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 →
At a glance
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.
- What was measured
- Breast cancer, heart disease, stroke, lung clots, hip fractures and other major illnesses in healthy women after menopause.
- How big
- Each year, for every 10,000 women taking it, there was a net excess of 12 harmful events in women aged 50 to 59 and 38 in women aged 70 to 79, counting harms such as breast cancer and stroke against benefits such as fewer hip fractures.Read from the summary of 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.
- Who it applies to
- 16,608 healthy women aged 50 to 79 after menopause with an intact uterus, taking one estrogen and progestin pill to prevent disease, not to treat hot flashes.
- Safety
- The harm is the finding: invasive breast cancer, stroke, blood clots and dementia in women 65 and over went up. Deaths from any cause did not change.
- Compared with
- A dummy pill.
- Certainty
- Grade D, resting on: 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. with extended follow-up + systematic reviews A review that searches for every study on a question using a method set in advance, then assesses them together..
- What would change this grade
- Could rise to C with: Randomized, double-blind Neither the participants nor the people assessing them know who received the real treatment until the trial ends., placebo-controlled trial of conjugated equine estrogen 0.625 mg with medroxyprogesterone acetate 2.5 mg, the regimen this letter grades, given for chronic disease prevention. Who: Healthy postmenopausal women aged 50 to 79 with an intact uterus, at least 5,000 per arm. Measured: Heart attack, stroke, breast cancer, blood clots and death. Length: At least 10 years.
- Cost
- No price recorded yet.
- Sources
- 5 studies cited on this record, listed under Sources.
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 letter
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 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. 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 →
Who responds: this record's trial reading reports no subgroup that identifies who responds.
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: October 2026
The trial that would change this grade.
A positive trial of this shape would move this entry to C.
Why the current trials fall short
The large trial of this regimen, in women who averaged more than a decade past menopause, found more invasive breast cancer, stroke, pulmonary embolism and, in women 65 and over, dementia, with no change in deaths. A letter above D would need a prevention trial of the same regimen that shows benefit without repeating that harm. Transdermal estradiol with micronized progesterone, or starting close to menopause, is a different question this letter does not grade.
Why people believe itOne human source; two published case reports of benefit; three reports of harm.
The case for combined hormone therapy in healthy women is that estrogen improves cholesterol and blood vessel function, and that large observational Research that watches what people already do rather than assigning a treatment. It can show that two things travel together, not that one causes the other. studies of nurses found hormone users had far less heart disease than non-users. Those studies made prevention a main reason for prescribing it until the randomized trial found harm.
What supporters point to, and what each source actually shows. None of it is enough to move this letter higher; the trial described above under Evidence wanted is what would.
- Population study, not a trialIn 59,337 nurses followed for up to 16 years, women taking estrogen with progestin had about 60 percent less major heart disease than women not taking hormones. Users were healthier to begin with, and the randomized trial did not confirm it. PMID 8672166
A case report describes what happened to one or a few patients. It cannot show the treatment caused the change, and reports of success are published more often than reports of failure.
- A 51-year-old woman with epilepsy started estradiol, then added medroxyprogesterone, and had fewer seizures, no more hot flashes and better sleep. Symptom relief in one patient, not prevention. PMID 10981250
- In 15 Japanese women around menopause given estradiol with micronized progesterone, sleep quality improved. A small study with no comparison group, for symptoms rather than prevention. PMID 40347165
- Three patients had a stroke from a traveling clot while on hormone treatments: a 73-year-old woman with a prior transient ischemic attack after about 6 years of estrogen with medroxyprogesterone for menopause symptoms, a woman taking medroxyprogesterone for breast cancer, and a woman taking tamoxifen to prevent breast cancer relapse. PMID 11422601
- Two women developed endometrial cancer after 15 months of combined hormone therapy, with high estradiol blood levels after each tablet. PMID 10340283
- A woman was diagnosed with an aggressive endometrial cancer during 3 years of sequential estrogen and progestin treatment around menopause. The authors note this cancer type is not hormone dependent and that a link to the treatment is unproven. PMID 39650060
Searched PubMed, October 2026: 9 case report record(s) returned. Five describe harm during hormone therapy, including strokes from clots, endometrial cancer, eye changes linked to thyroid disease and unscheduled bleeding; three are listed. Two describe symptom relief and are listed. Two are a controlled trial indexed as a case report and a discussion of hormone therapy after stroke.
ClinicalTrials.gov, the public registry run by the U.S. National Library of Medicine, lists studies that are recruiting volunteers. The link below searches it for Hormone Replacement Therapy among studies recruiting now. EBL has no relationship with any listed study and receives no payment for this link.
Search recruiting studies of Hormone Replacement Therapy on ClinicalTrials.gov
Dose, form and timing
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 judgment 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. When HRT is used therapeutically under physician direction, the measures are 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.
Safety
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.
Cautions documented in human studies. Each caution on this record, sorted by what it rests on.
- Breast cancer, stroke and blood clots: in the Women's Health Initiative, combined estrogen plus progestin raised invasive breast cancer, stroke and venous thromboembolism (PMID 12117397 PMID 24084921)
- Dementia: probable dementia rose in women 65 and over on combined estrogen plus progestin in the Women's Health Initiative (PMID 12117397)
- 3 published case reports of harm, described in the record's reports of harm (PMID 11422601 PMID 10340283 PMID 39650060)
None recorded.
None recorded.
Does not apply: human harm data are listed above.
Grade history
How this letter has changedLatest: No. 164 · October 2026 · Corrected.
The grade basis listed excess coronary heart disease as a finding; the 2002 interim hazard ratio was only nominally significant and the final adjudicated result, Manson 2013 (PMID 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
Every change to a letter on this site is dated and published. The full evidence log →
Sources
- Citations
- Every paper cited on this page is matched to its PubMed record on every build.
- Retractions
- None of these papers is retracted or under a journal expression of concern. PubMed is checked again on every build.
- Read against the papers
- August 2026. By a language model (AI-assisted reading), not yet reviewed by a clinician.
- Outside review
- Not yet done. No reviewer outside EBL has checked this record.
What each of these checks can and cannot show: evidence integrity.
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.
How EBL searched for the trials (1 search)
The search that was run, what it returned, and what was left out and why, so the absence of evidence can be checked as well as its presence.
("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])PubMed watch: does a new study change the grade? (nothing new)
No new paper matching the search behind this grade has been added to PubMed since October 2026.
Last run October 2026. A letter on EBL moves only after a logged review. A new paper never moves a letter by arriving: it is read, the answer is written here, and any change to the letter is published in the evidence log.
Disclosure
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