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Cited by 4,534Menopause: Health Impacts and TreatmentsEstrogen and related hormone effectsPhytoestrogen effects and research

Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy: The Women's Health Initiative Randomized Controlled Trial

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The Women's Health Initiative Steering Committee*·2004·JAMA
DOI 10.1001/jama.291.14.1701
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Abstract

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.

    “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”

    From The Flaws and Human Harms of Animal Experimentation (2015) · cites this paper as [36]

    The Limitations and Statistical Power and Analyses sections concern a human trial of conjugated equine estrogen, not drug-development failure rates. Searches for animal models, preclinical studies, and their predictive value found no passage addressing the claim. Passage-level page numbers were not available in our copy. (LLM, conf=0.76)

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  • The proportion of individuals compliant (≥80% adherence) with lipid-lowering or antihypertensive drugs typically ranges from 65% to 85% in clinical trials to <50% in clinical practice.

    “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”

    From Beyond Established and Novel Risk Factors: Lifestyle Risk Factors for Cardiovascular Disease (2008) · cites this paper as [106]

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Research works printed but not linked: 6

  1. Grady D, Hulley SB, Furberg C. Venous throm- boembolic events associated with hormone replace- ment therapy [letter]. JAMA. 1997;278:477.
  2. Anderson GL, Manson J, Wallace R, et al. Imple- mentation of the Women's Health Initiative study de- sign. Ann Epidemiol. 2003;13:S5-S17.
  3. Cox DR. Regression analysis and life tables. J R Stat Soc. 1972;34:187-220.
  4. ESPRIT Team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a random- ized placebo controlled trial. Lancet. 2002;360:2001- 2008.
  5. Nelson HD, Humphrey LL, Nygren P, et al. Post- menopausal hormone replacement therapy. JAMA. 2002;288:872-881.
  6. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk. J Natl Cancer Inst. 2000;92:328-332.

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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
DOI
10.1001/jama.291.14.1701
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
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 › Genetics › Estrogen and related hormone effects
  • Health Sciences › Medicine › Pathology and Forensic Medicine › 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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