Protocol
Hormone replacement therapy (combined estrogen + progestin, primary prevention)
Tested in 16,608 healthy postmenopausal women and stopped early because risks exceeded benefits.
Grade D, tested: in a human randomized trial, the treated group did worse on the endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score. graded. How to read a grade →
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How this letter has changedLatest: October 2026 · Corrected.
The grade basis listed excess coronary heart disease as a finding; the 2002 interim hazard ratio How often an event happened in the treated group compared with the control group over the same period. A ratio of 0.80 means 20 percent fewer events. was only nominally significant and the final adjudicated result, Manson 2013 (PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 24084921), was 1.18 (95% CI 0.95 to 1.45), which the 2026 Cochrane review, Bofill Rodriguez (PMID 42695385), rates as probably little to no difference. The firm harms, invasive breast cancer, stroke, venous thromboembolism, dementia in women 65 and over and gallbladder disease, are now what the record names. Manson 2017 (PMID 28898378) is added so the record says all-cause mortality was not changed during the trial or over 18 years, which the earlier text could be read as implying. Gartlehner 2022 (PMID 36318128), the USPSTF review, is added. Rossouw 2002 (PMID 12117397) is relabeled as the interim report. Whether the manufacturer supplied study drug is not asserted, because the full text was not read. Letter unchanged.PMID 24084921 PMID 42695385 PMID 28898378 PMID 36318128 PMID 12117397
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This is hormone therapy with estrogen plus a progestin, taken by healthy women after menopause to prevent disease. A large study of over 16,000 women tested it. It was stopped early because the risks were greater than the gains. Breast cancer, strokes and blood clots in the lungs went up, while hip fractures went down. This is about preventing disease, not treating hot flashes.
Tested in 16,608 healthy postmenopausal women and stopped early because risks exceeded benefits. The firm harms are invasive breast cancer, stroke, venous thromboembolism, dementia in women 65 and over, and gallbladder disease; the coronary heart disease excess seen in the 2002 interim report was not significant at final adjudication, and all-cause mortality was unchanged during the trial and over 18 years of follow-up. This is about disease prevention in healthy women, not about symptom relief.
Why this gradeGrade D, tested, harm found. The reasoning, and what the grade does not cover.
Grade D on Route 2 Human randomized trials have been run and did not show benefit on the stated outcome. One of the two routes to the lowest letter on EBL's scale.: tested, harm found. The Women's Health Initiative randomized 16,608 healthy postmenopausal women aged 50 to 79 with an intact uterus to conjugated equine estrogen plus medroxyprogesterone acetate or placebo An inactive substitute made to look like the real treatment, so participants cannot tell which one they received., to find out whether it prevented chronic disease. It was stopped early because overall risks exceeded benefits. The firm harms are invasive breast cancer (hazard ratio 1.24 in the final intervention-phase analysis, PMID 24084921), stroke, pulmonary embolism, dementia in women 65 and over, and gallbladder disease, alongside fewer hip fractures and less diabetes. The coronary heart disease excess in the 2002 interim report (hazard ratio 1.29) was only nominally significant; at final adjudication it was 1.18 (95% CI 0.95 to 1.45), and the 2026 Cochrane review rates the coronary effect as probably little to no difference (RR 1.17, 0.95 to 1.44). All-cause mortality was not changed during the trial or over 18 years of follow-up (hazard ratio 1.02, PMID 28898378); the D records harm on specific outcomes, not excess deaths.
WHAT THIS GRADE DOES NOT COVER, AND THIS IS THE MOST OVER-READ RESULT IN MODERN MEDICINEthis letter grades one formulation, one route, one dose pair, given for chronic-disease prevention, in women averaging more than a decade past menopause. It does not grade hormone therapy for menopausal symptoms, a different question with different evidence that this site does not grade. It does not grade estrogen-alone therapy after hysterectomy, which produced a materially different risk profile within the same program. It does not grade transdermal routes, other progestogens, or initiation close to menopause. This letter is a statement about prevention trials, not about any individual prescription.
A grade describes the human evidence for a named use. It is not advice, and it is not a judgment on any individual prescription. How the letters are decided →
The harm is the finding. The Women's Health Initiative randomized 16,608 postmenopausal women and found combined estrogen plus progestin, used for primary prevention, raised invasive breast cancer, stroke, venous thromboembolism and dementia in women 65 and over; it did not change all-cause mortality. This record is a Route 2 D and covers primary prevention only; treatment of menopausal symptoms is a separate question this letter does not address.
The evidence, in fullFive papers, each linked to its PubMed record.
Writing Group for the Women's Health Initiative / Rossouw et al. (JAMA, 2002; PMID 12117397): the interim principal-results report at a mean 5.2 years; 16,608 postmenopausal women aged 50 to 79 with an intact uterus randomized to conjugated equine estrogen 0.625 mg with medroxyprogesterone acetate 2.5 mg or placebo; stopped when invasive breast cancer crossed its boundary and the global index showed net harm; its coronary result was superseded by later adjudicated analyses. Manson et al. (JAMA, 2013; PMID 24084921): the extended follow-up at 13 years; during the intervention, coronary heart disease hazard ratio 1.18 (95% CI 0.95 to 1.45), not significant; invasive breast cancer 1.24 (1.01 to 1.53); stroke, pulmonary embolism, dementia in women 65 and over, gallbladder disease and urinary incontinence increased; hip fractures and diabetes decreased; most risks dissipated after stopping, with breast cancer risk persisting (hazard ratio 1.28 cumulatively). Manson et al. (JAMA, 2017; PMID 28898378): 18-year mortality follow-up; all-cause mortality hazard ratio 1.02 (0.96 to 1.08) for estrogen plus progestin, with no change in cardiovascular or cancer mortality. Gartlehner et al. (JAMA, 2022; PMID 36318128): the USPSTF evidence review, 20 trials, 39,145 participants; quantified harms and benefits per 10,000 persons for estrogen plus progestin and estrogen alone. Bofill Rodriguez et al. (Cochrane Database Syst Rev, 2026; PMID 42695385): long-term hormone therapy, 24 studies, 45,660 participants; combined therapy probably makes little to no difference to coronary events (RR 1.17), may increase stroke and venous thromboembolism, and probably increases breast cancer (RR 1.27). D Route 2: tested at scale for prevention, with harm on breast cancer, stroke, venous thromboembolism and dementia, and no mortality benefit.
This D covers PRIMARY PREVENTION in the WHI population only. Treating menopausal symptoms is a different question, with different evidence, and this site does not grade it. So is the timing hypothesis, and so are other formulations and routes. Do not read this letter as a judgement on symptom treatment or as a reason to change a prescription. The WHI RCT Randomized controlled trial: people are assigned to the treatment or a comparison by chance, so the groups differ only in what they received. It is the design that can show cause and effect. for combined estrogen plus progestin in primary prevention showed harm, not benefit. If HRT is being used therapeutically under physician direction, track vasomotor symptom scores (MENQOL or MRS) and bone density (DEXA) at baseline and 12 months. Annual mammography and endometrial surveillance as directed by your physician.
Evidence notes: randomized trial, meta-analysis A study that pools the numbers from several trials into one combined estimate.
Endpoint graded: Chronic disease in healthy postmenopausal women, including breast cancer, stroke and blood clots (hard)
Last reviewed: July 2026
Educational use only · Not medical advice · EBL grades published human evidence and does not recommend treatment. Stopping a prescription is a decision for your physician.
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("Women's Health Initiative"[tiab] OR "hormone therapy"[tiab]) AND postmenopausal[tiab] AND (primary prevention[tiab] OR mortality[tiab]) AND (randomized controlled trial[pt] OR systematic review[pt])Grades move when new trials publish. A free monthly email lists every grade EBL moved, with the reason and the trial behind it: the sign-up is on the Evidence Log →