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Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy: The Women's Health Initiative Randomized Controlled Trial
Open accessAbstract
CONTEXT: Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain. OBJECTIVE: To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity. INTERVENTION: Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo. MAIN OUTCOME MEASURES: The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects. RESULTS: In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years. CONCLUSIONS: The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.
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“The high clinical failure rate in drug development across all disease categories is based, at least in part, on the inability to adequately model human diseases in animals and the poor predictability of animal models.36”
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“The proportion of individuals compliant (Ն80% adherence) with lipid-lowering or antihypertensive drugs typically ranges from 65% to 85% in clinical trials to Ͻ50% in clinical practice.106 -108”
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Metadata
- Authors
- The Women's Health Initiative Steering Committee*
- Affiliations
- Fred Hutch Cancer Center (US)
- Corresponding author
- The Women's Health Initiative Steering Committee*
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2004-04-14
- Volume
- 291
- Issue
- 14
- Pages
- 1701
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W1586699954
- Cited by
- 4,534
- References
- 64
- Citations by year
- 2026: 78 · 2025: 67 · 2024: 90 · 2023: 87 · 2022: 145 · 2021: 109 · 2020: 101 · 2019: 142 · 2018: 125 · 2017: 147 · 2016: 137 · 2015: 160 · 2014: 177 · 2013: 226 · 2012: 229
- FWCI
- 284.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Nursing › Nutrition and Dietetics › Phytoestrogen effects and research
- Keywords
- conjugated equine estrogens, postmenopausal women, hysterectomy, coronary artery disease, breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, cardiovascular disease, risk-benefit assessment, Women's Health Initiative, early trial termination, disease prevention, racial and ethnic minorities, cardiovascular risk factors, menopausal symptoms, hot flashes
- MeSH terms
- Aged, Breast Neoplasms, Cause of Death, Coronary Disease, Double-Blind Method, Estrogens, Conjugated (USP), Estrogens, Female, Hip Fractures, Humans, Hysterectomy, Middle Aged, Pulmonary Embolism, Colorectal Neoplasms, Estrogen Replacement Therapy, Proportional Hazards Models, Postmenopause, Risk Assessment, Stroke
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