Current commentaryPerspectives on the Women’s Health Initiative trial of hormone replacement therapy
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
References (86)
- et al.
Reduced mortality associated with long-term postmenopausal estrogen therapy
Obstet Gynecol
(1996) - et al.
Effects of contraceptive steroids on serum lipoproteins and cardiovascular disease scrutinized at workshop in Bethesda
Contraception
(1980) - et al.
The CONSORT statementRevised recommendations for improving the quality of reports of parallel-group randomised trials
Lancet
(2001) - et al.
Risk of venous thromboembolism in users of hormone replacement therapy
Lancet
(1996) - et al.
Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens
Lancet
(1996) - et al.
Prospective study of exogenous hormones and risk of pulmonary embolism in women
Lancet
(1996) - et al.
Stroke prevention and oestrogen replacement therapy
Lancet
(1989) - et al.
Hormone replacement therapy and the risk of death from breast cancerA systematic review
Am J Obstet Gynecol
(2002) Treatment of postmenopausal osteoporosis
Lancet
(2002)- et al.
Hormone replacement therapy and the risk of colorectal cancerA meta-analysis
Obstet Gynecol
(1999)