness and to respond to a series of specific questions about the document. After assembling these external review comments and documenting the proposed response to key comments, the topic team presents this information to the Task Force in memo form. In this way, the Task Force can consider these external comments and a final version of the systematic review before it votes on its recommendations about the service. Draft recommendations are then circulated for comment from reviewers representing professional societies, voluntary organizations, and Federal agencies. These comments are discussed before the whole U.S. Preventive Services Task Force before final recommendations are confirmed.

Recommendations of Others. Recommendations regarding the use of hormone therapy for the prevention of chronic diseases in postmenopausal women from the following groups were discussed: the American College of Obstetricians and Gynecologists (ACOG), the American Heart Association (AHA), the Canadian Task Force on Preventive Health Care (CTFPHC), and the North American Menopause Society (NAMS).

None provided

The updated statement is based on the results of the Women's Health Initiative randomized controlled trial as well as the information in the 2002 summary of the evidence on this topic. The type of evidence supporting each recommendation is identified in the "Major Recommendations" field.

Osteoporosis and Fractures

Good evidence from observational studies and randomized clinical trials demonstrates that estrogen therapy increases bone density and reduces the risk for fractures. The combined estrogen-progestin arm of the Women's Health Initiative (WHI) trial, a fair-quality study, found significant reductions in total fracture risk (hazard ratio [HR], 0.76; adjusted 95% confidence interval [CI], 0.63-0.92) among healthy women taking estrogen and progestin. This arm of the WHI trial also showed reductions for hip and vertebral fracture, although these did not achieve statistical significance. (In its analysis, the USPSTF used nominal 95% CIs for the primary outcomes and adjusted 95% CIs for all secondary outcomes.)

The estrogen-only arm of the WHI trial also reported decreased risk for hip and vertebral fracture, which also did not reach statistical significance. A meta-analysis of 22 trials of estrogen reported an overall 27% reduction in non-vertebral fractures (relative risk [RR], 0.73; [95% CI, 0.56-0.94]), although the quality of individual studies varied. The Heart and Estrogen/progestin Replacement Study (HERS) and its unblinded follow-up study, HERS II, a fair-quality trial of combined estrogen-progestin for the secondary prevention of heart disease that reported many other outcomes, found no reduction in hip, wrist, vertebral, or total fractures with hormone therapy (relative hazard [RH] for total fractures, 1.04; 95% CI, 0.87-1.25). Overall, a good-quality body of evidence supports the efficacy of hormone therapy in increasing bone density and decreasing fracture risk.

Colorectal Cancer

Results from the WHI study and HERS showed a trend toward reduced incidence of colon cancer (HR, 0.63; adjusted 95% CI, 0.32-1.24 and RH, 0.81; 95% CI, 0.46-1.45, respectively), but the trend did not reach statistical significance. The estrogen-only arm of the WHI trial showed neither benefit nor harm for colorectal cancer risk (HR, 1.08; adjusted 95% CI, 0.63-1.86). A meta-analysis of 18 observational studies of postmenopausal women reported a 20% reduction in colon cancer (RR, 0.80; 95% CI, 0.74-0.86) and a 19% reduction in rectal cancer (RR, 0.81; 95% CI, 0.72-0.92) among women who had ever used combined estrogen-progestin or estrogen alone compared with women who had never used hormone therapy. This decrease in risk was more apparent when current users were compared with those who had never used hormone therapy (RR, 0.66; 95% CI, 0.59-0.74). Overall, the evidence suggesting a trend toward reduction of colorectal cancer risk with combined hormone therapy should be interpreted cautiously until controlled trials clarify whether therapy has either no benefit or modest benefit.

Breast Cancer

The estrogen-progestin arm of the Women's Health Initiative (WHI) study was terminated after an average of 5.2 years of follow-up because "evidence for breast cancer harm, along with evidence for some increase in coronary heart disease (CHD), stroke, and pulmonary embolism, outweighed the evidence of benefit for fractures and possible benefit for colon cancer." This study showed an increased invasive breast cancer incidence (hazard ratio [HR], 1.26; nominal 95% confidence interval [CI], 1.00-1.59). However, no effect on breast cancer mortality was observed. Comparable increases in breast cancer incidence were observed among women taking estrogen and progestin over 6.8 years of follow-up in the Heart and Estrogen/progestin Replacement Study (HERS). The U.K. Million Women Study, a fair-quality study, showed an increased risk for breast cancer in current users of combined estrogen-progestin (relative risk [RR], 2.00; 95% CI, 1.91-2.09) compared with those who had never used hormone therapy. Results from two good-quality cohort studies conflict on the effects of long-term hormone therapy on breast cancer mortality. Overall, there is a good-quality body of evidence indicating that combined estrogen-progestin increases breast cancer risk. It is unclear whether the combination of estrogen-progestin confers a greater breast cancer risk than estrogen alone. In studies of estrogen alone, the results are conflicting: the Million Women Study showed an increased risk for breast cancer in current users of estrogen only (RR, 1.30; 95% CI, 1.22-1.38) compared with those who had never used it; but the estrogen-only arm of the WHI trial showed a trend toward breast cancer prevention (HR, 0.77; nominal 95% CI, 0.59-1.01).

Coronary Heart Disease (CHD)

In the WHI study, women who took combined estrogen-progestin daily, compared with women taking placebo, had an increased risk for CHD (fatal and non-fatal myocardial infarctions), which became evident shortly after initiation of the study (HR, 1.29; nominal 95% CI, 1.02-1.63). However, mortality from CHD was not significantly increased among the women taking combined hormone therapy daily. One meta-analysis of observational studies showed a statistically significant reduction in CHD (RR, 0.80; 95% CI, 0.68-0.95) among current hormone therapy users, but not among those who had used hormone therapy in the past or among those who had never used it. This meta-analysis also showed that CHD mortality in observational studies was reduced among current hormone therapy users (RR, 0.62; 95% CI, 0.40-0.90) but was not reduced among those who had used hormone therapy in the past. However, among studies that controlled for socioeconomic status (social class, education, or income), no CHD benefit was seen among current hormone therapy users, suggesting that the observed difference may be due to confounding by socioeconomic status and other lifestyle factors (e.g., exercise or alcohol use) rather than use of hormone therapy. Thus, selection bias (in this case, the tendency of healthier women to use hormone therapy) appears to explain the apparent protective effect of estrogen against CHD seen in observational studies. The estrogen-only arm of the WHI trial showed no decreased risk for CHD.

Stroke

A meta-analysis of 9 observational primary prevention studies suggests that hormone therapy is associated with a small increase in stroke incidence (RR, 1.12; 95% CI, 1.01-1.23), due primarily to an increase in thromboembolic stroke (RR, 1.20; 95% CI, 1.01-1.40). The risk for subarachnoid bleeding and hemorrhagic stroke was not increased, and the overall stroke mortality was marginally reduced (RR, 0.81; 95% CI, 0.71-0.92). These results are consistent with findings from the WHI, which reported increased incidence of stroke in women taking combined estrogen-progestin daily (HR, 1.41; adjusted 95% CI, 0.86-2.31). The estrogen-only arm of the WHI trial, which was terminated after an average of 6.8 years of follow-up, showed a trend toward increased stroke risk with unopposed estrogen use (HR, 1.39; adjusted 95% CI, 0.97-1.99).

Venous Thromboembolism (Deep Venous Thrombosis and Pulmonary Embolism)

In a meta-analysis of 12 studies (3 randomized controlled trials, 8 case-control studies, and 1 cohort study), hormone therapy (estrogen alone or in combination with progestin) was associated with an increased risk for venous thromboembolism (RR, 2.14; 95% CI, 1.64-2.81). Five of 6 studies that examined the effects of hormone therapy over time reported that the risk was highest within the first year of use (RR, 3.49; 95% CI, 2.33-5.59). These results are consistent with the findings in the estrogen-progestin arm of the WHI, which reported a 2-fold increased rate of venous thromboembolic disease, including deep venous thrombosis and pulmonary embolism, in women taking combined estrogen-progestin daily. The estrogen-only arm of the WHI trial showed a trend toward increased risk for venous thromboembolism with unopposed estrogen use (HR, 1.33; adjusted 95% CI, 0.86-2.08).

Cognition and Dementia

While earlier studies showed a beneficial effect of hormone therapy on cognition, these studies had marked heterogeneity and variation in assessment of outcomes. For example, 9 randomized controlled trials examining the effect of hormone therapy on cognition in women showed improvement in verbal memory, vigilance, reasoning, and motor speed; however, these trials may have biased results, since they were conducted with women experiencing menopausal symptoms at baseline. A meta-analysis of 12 observational studies (1 of good quality, 3 of fair quality, and 8 of poor quality) showed a reduction in the risk for dementia among postmenopausal women taking hormone therapy (RR, 0.66; 95% CI, 0.53-0.82). Because of issues of internal and external validity from these previous studies, the more recent, fair-quality WHI memory studies are more likely to represent the effects of hormone therapy use in the healthy postmenopausal population. The WHI memory study showed decreased global cognitive function (measured by the modified Mini-Mental State Examination) in women taking estrogen alone and in the pooled group of women taking estrogen alone or estrogen-progestin. The WHI memory study also showed an increased risk for probable dementia or mild cognitive impairment in both the estrogen-alone (HR, 1.38; 95% CI, 1.01-1.89) and estrogen-progestin (HR, 1.44; 95% CI, 1.04-1.99) arms of the trial. The overall evidence supports harmful effects of hormone therapy on cognitive function, although the clinical relevance of this difference in cognitive function is unclear.

Endometrial and Ovarian Cancer

Results of a meta-analysis of 29 good-quality observational studies of endometrial cancer reported a relative risk of 2.3 for users of unopposed estrogen compared with nonusers. Risks increased with increasing duration of use (RR, 9.5 for 10 years of use), and the risk for endometrial cancer remained elevated 5 or more years after discontinuation of unopposed estrogen therapy. Estrogen and progestin did not increase the risk for endometrial cancer in HERS or in the WHI.

Data on the association between the use of hormone therapy and the risk for ovarian cancer are inconsistent. Two good-quality cohort studies reported increased risks for ovarian cancer or ovarian cancer mortality among women who had taken hormone therapy for 10 years or more. However, a third study found no effect of hormone therapy on ovarian cancer mortality. One study suggested higher risk with unopposed estrogen than with estrogen-progestin therapy, but data are insufficient to resolve the effects of different formulations or doses of hormone therapy on ovarian cancer risk. Neither the WHI nor HERS reported risk for ovarian cancer.

Cholecystitis

Results from the Nurses' Health Study, a good-quality cohort study, reported an increased risk for cholecystitis among current hormone therapy users and long-term users (>5 years) compared with nonusers. Risk for cholecystitis remained elevated among past users. An increase in biliary tract surgery during 6.8 years of follow-up was reported among women taking estrogen plus progestin compared with those taking placebo in HERS. The WHI has not reported on outcomes for biliary tract disease among women taking hormone therapy.

Recommendations made by the U.S. Preventive Services Task Force (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 (AHRQ) or the U.S. Department of Health and Human Services.

Staying Healthy

Effectiveness
Patient-centeredness

Not applicable: The guideline was not adapted from another source.

1996 (revised 2005 May 17)

United States Preventive Services Task Force - Independent Expert Panel

The U.S. Preventive Services Task Force (USPSTF) is a Federally-appointed panel of independent experts. Conclusions of the USPSTF do not necessarily reflect policy of the U.S. Department of Health and Human Services (DHHS) or DHHS agencies.

United States Government

U.S. Preventive Services Task Force (USPSTF)

The U.S. Preventive Services Task force has an explicit policy concerning conflict of interest. All members and evidence-based practice center (EPC) staff disclose at each meeting if they have an important financial conflict for each topic being discussed. Task Force members and EPC staff with conflicts can participate in discussions about evidence, but members abstain from voting on recommendations about the topic in question.

Steven M. Teutsch, MD, MPH, recused himself from voting on this topic.

From: Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow, CD, Teutsch SM, Atkins D. Current methods of the U.S. Preventive Services Task Force: a review of the process. Methods Work Group, Third U.S. Preventive Services Task Force. Am J Prev Med 2001 Apr;20(3S):21-35.

This is the current release of the guideline.

This release updates a previously published guideline: Postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. Ann Intern Med 2002 Nov 19;137(10):834-9.

This summary was completed by ECRI on June 30, 1998. The information was verified by the guideline developer on December 1, 1998. This summary was updated on October 11, 2002. The information was verified by the guideline developer on October 11, 2002. This summary was updated by ECRI on May 3, 2005. The information was verified by the guideline developer on May 9, 2005.