Discussion

Conclusions

Table 4 summarizes the quality of evidence for each key question addressed in this review. According to our analysis of observational studies and results of the WHI, using HRT to prevent CHD and CVD does not reduce these events. However, HRT use does not increase mortality from CHD and CVD based on these studies. Stroke incidence, specifically thromboembolic stroke—but not stroke mortality—is increased with HRT use according to our meta-analysis and results of the WHI. Prevention of colorectal cancer is also supported by the WHI and observational studies, although this evidence is weaker because WHI findings are not significant when the analysis is adjusted and observational studies are biased. Prevention of osteoporotic fractures is supported by results of the WHI and several consistent, good-quality observational studies of fractures and RCTs of bone density, an important intermediate outcome and risk factor for fracture. HRT effects on cognition were reported only in women with symptoms of menopause. Prevention of dementia is supported only by observational studies with important methodological limitations.

Several harms of HRT use are supported by an increasingly strong body of evidence. Our meta-analysis, the WHI, and HERS II are consistent in reporting a two-fold increase in thromboembolic events with HRT use. Risk is highest in the first year of use. Observational studies support the WHI finding that breast cancer incidence was increased in those using HRT at the time of assessment after 5 or more years of use. Our review indicated that those who used estrogen previously but not at the time of assessment and short-term users were not at increased risk for breast cancer, and mortality was not increased for any group. Risks for endometrial cancer are increased with unopposed estrogen use but not with combined regimens. Studies are consistent in reporting increased risk for cholecystitis among those using HRT at the time of assessment which appears to increase with time.

New studies reporting associations between HRT use and ovarian cancer have been recently reported since this review was completed. Results indicate that women using unopposed estrogen for prolonged durations may have an increased risk for ovarian cancer.^167-169

Limitations of the Literature

Studies of HRT, particularly observational studies, have many limitations. Women who take HRT differ from those who do not in many ways that are known or believed to alter risk. Hormone replacement therapy users tend to be more affluent, leaner, and more educated, and they tend to exercise more often and drink alcohol more frequently than those who do not use HRT.^31,78,170 These lifestyle factors are associated with increased risk for breast cancer and decreased risk for cardiovascular disease.^31,170-172 Also, by definition, women who take HRT have access to health care and have a greater likelihood of being treated for other comorbid conditions that may also decrease their risks for certain clinical outcomes. Long-term HRT users are treatment-compliant, itself a factor associated with better health.^173,174 Women often stop HRT when they become ill, a tendency that would bias studies evaluating recent or current use by underestimating HRT use in ill patients. Hormone replacement therapy is used more often by women who have undergone hysterectomy and oophorectomy, conditions associated with decreased risks for breast cancer and increased risks for osteoporosis.

There have been significant changes in clinical practice regarding the use of estrogen, including type, administration, and dose, as well as the relatively recent practice of adding progestins to estrogen therapy. For many of the years represented in these studies, hypertension, diabetes, and heart disease were considered contraindications to the use of HRT. Practicing physicians may have been more likely to offer and prescribe HRT to women for whom the physicians' sense of overall health was higher. This type of selection bias is difficult to measure and may have led to systematic overestimates of the benefit of HRT. Also, most studies measured estrogen use at one point only or asked women if they had ever used estrogen. Thus, those who had ever used HRT and those who used HRT at the time of assessment could have used HRT for either long or short periods of time.

Our review is also limited by assumptions in Table 2 that lead to the estimated cases in Table 3. In many cases, a variety of relative risks was available for certain outcomes, and we selected a value according to our judgment of the best evidence. This judgment may differ from that of other reviewers of the evidence. Sources for population incidence and mortality rates for health outcomes varied in their reliability and may not be directly comparable. The applicability of population estimates when risks are determined for individuals is unknown. Our estimates do not account for racial and ethnic differences or important risk factors. These estimates are most valuable when relative magnitudes of benefits and harms are compared in conjunction with patient preferences.

Future Research

Additional evidence from RCTs is needed to more accurately weigh the benefits and harms of HRT. Areas of future research could include the following:

• The roles of progestins and types and doses of estrogen on outcomes are alluded to in the literature but are unresolved. Results of the WHI were based on use of a daily combined regimen in women with an intact uterus. A smaller arm of the study consisting of women with hysterectomies and using estrogen alone is continuing and apparently has not experienced statistically significant adverse outcomes. Additional studies may find that women taking unopposed estrogen have reduced risks for some outcomes, but increased risk for others.
• As selective estrogen receptor modulators (SERMs) and other estrogen-like agents are developed, direct comparisons with estrogen in addition to placebo during trials will be important. Careful monitoring and reporting of adverse events would contribute additional knowledge of the consequences of HRT use.
• Effects of HRT may differ by age or other important risk factors. Practice could be influenced if women who experience thromboembolic events, for example, are different from those who do not and could be identified prior to initiating HRT. Results from other studies indicate that women with a prior history of venous thromboembolism while taking HRT, those with the Factor V Leiden mutation, or those with hip or lower extremity fracture, cancer, hospitalization, or surgery are at increased risk for thromboembolism.
• It is unclear how age modifies the impact of estrogen. Understanding the optimal duration of effect would allow targeting of estrogen use to enhance beneficial effects and avoid harms.
• Although our review supports an association between HRT and increased risk for venous thromboembolism, as well as HRT and reduced risk for colorectal cancer, the pathophysiology of these relationships is not well understood.
• Clarification of potential increased risk for breast cancer with HRT use among subpopulations of women already considered at high-risk would help these women make decisions about HRT use.
• Studies can be designed to evaluate whether HRT has different effects in women with BRCA 1 and/or BRCA 2 tumor suppressor gene mutations. Are women with these mutations at any higher risk for breast cancer if they use HRT?
• Research on the effects of HRT on cognitive performance should focus on older, asymptomatic women instead of perimenopausal women.
• Studies of cognition need to use standardized outcome measures. The tests should not have ceiling values and need to be sensitive to very small differences because the effects of estrogen on cognition may be subtle. These tests should examine particular cognitive domains because the evidence indicates that estrogen may have neural and cognitive specificity. Future studies should include measures of the ability to care for oneself, live independently, and complete activities of daily living.
• Estrogen's cognitive and neural specificity should also be considered when interpreting the results of future research studies, including the two ongoing primary prevention trials of HRT and cognition, the Women's Health Initiative Study of Cognitive Aging (WHISCA)¹⁷⁵ and the Women's International Study of Long Duration Oestrogen after Menopause in the United Kingdom.¹⁷⁶

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Acknowledgments

This summary of the evidence was prepared for the Agency for Healthcare Research and Quality (Contract No. 290-97-0018, task order No. 2) to be used by the U.S. Preventive Services Task Force.

Erin LeBlanc M.D., M.P.H., Jill Miller M.D., and Lina Takano M.D., M.S. were fellows in a Women's Health Fellowship at the Portland Veterans Affairs Medical Center when this work was conducted. Task Force members Janet Allan, Ph.D., R.N., and Steven Teutsch, M.D., M.P.H., served as liaisons. Mark Helfand, M.D., M.S., and David Atkins, M.D., M.P.H. provided scientific expertise. Oregon Health & Science University Evidence-based Practice Center staff who contributed to this project included Kathryn Krages, EPC administrator, Susan Wingenfeld, administrative assistant, and Patty Davies, M.A., librarian.

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