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.