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Nelson HD, Walker M, Zakher B, et al. Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: Systematic Review to Update the 2002 and 2005 U.S. Preventive Services Task Force Recommendations. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 May. (Evidence Syntheses, No. 93.)

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Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: Systematic Review to Update the 2002 and 2005 U.S. Preventive Services Task Force Recommendations.

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Summary of Review Findings

Nine trials comparing the effects of estrogen plus progestin or estrogen only against placebo for the prevention of chronic conditions in postmenopausal women have been published since 2002 and provided data for this review. A summary of the evidence is provided in Table 6. Trials included the WHI trials of estrogen plus progestin and estrogen only, two trials enrolling subsamples from WHI—WHIMS and WHISCA—and EMS, HERS, ESPRIT, ULTRA, and WISDOM. WHI is the only trial designed and powered to evaluate the effectiveness of hormone therapy for primary prevention of the multiple conditions that are the focus of this review. WHI met criteria for fair quality, provided most of the estimates of benefits and harms, had 11 years of followup, and was most applicable to the target population. Results of the other trials, such as HERS, were consistent with WHI for selected outcomes, such as diabetes. However, most outcomes of the other trials were either not measured or were inadequately powered to detect significant differences between groups.

Table 6. Summary of Evidence.

Table 6

Summary of Evidence.

Results of WHI indicated some benefits with hormone therapy (key question 1). For women using estrogen plus progestin, fractures (hip: 6/10,000; vertebral: 6/10,000; total: 46/10,000) and diabetes (15/10,000) were significantly reduced compared with placebo. For women using estrogen only, fractures (hip: 7/10,000 women-years; vertebral: 6/10,000; total: 56/10,000) and invasive breast cancer incidence (8/10,000) and death (2/10,000) were reduced. While fractures were a major secondary outcome of the trials and were determined by clinical and radiographic criteria, diabetes was based on post hoc analysis of self-reports. In comparison, women in HERS using estrogen plus progestin also had reduced risk for diabetes based on blood glucose levels, but not reduced fractures.

Several harms were also demonstrated by WHI (key question 2). For women using estrogen plus progestin, invasive breast cancer (8/10,000), stroke (9/10,000), DVT (12/10,000) and PE (9/10,000), lung cancer death (5/10,000), gallbladder disease (20/10,000), probable dementia (22/10,000), and urinary incontinence (872/10,000) were significantly increased compared with placebo. For women using estrogen only, stroke (11/10,000), DVT (7/10,000), gallbladder disease (33/10,000), and urinary incontinence (1271/10,000) were increased. Women in HERS using estrogen plus progestin also had increased risk for urinary incontinence.

Trials did not report results for subgroups of women with premature menopause, women with surgical menopause, or using various types, doses, and modes of delivery of hormones (key question 3). Subgroup analyses based on age and comorbidities were limited by lack of power for many of the comparisons, and indicated few statistically significant differences. These included increased risk for breast cancer for women randomized to estrogen plus progestin with prior oral contraceptive use, prior estrogen plus progestin use, or who smoke; increased CHD risk for women randomized to estrogen plus progestin with high LDL cholesterol levels, or women randomized to estrogen only with high C-reactive protein levels; increased thromboembolic disease for women randomized to estrogen plus progestin who were older, obese, or possessed Factor V Leiden; and increased urinary incontinence for older women using either regimen. Other than these findings, trials provided few results applicable to clinical decisions about selecting hormone therapy based on individual patient characteristics.

Limitations and Future Research

This review was limited by the small number of trials that met inclusion criteria, although the number of participants was large. The review was also limited to trials published in English-language journals, although no relevant trials were identified from English-language abstracts of non-English journals, additional citation searches, or expert reviewers.

Few outcomes were reported in more than two trials. Some outcomes were especially affected by potential bias, such as diabetes, based on post hoc analysis, and cognitive function, limited by disparate adherence rates (WHIMS, 61.4 percent for placebo vs. 32.3 percent for estrogen plus progestin). Trials often used different measures for ascertaining outcomes, limiting comparisons across trials. For cognitive function, WHIMS was the only trial to use a thorough adjudication process for probable dementia and mild cognitive impairment, while other trials used batteries of cognitive tests. For diabetes, WHI relied on participants’ self-reports of new diagnoses or new treatment for diabetes, while HERS used fasting glucose levels. For urinary incontinence, all trials relied on self-reported measures.

Most trials had high attrition or low adherence to medications, including WHI, in which 40 to 50 percent of participants discontinued their medications during the course of the trial. Although trials of various forms of hormone therapy have been published, results for most outcomes have been derived from large trials using CEE and MPA, restricting comparative effectiveness evaluations. Use of post hoc analysis and small subgroup comparisons provided limited additional findings.

The average age of participants in the trials was generally in the mid 60s, restricting the applicability of the findings. Research directed at women transitioning through menopause or immediately postmenopausal would be useful to women in these age groups who now make up the majority of hormone users.

Continuing research on long-term outcomes, such as cancer and mortality, will be important to fully understand the implications of hormone therapy. In the WHI estrogen only trial, a significant reduction in invasive breast cancer among estrogen users was only recently reported after nearly 11 years of followup. The results of the estrogen plus progestin trial indicated the opposite effect—a significant increase in breast cancer. Whether this discrepancy can be explained by the concomitant use of progestin, the differences in characteristics of women who had a hysterectomy or not, or other reasons is unclear at this point.


Evidence from trials published since 2002 indicated that both hormone therapy regimens decreased fractures but increased stroke, thromboembolic events, gallbladder disease, and urinary incontinence. Estrogen plus progestin also increased breast cancer and probable dementia, while estrogen alone decreased breast cancer.


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