Elsevier

Obstetrics & Gynecology

Volume 100, Issue 6, December 2002, Pages 1344-1353
Obstetrics & Gynecology

Current commentary
Perspectives on the Women’s Health Initiative trial of hormone replacement therapy

https://doi.org/10.1016/S0029-7844(02)02503-6Get rights and content

Abstract

The premature termination of one comparison in the Women’s Health Initiative primary prevention trial due to stopping rules being reached necessitates a reconsideration of hormone replacement therapy (HRT). This part of the Women’s Health Initiative trial, however, examined only one popular HRT regimen (conjugated equine estrogen [0.625 mg] and medroxyprogesterone acetate [2.5 mg] daily) in asymptomatic postmenopausal women. To help clinicians understand this large, complex trial, we describe several pervasive biases in earlier observational studies, review the principal findings of the trial, summarize recent systematic reviews, and offer clinical suggestions for HRT. Observational studies of HRT have found consistent, powerful protection against heart disease; this now appears due to consistent, powerful selection biases. These biases have the same net effect: Women using HRT in observational studies were healthier than those not using it. The Women’s Health Initiative trial found that the overall risk-benefit ratio tipped against using HRT for prevention. Cardiovascular disease and breast cancer were increased among users, whereas colorectal cancer and osteoporotic fractures were reduced. Whether these findings relate to women with menopausal symptoms and to different HRT regimens is unknown. Hormone replacement therapy remains the best treatment for menopausal symptoms. Although estrogen has proven benefit for osteoporosis prevention, alternatives include raloxifene, alendronate, and risedronate. For women needing HRT, use of a low dose, with reassessments at least annually, appears prudent. Heart disease prevention strategies of proven value include exercise, weight control, blood pressure and lipid control, and avoidance of smoking. Hormone replacement therapy should not be used for this purpose.

Section snippets

Prior studies

Both strong basic science and clinical data suggested that estrogen benefits the cardiovascular system in older women. Estrogen receptor (α or β)—mediated mechanisms, both genomic and nongenomic, have been shown to improve lipids, enhance endothelial function, dilate coronary arteries, and inhibit the progression of atherosclerosis.5, 6, 7, 8, 9 Basic laboratory studies and prospective trials in animals as well as in postmenopausal women have shown this benefit with a variety of surrogate end

Shortcomings of surrogate markers

For logistical reasons, investigators often study surrogate markers,21 such as laboratory tests,22 instead of primary clinical outcomes (eg, illness or death). Unless compelling evidence supports the use of surrogate markers as valid predictors of illness, the primary outcome should always be the focus of clinical research.

Serum lipids are a frequent surrogate marker in cardiovascular research; they can also be misleading. Based on laboratory measurements, clofibrate and similar drugs were

Women who take HRT: healthy, wealthy, and well educated

Selection biases probably account for the putative cardiac benefits of HRT seen in most observational studies.28, 29, 30, 31, 32, 33, 34 Women who choose to take HRT differ from other women; these differences, rather than HRT, likely accounted for the better outcomes. Simply put: Women who choose to use HRT are healthier, more affluent, and better educated than those who do not take these hormones (healthy user bias). These women are younger, leaner, more likely to use alcohol (which in

Trial validity

Randomized controlled trials have two types of validity: internal and external. Internal validity implies that the trial answered the question it set out to answer. Stated alternatively, is the trial free of bias that might have distorted the results? The gold standard for assessing trial quality is reflected in the CONSORT guidelines.38 Major elements include a sample size large enough to find important differences, truly random assignment to treatments, concealment of the upcoming assignment

Clinical outcomes: cardiovascular disease

With aging, even in the absence of a documented cardiac event such as a myocardial infarction, women have substantial atherosclerosis. Based on the monkey model,41 the diminished ability for estrogen to inhibit coronary atherosclerosis can occur as early as 6 years after menopause if no hormones have been administered. This is aggravated if other cardiovascular risk factors exist. In the Women’s Health Initiative trial 36% of women assigned to HRT had hypertension, 49% were current or past

Breast cancer

The potential association between ERT or HRT and breast cancer has received intensive scrutiny over the years.50, 51 The findings of the Women’s Health Initiative are consistent with a small increase in risk (26%) (Figure 1). No increase in the risk of in situ cancers was evident. In the largest meta-analysis,52 the risk of breast cancer was related to duration of use (with standard doses of estrogen) and was compatible with the findings of the Women’s Health Initiative trial.

Women who develop

Fractures

For many years, observational data have linked use of ERT or HRT with a reduction in vertebral and hip fractures.57, 58 Although a prospective clinical trial showed a reduction in vertebral fractures with transdermal estradiol,59 no confirmatory prospective data for hip fractures had been available until the results from the Women’s Health Initiative. Because bone mineral density changes do not always correlate with fracture incidence, the results of the Women’s Health Initiative are helpful in

Colorectal cancer

The Women’s Health Initiative trial also corroborates epidemiological studies suggesting that estrogen reduces the risk of colorectal cancer.62, 63 Some studies have found greater protection with increasing duration of use. Although the mechanism(s) are unclear, the confirmation of this protective effect in a randomized controlled trial eliminates the concern of a “healthy user effect,” which has been a criticism in assessing the observational data. Stated alternatively, the effect appears to

Concerns voiced by some clinicians

Was the Women’s Health Initiative trial stopped prematurely? Some have noted that the adjusted 95% confidence intervals for many outcomes crossed 1.0, indicating a lack of statistical significance at the traditional .05 level. The stopping rules in the Women’s Health Initiative trial were not based on the frequency of any single outcome. In an earlier publication,64 the investigators pointed out that stopping rules in a prevention trial should be different than those in a treatment trial. The

Unanswered questions

Estrogen may have an important effect on the brain.2, 69, 70, 71 Nine randomized controlled trials among symptomatic women, although not entirely consistent, have demonstrated a beneficial effect on verbal memory,72 vigilance, motor speed, and reasoning.2 Observational data with important methodological weaknesses also show a significant reduction in the risk of developing Alzheimer disease in users of estrogen.73 However, estrogen does not appear to be of benefit once Alzheimer disease has

The Women’s Health Initiative trial in perspective

The Women’s Health Initiative study is the largest trial of HRT ever conducted. The data are valuable and will continue to be analyzed and reanalyzed in the years to come. However, the results of the Women’s Health Initiative trial need to be put into perspective. The results pertain only to this particular regimen (conjugated equine estrogen [0.625 mg] with medroxyprogesterone acetate [2.5 mg]) in asymptomatic women with a mean age of 63 years, most of whom had never used hormones.

Recent systematic reviews

Two systematic reviews of the literature concerning HRT appeared soon after the Women’s Health Initiative trial report.2, 28 Prepared as background articles for the third United States Preventive Services Task Force report, these syntheses comprehensively and critically summarize existing medical knowledge. A unique contribution of both was exclusion of poor-quality observational studies from the data synthesis.37 Aside from treating menopausal symptoms, benefits of HRT include reduction in the

Clinical recommendations

Hormone replacement therapy remains the most effective treatment of menopausal symptoms.76 Clearly, other regimens and routes of administration besides that used in the Women’s Health Initiative trial should also be considered: All doses and routes of estrogen administration appear equivalent in treating symptoms. Lower dose regimens may be safer for long-term use, although data are lacking.77 Indeed, even in young symptomatic women, combinations of conjugated equine estrogen and

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