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U.S. Preventive Services Task Force


Postmenopausal Hormone Replacement Therapy for Primary Prevention of Chronic Conditions

Summary of the Evidence


Heidi D. Nelson, M.D., M.P.H.a; Linda L. Humphrey, M.D., M.P.H.a; Erin LeBlanc M.D., M.P.H.a; Jill Miller, M.D.; Lina Takano, M.D., M.S.a; Benjamin K.S. Chan, M.S.a; Peggy Nygren, M.A.a; Janet D. Allan, Ph.D., R.N.b; Steven M. Teutsch, M.D., M.P.H.b.

Address correspondence to: Heidi D. Nelson, M.D., M.P.H., Oregon Health & Science University; Mail code BICC 504; 3181 SW Sam Jackson Park Road; Portland, OR 97201; E-mail: nelsonh@ohsu.edu.

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The summaries of the evidence briefly present evidence of effectiveness for preventive health services used in primary care clinical settings, including screening tests, counseling, and chemoprevention. They summarize the more detailed Systematic Evidence Reviews, which are used by the U.S. Preventive Services Task Force (USPSTF) to make recommendations.


Contents

Epidemiology
Prior Recommendations
Analytic Frameworks and Key Questions
Methods
Results
Discussion
Acknowledgments
References
Notes


Epidemiology

Epidemiology

Hormone replacement therapy (HRT), either estrogen alone or estrogen combined with progestin, is used in the United States and worldwide to treat symptoms of menopause and to prevent chronic conditions such as osteoporosis. t is one of the most commonly prescribed drugs in the United States. A survey conducted in 1995 of postmenopausal women aged 50 to 75 showed that nearly 38 percent of women were using HRT at the time of the survey.1 Recently published studies, however, suggest that HRT use is associated with potential harms that were not previously appreciated, causing many to reconsider the appropriateness of its use for prevention.

To determine the current status of benefits and harms of HRT use, we conducted systematic searches of the literature on HRT use among postmenopausal women, its effectiveness for the primary prevention of chronic conditions, and its association with harmful outcomes. Several reports and publications provide additional details of these reviews on the effects of HRT on cardiovascular disease,2,3 thromboembolism,4,5 breast cancer,6 osteoporosis,7 cognition and dementia,8,9 as well as overall benefits and harms.10

This report serves as a summary of the evidence with the objective of aiding the U.S. Preventive Services Task Force (USPSTF) in updating its recommendations on HRT scheduled for release in October 2002.

Use of HRT for the treatment of symptoms of menopause and for the treatment of preexisting conditions are outside the scope of the USPSTF recommendation, and this literature was not reviewed. All papers included in this review met inclusion criteria and were rated for quality (Inclusion/Exclusion Criteria). We focused on health outcomes such as myocardial infarction rather than intermediate outcomes such as lipid levels. To provide an overview of benefits and harms, we conducted several meta-analyses and used these results, as well as those from selected published papers, to calculate numbers of events prevented or caused by HRT for specific outcomes in a hypothetical population of postmenopausal women.

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Prior Recommendations

In 1996, the USPSTF recommended counseling all perimenopausal and postmenopausal women about the potential benefits and harms of HRT.11 They determined that there was insufficient evidence to recommend for or against HRT for all women, but thought that individual decisions should be based on patient risk factors, an understanding of the probable benefits (for example, the prevention of myocardial infarction or fracture) and harms (for example, endometrial cancer with unopposed estrogen or breast cancer), and personal preferences.

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Analytic Frameworks and Key Questions

The analytic frameworks in Figures 1 (25 KB) and 2 (17 KB) show the target populations, interventions, and health outcome measures we examined for the overall question of the benefits and harms of HRT used by postmenopausal women to prevent chronic conditions. Numbered arrows in the figures correspond to key questions specifically covered in this report (Figure 3). We were concerned with HRT as chemoprevention for primary prevention and therefore focused on the use of either estrogen alone (unopposed) or estrogen combined with progestins (combined) in healthy, postmenopausal women.

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Methods

Literature Search Strategy

Methods of searching the literature, selecting abstracts, reviewing, abstracting, and rating studies, and conducting meta-analyses were standardized for all topics. Because the literature for each topic varied, each review was also subject to topic-specific modifications in methods. Detailed methods for each topic are presented elsewhere.2-10

In conjunction with a medical librarian, we conducted topic-specific searches using MEDLINE® (1966-2001), HealthSTAR (1975-2001), and the Cochrane Controlled Trials Register (http://www.cochranelibrary.com); dates of searches varied with some topics. Additional articles were obtained by consulting experts and by reviewing reference lists of pertinent studies, reviews, and editorials. We used only published data in meta-analyses.

Inclusion/Exclusion Criteria

Inclusion and exclusion criteria were developed by the investigators for each topic. In general, studies were included if they contained a comparison group of HRT nonusers and reported data relating to HRT use and clinical outcomes of interest. Studies were excluded if the population was selected according to prior events or presence of conditions associated with higher risks for targeted outcomes. Hormone replacement therapy use was classified as unopposed estrogen replacement (estrogen only) or combined (estrogen plus progestin) when specified. When data were available, we reported effects of formulation, dose, and duration. In studies with multiple publications from the same cohort or population, only data from the most recent publication were included in the meta-analyses. We used adjusted statistics when reported.

Two reviewers independently rated each study's quality by using criteria specific to different study designs developed by the USPSTF and categorized them as good, fair, or poor.12 When reviewers disagreed, a final rating was reached through consensus.

In addition to the systematic literature review, we included two recently published randomized controlled trials (RCTs) with pertinent findings. The Women's Health Initiative (WHI), a primary prevention trial, reported results of 16,608 healthy postmenopausal women after 5.2 years of daily combined HRT or placebo.13 We also cite the noncardiac outcomes of the Heart and Estrogen/Progestin Replacement Study Followup (HERS II),14 a trial of daily combined HRT in 2,321 postmenopausal women with preexisting coronary heart disease after 6.8 years.15,16

Data Extraction and Synthesis

Meta-analyses were conducted for some of the topics because either previous meta-analyses had not been published, or they were outdated or inadequate. We used adjusted relative risk (RR) estimates when available or calculated them when possible. Under the modeling assumptions made by each study, the logarithm of the relative risk (logRR) had a normal distribution. Standard errors (SEs) for logRR were calculated from reported confidence intervals (CIs) or P values. The logRR and standard errors provided the data points for the meta-analyses. Heterogeneity was assessed with study-level stratification factors in the regression models. Fixed and random-effects models were fit on the data by using the Bayesian data analytic framework.17 We report only the random-effects model because the results of the two models were similar in all cases. Inference on the parameters was done via posterior probability distributions. The data were analyzed with WinBUGS software,18 which uses a method of Markov chain Monte Carlo called Gibbs sampling to simulate posterior probability distributions.

Sensitivity analysis was performed with different prior distributions, combining only studies with similar methods and excluding poor-quality studies and those with important biases or limitations. Sensitivity analysis varied according to the needs of each meta-analysis.

We also evaluated studies for selection bias by using funnel plots19 and investigated the sensitivity of the analysis to studies possibly missed because of publication bias by trim and fill.20,21 Results were unaffected, although this technique does not entirely rule out potential publication bias.

Estimates of Benefits and Harms

We calculated the number of events prevented or caused by HRT per year of use in 10,000 women by using relative risks for clinical outcomes derived from the reviewed studies and meta-analyses. We also used population-based estimates of incidence and mortality.22-29 We stratified event rates by 10-year age intervals because incidence rates for some outcomes are strongly age-related. Data sources for incidence and mortality rates did not allow further breakdown by race, preexisting disease, risk factors, or other variables and varied in quality. These estimates, therefore, do not consider special subgroups and would be most applicable to the general population of postmenopausal women.

We used the best evidence available to determine the relative risk for each outcome.30 Some estimates were derived from extensive literature reviews and meta-analysis; others, from a single study representing the only or best literature available. We sought data from RCTs when available. When evaluating observational studies, we looked carefully at the potential for confounding and took measures to reduce its influence by including only studies that controlled for important confounders, selecting outcomes less prone to confounding, or factoring the potential for confounding into our overall conclusions. In general, observational studies allowed examination of issues of duration and currency of use and examined end points that are difficult to study in RCTs because they are infrequent or develop slowly.

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Results

Cardiovascular Disease

Studies of HRT and the primary prevention of cardiovascular disease (CVD) report various outcomes. Some studies examined coronary heart disease (CHD) and stroke as separate categories, while others combined them into an overall cardiovascular disease category. We describe these as they were reported in the original sources. We evaluated results by type of use as they were defined in each study:

We also created a category, all use, that combined all mutually exclusive types of use (ever, past, and current) for purposes of pooling studies in the meta-analysis. Our review and meta-analysis focuses on the studies we rated good or fair-quality using USPSTF criteria. Characteristics of poor-quality studies included little or no control for confounding, nonrepresentative cohorts, poor definition of outcomes, poor characterization of exposure, and bias in control selection.

Overall Cardiovascular Disease

Eight observational studies evaluated overall CVD mortality.31-38 The summary relative risk for CVD mortality was significantly reduced among those using HRT at the time of assessment (RR, 0.64; 95 percent CI, 0.44-0.93) but not among ever, past, or any users (Table 1). Two cohort studies,31,32 one case-control study,39 and data from a published meta-analysis40 reported CVD incidence. The summary relative risk with any use was 1.28 (95 percent CI, 0.86-2.00) (Table 1). Results were similar for those who were using estrogen at the time of assessment, those who used estrogen previously but not at the time of assessment, and those who had ever used estrogen.

Coronary Heart Disease

Five studies evaluated the risk for CHD mortality.32,34,35,41,42 Combined data from these studies indicated that mortality was significantly reduced among those using HRT at the time of assessment (RR, 0.62; 95 percent CI, 0.40-0.90), but not among any, past, or ever users (Table 1).

The association between HRT use and CHD incidence was evaluated in three cohort studies;22,31,32 nine case-control studies;43-51 and one small randomized, controlled trial.33 Combined data indicated that CHD incidence was also reduced among those using HRT at the time of assessment (RR, 0.80; 95 percent CI, 0.68-0.95), but not among any, past, or ever users (Table 1). Further analysis of studies adjusting for socioeconomic status by using measures of social class such as education or income indicated no significant reductions in risk for any of the groups who used HRT (Table 1). Similar results were found when the analysis was stratified by studies adjusting for alcohol consumption and/or exercise, in addition to other major risk factors, suggesting confounding by these factors.

The WHI reported an increased risk for CHD events (hazard ratio [HR], 1.29; 95 percent CI, 1.02-1.63), including nonfatal myocardial infarction (HR, 1.32; 95 percent CI, 1.02-1.72) among estrogen users.13 Coronary heart disease mortality and rates of coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty were not increased. Results from HERS II indicated no significant decreases in rates of primary or secondary CHD events among estrogen users.16

Stroke

Hormone replacement therapy and stroke mortality were evaluated in 8 cohort studies and one case control study.32,34,36,37,41,42,52-54 After combining data from these studies, the summary relative risk for stroke mortality was 0.81 (95 percent CI, 0.71-0.92) among HRT users (Table 1). Two cohort studies, each of good quality, evaluated long-term use of estrogen and risk for stroke mortality and identified no significant association.41,42 The majority of studies did not differentiate between unopposed and combined estrogen regimens.

Combining nine studies of stroke incidence resulted in a summary relative risk of 1.12 (95 percent CI, 1.01-1.23), indicating a small increase in stroke in association with HRT use (Table 1).22,31,32,39,50,52,53,55-57 Results of a sub-analysis indicate a significant increase in risk for thromboembolic stroke (RR, 1.20; 95 percent CI,1.01-1.40)54,55,57,58 but not subarachnoid hemorrhage (RR, 0.80; 95 percent CI, 0.57-1.04)57,59,60 or intracerebral hemorrhage (RR, 0.71; 95 percent CI, 0.25-1.29)50,55,57,61 among women who had ever taken HRT.

One cohort and one case-control study evaluated the effect of long-term use (≥5 years) of estrogen and the risk for stroke and neither showed an association.22,57 The Nurses Health Study reported a significant dose-response relationship between stroke and HRT use, with graded risks of 0.54 (95 percent CI, 0.28-1.06), 1.35 (95 percent CI, 1.08-1.68), and 1.63 (95 percent CI, 1.18-2.26) for estrogen doses of 0.3 mg, 0.625 mg, and 1.25 mg or more, respectively.22 A 45-percent higher risk for stroke among women taking combined regimens compared with women who had never used HRT was also shown in the Nurses Health Study (RR, 1.45; 95 percent CI, 1.10-1.92);22 the association between stroke and unopposed estrogen use also was increased (RR, 1.18; 95 percent CI, 0.95-1.46), though was not statistically significant.

The WHI reported an increased risk for nonfatal strokes, although the confidence interval crossed 1.0 in adjusted analysis (HR, 1.50; 95 percent CI 0.83-2.70).13 HERS II reported no increase in stroke or transient ischemic attacks.16

Thromboembolism

Twelve abstracts met inclusion criteria and contained primary data (three randomized controlled trials,15,62,63 eight case-control studies,29,64-70 and one cohort study60). No studies were designed to report venous thromboembolic events (i.e., deep vein thrombosis and/or pulmonary embolism) as primary outcomes. Studies varied in quality with the most important limitations including lack of controlling for key confounders such as smoking, not reporting dose or duration of estrogen use, differences in characteristics of patients and controls, small numbers of cases, and variation in outcome assessment. Despite differences in design and quality, the studies had consistent results, with 11 of 12 reporting relative risk point estimates above 1.0, and 6 of these with confidence intervals above 1.0.

When studies were combined by meta-analysis, results indicated that use of HRT at the time of the studies was associated with an increased risk for venous thromboembolism (RR, 2.14; 95 percent CI, 1.64-2.81). Estimates did not significantly change when pooling studies by type of study design, quality rating, or whether subjects had preexisting coronary artery disease. Using a baseline risk of 1.3 events per 10,000 woman-years based on a study with 10,000 controls, an additional 1.5 events per 10,000 women each year would be expected.29 Six studies that reported risk according to duration of use found the highest risks in the first 1 to 2 years (combined RR for first year was 3.49; 95 percent CI, 2.33-5.59).15,29,65,67-69

Some studies reported the effects of dose and regimen, although the numbers of study participants were small. Three studies reported a higher risk for increased doses of estrogen (>0.625 mg conjugated) compared with lower doses.29,65,67 A higher risk (OR, 2.2-5.3) for estrogen combined with progestin compared with estrogen alone was reported by 3 studies.29,65,68 A comparison of oral (OR, 4.6; 95 percent CI, 2.1-10.1) and transdermal (OR, 2.0; 95 percent CI, 0.5-7.6) estrogen was reported by only one study.65

Both the WHI and HERS II reported statistically significant 2-fold increases in thromboembolic events among estrogen users with trends toward higher rates early in the course of use.13,15

Breast Cancer

Our search identified studies that evaluated breast cancer incidence or mortality as primary or secondary outcomes in association with HRT use. Those meeting inclusion criteria included 8 meta-analyses,71-78 15 case-control studies,79-93 and 15 cohort studies.94-109

The WHI results indicated increased breast cancer risk for women using estrogen combined with progestin after 5.2 years of use (HR, 1.26; 95 percent CI, 1.00-1.59).13 Trend data indicated increasing risk for breast cancer with increasing duration of use. Studies identified by our literature search support these findings. Current estrogen users have an increased risk for breast cancer according to most recent good-quality studies including three meta-analyses (relative risks range from 1.21 to 1.40).71-73 Risk increases with longer duration of use (relative risks range from 1.23 to 1.35 based on all six meta-analyses that evaluated this relationship).71-77 Few studies and no meta-analyses specifically evaluated estrogen combined with progestin, although some recent studies suggest increased risk above that of unopposed estrogen,78-81,94 while others do not.82-85

In contrast to studies of current users, the majority of studies of women who have ever used HRT, including 14 of 18 observational studies and 7 of 8 meta-analyses, reported no increase in risk for breast cancer (relative risks range from 0.85 to 1.14 from 8 meta-analyses).40,71-77

No meta-analyses have evaluated breast cancer mortality. All 6 recent cohort studies that evaluated breast cancer mortality showed either no effect or decreased mortality among those who had ever used HRT, or among those who used HRT in the short-term (<5 years) (relative risks ranging from 0.5 to 1.0).78,95-99 Risk by duration of use was evaluated in 5 studies of mixed quality that evaluated mortality in different ways, including by tumor node status and family history.78,95,96,98,99 Two good-quality studies that reported results for use longer than 5 years have conflicting results.78,98

Colon Cancer

A published meta-analysis of 18 observational studies of colorectal cancer and HRT indicated a 20 percent reduction in colon cancer among those who had ever used HRT compared with those who had never used HRT (RR, 0.80; 95 percent CI, 0.74-0.86) and a 34-percent reduction among those using HRT at the time of assessment (RR, 0.66; 95 percent CI, 0.59-0.74).110 Duration of HRT use did not influence risk estimates. Results were similar for rectal cancer. These results were based entirely on observational studies that included estrogen users who were healthier, less obese, more physically active, and had healthier diets than nonusers, and who may have been at a lower risk for developing colorectal cancer based on these factors.

The WHI is the first RCT to report similar outcomes, although results were not significant when adjusted analysis was used.13 Risk was not reduced among HRT users in HERS II.14

Endometrial Cancer

A meta-analysis of 29 observational studies reported a significantly elevated relative risk for endometrial cancer for unopposed estrogen users compared with nonusers (RR, 2.3; 95 percent CI, 2.1-2.5).111 Increased risk was associated with increasing duration of use, and risk remained elevated 5 or more years after discontinuation of unopposed estrogen therapy. Users of unopposed conjugated estrogen had a greater increase in risk than users of synthetic estrogens. Mortality from endometrial cancer was not significantly elevated (RR, 2.7; 95 percent CI, 0.9-8.0).

A meta-analysis of seven studies evaluating the effects of combined HRT regimens (estrogen with progestin) on endometrial cancer incidence reported a relative risk of 0.8 (95 percent CI, 0.6-1.2).111 Three cohort studies indicated a decreased risk for endometrial cancer (RR, 0.4; 95 percent CI, 0.2-0.6),112-114 and three case-control studies showed an increase in risk (RR, 1.8; 95 percent CI, 1.1-3.1).115-117 Neither the WHI nor HERS II reported an increase in endometrial cancer when a daily combined HRT regimen was used.13,14

Osteoporosis

For bone density outcomes, RCTs consistently indicated improved bone density with estrogen use. An unpublished Cochrane systematic review reported combined results of 57 RCTs enrolling postmenopausal women for more than 1 year that compared HRT with placebo or calcium/vitamin D use.118 Findings were similar between prevention and treatment trials, opposed and unopposed regimens, oral and transdermal forms of estrogen, and types of progestins. Results differed, however, with different doses and duration of estrogen use. Use of usual doses (e.g., 0.625 mg of conjugated estrogen) resulted in greater bone density increases at lumbar, femoral neck, and forearm sites than use of lower doses (0.3 mg). Two-year trials resulted in greater increases than one-year trials.

For fracture outcomes, a meta-analysis of 22 trials of estrogen reported an overall 27 percent reduction in nonvertebral fractures (RR, 0.73; 95 percent CI, 0.56-0.94).119 Although the meta-analysis itself met USPSTF criteria for a good-quality rating, 21 trials included in the meta-analysis did not meet inclusion criteria for our review because they used unpublished data; did not verify fractures radiographically; or included traumatic fractures, women with preexisting osteoporosis, or those who were hospitalized or had secondary causes of osteoporosis.

We identified four trials13,14120-122 that met inclusion criteria and reported fracture outcomes. A primary prevention trial enrolled a subgroup of a large prospective osteoporosis study based in Finland.120 In this study, early postmenopausal women without osteoporosis were randomly assigned to one of four treatment groups. New, symptomatic, radiographically confirmed nonvertebral fractures were recorded during a mean 4.3 years of followup. Compared with the groups given placebo, the risk for fracture was significantly lower for the group using estrogen/progestin alone (RR, 0.29; 95 percent CI, 0.10-0.90), but not for the group using estrogen/progestin and vitamin D, or the group using vitamin D alone when adjusted for baseline bone density and prior fractures. Another primary prevention trial randomized early postmenopausal women in Denmark to oral HRT or placebo. After 5 years, the relative risk for all types of fractures was 0.82 (95 percent CI, 0.53-1.29) and for forearm fractures it was 0.40 (95 percent CI, 0.16-1.01).121 The WHI is the first RCT to demonstrate reduction of hip fracture risk with estrogen use, although the confidence interval crosses 1.0 when adjusted analysis is used.13 Risk for other osteoporotic fractures was significantly reduced (HR, 0.77; 95 percent CI, 0.63-0.94). No risk reduction for hip or other types of fractures was evident in HERS122 or HERS II.14

Six good-quality cohort studies were also identified,123-128 and three of four studies reported 20-percent to 35-percent reductions in adjusted relative risks for hip fractures among those who had ever used HRT (combined RR for 4 studies, 0.76; 95 percent CI, 0.56-1.01).124-127 Cohort studies also reported reduced risks for wrist (RR, 0.44; 95 percent CI, 0.23-0.84),123,125 vertebral (RR, 0.60; 95 percent CI, 0.74-0.86),125 and nonvertebral fractures.123 Cohort studies included large numbers of women, often recruited from community-based populations, and followed them up for longer periods than did the RCTs.

Cognitive Function and Dementia

Twenty-nine studies met inclusion criteria, including 9 RCTs129-137 and 8 cohort studies138-145 describing the effects of HRT on cognitive decline and 2 cohort146,147 and 10 case-control studies148-157 providing estimates for dementia risk.

Studies measuring the effects of estrogen on cognition in women without pre-existing dementia were not combined quantitatively because of their heterogeneity. These studies used more than 40 different tests among them and administered these tests in nonstandardized ways. They also differed in their study design and patient populations. Results indicated that women with menopausal symptoms experienced improved verbal memory, vigilance, reasoning, and motor speed, but no enhancement of other cognitive functions. Generally, no benefits were observed in asymptomatic women.

Our meta-analysis of 12 observational studies with dementia outcomes146-157 suggested that HRT was associated with a decreased risk for dementia (summary OR, 0.66; 95 percent CI, 0.53-0.82). However, these studies commonly used self-reported outcomes for controls and proxy for cases, used interviewers who were not blinded to the outcome, did not control for education, and included only those using estrogen at the time of assessment. Possible biases and lack of control for potential confounders limit interpretation of these studies. Studies did not contain enough information to adequately assess the effects of progestin use, various estrogen preparations or doses, or duration of therapy.

Neither the WHI nor HERS II reported effects of HRT on cognition and dementia.13,14 We considered the relationship between HRT and dementia to be an uncertain benefit because of lack of RCT evidence and the methodologic limitations and inconsistencies among observational studies.

Cholecystitis

The relationship between HRT and cholecystitis is well-described in a publication from the Nurses Health Study, a good-quality cohort study.28 When compared with those who had never used HRT, those who were using HRT for the short-term at the time of assessment had an age-adjusted relative risk for cholecystitis of 1.8 (95 percent CI, 1.6-2.0). This risk increased after 5 years of use and remained elevated at this rate for women who had used HRT for 10 years or more. Among those who used HRT in the past, the risk decreased to between 1.4 and 1.7 but still remained significantly elevated as compared with those who had never used HRT.

Other studies support these findings,64,79,158-160 although some do not.161-165 The HERS II trial reported an increase in biliary tract surgery among HRT users compared with those receiving placebo during 6.8 years of followup (RR, 1.44; 95 percent CI, 1.10-1.90).14 This outcome has not yet been reported by the WHI. Another study evaluated data from 800,000 women in Canada to explore the relationship of a variety of medications with gallbladder and other diseases.166 In this study, estrogen users were significantly more likely than users of other medications to have cholecystectomy and primary appendectomy.

Benefits and Harms Outcomes Table

Our review of the evidence and the results of our meta-analyses, as well as recent results from the WHI, provided risk estimate assumptions for a table summarizing the benefits and harms of HRT (Table 2). We obtained incidence rates for target conditions from population-based sources and calculated the number of events prevented or caused by HRT per year in 10,000 postmenopausal women. We calculated outcomes twice, once using results of this literature review and meta-analysis and once using recent results of the WHI. We predominantly used incidence rates because our review of evidence indicated that either HRT did not significantly protect against mortality for specific outcomes (stroke and breast cancer) or mortality outcomes were not studied (fractures, colon cancer, and thromboembolism).

For most clinical outcomes, we used relative risk estimates from those who had ever used HRT as opposed to those who were using HRT at the time of assessment or those who had used HRT in the past. The groups who had ever used HRT were the most consistently reported across studies and would be expected to bias results less than those who were using HRT at the time of assessment. Cholecystitis and thromboembolism were associated with HRT use at the time of assessment; rates for those who had ever used HRT were not provided, the relative risk estimates for those who were taking HRT at the time of assessment was used. For some outcomes, such as cholecystitis and breast cancer, risk increases with duration of use. To reflect these changing risks, we calculated events for short-term (<5 years) and long-term (≥5 years) users. Data support an increased risk for thromboembolic events in the first year of use, but because most HRT users intend a longer course to prevent chronic conditions, we calculated first-year and overall event rates.

We did not calculate endometrial cancer outcomes because the association between unopposed estrogen and endometrial cancer is well known and the standard of care is to provide combined therapy for women who have not had a hysterectomy. Combined therapy is not associated with increased risk for endometrial cancer. Eight published meta-analyses71-78 of breast cancer incidence provided different risk estimates. To reflect this range of risk, we calculated a potential range of cases of endometrial cancer caused by HRT use.

Table 3 summarizes these results by 10-year age groups for women aged 55 to 84. Event rates for benefits and harms are generally lower in younger women and higher in older women. Except for CHD, rates are similar when WHI hazard ratios rather than relative risks from our review are used.

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