Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause
Open accessAbstract
CONTEXT: The timing of initiation of hormone therapy may influence its effect on cardiovascular disease. OBJECTIVE: To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began. DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of the Women's Health Initiative (WHI) randomized controlled trials of hormone therapy in which 10,739 postmenopausal women who had undergone a hysterectomy were randomized to conjugated equine estrogens (CEE) or placebo and 16,608 postmenopausal women who had not had a hysterectomy were randomized to CEE plus medroxyprogesterone acetate (CEE + MPA) or placebo. Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998. MAIN OUTCOME MEASURES: Statistical test for trend of the effect of hormone therapy on coronary heart disease (CHD) and stroke across categories of age and years since menopause in the combined trials. RESULTS: In the combined trials, there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 370 [corrected] cases of CHD and 239 cases of stroke in the placebo group. For women with less than 10 years since menopause began, the hazard ratio (HR) for CHD was 0.76 (95% confidence interval [CI], 0.50-1.16); 10 to 19 years, 1.10 (95% CI, 0.84-1.45); and 20 or more years, 1.28 (95% CI, 1.03-1.58) (P for trend = .02). The estimated absolute excess risk for CHD for women within 10 years of menopause was -6 per 10,000 person-years; for women 10 to 19 years since menopause began, 4 per 10,000 person-years; and for women 20 or more years from menopause onset, 17 per 10,000 person-years. For the age group of 50 to 59 years, the HR for CHD was 0.93 (95% CI, 0.65-1.33) and the absolute excess risk was -2 per 10,000 person-years; 60 to 69 years, 0.98 (95% CI, 0.79-1.21) and -1 per 10,000 person-years; and 70 to 79 years, 1.26 (95% CI, 1.00-1.59) and 19 per 10,000 person-years (P for trend = .16). Hormone therapy increased the risk of stroke (HR, 1.32; 95% CI, 1.12-1.56). Risk did not vary significantly by age or time since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend = .06). CONCLUSIONS: Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion for statistical significance. A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause. These data should be considered in regard to the short-term treatment of menopausal symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.
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Subsequent re-analyses of the Women's Health Initiative data revealed cardiometabolic benefits of MHT in women aged 50-59.
“subsequent re-analyses of the WHI data revealed cardiometabolic benefits of MHT in women aged 50-59 (216–218).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [218]
The paper’s Estimated Absolute Excess Risk section reports low or no excess cardiovascular risk at ages 50–59, and its introduction notes a nonsignificant reduction in coronary heart disease risk in one younger subgroup. But the Comment describes the findings near menopause as consistent with a neutral effect, while the paper does not establish broad cardiometabolic benefits; stroke risk was not shown to fall. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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- Authors
- Rossouw, J. E., Prentice, R. L., Manson, J. E., Wu, L., Barad, D., Barnabei, V. M., Ko, M., LaCroix, A. Z., Margolis, K. L., & Stefanick, M. L.
- Affiliations
- National Heart, Lung, and Blood Institute (US)
- Corresponding author
- Rossouw, Jacques E.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2007-04-04
- Volume
- 297
- Issue
- 13
- Pages
- 1465-77
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2143152245
- Cited by
- 1,741
- References
- 39
- Citations by year
- 2026: 35 · 2025: 54 · 2024: 41 · 2023: 44 · 2022: 48 · 2021: 44 · 2020: 53 · 2019: 76 · 2018: 69 · 2017: 67 · 2016: 76 · 2015: 74 · 2014: 88 · 2013: 122 · 2012: 129
- FWCI
- 145.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- hormone replacement therapy, cardiovascular disease, coronary artery disease, stroke, timing of hormone therapy, years since menopause, age, conjugated equine estrogens, medroxyprogesterone acetate, hysterectomy, Women's Health Initiative, postmenopausal women, estrogen-progestin combination therapy
- MeSH terms
- Age Factors, Aged, Cardiovascular Diseases, Estrogens, Conjugated (USP), Female, Humans, Middle Aged, Risk, Time Factors, Models, Statistical, Estrogen Replacement Therapy, Medroxyprogesterone Acetate, Postmenopause
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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