Menopause Hormone Therapy: What the Trials Found, and What Is Still Contested

The short version

• Prevention. The WHI authors concluded that the tablets they tested should not be used to prevent chronic disease.^[1][2][4]
• Two regimens, two results. Estrogen plus progestin (women with a uterus) and estrogen alone (women without one) behaved differently, most clearly for breast cancer.^[4][5]
• Timing. Some analyses suggest heart risk differs with years since menopause, but that trend did not meet the authors’ significance criterion, and an early-start advantage has not been shown. The evidence comes from secondary analyses and an imaging trial, and it is contested.^[3][6][8]
• Labels. FDA has started removing boxed-warning language. It cites a literature review, an expert panel and public comment.^[9][10]

On this page

• What the WHI tested
• Breast cancer: the results conflict
• Does timing matter?
• What the Menopause Society says
• What FDA changed, and what it didn’t
• What the evidence doesn’t cover
• Questions for your clinician
• References

About this post. It covers menopausal hormone therapy: estrogen, alone or with a progestogen (the class that includes the progestin used in the Women’s Health Initiative), as studied in disease-outcome trials and as discussed in menopause-symptom position statements. It does not cover birth control pills. Most of the best-known evidence comes from one trial program, the Women’s Health Initiative (WHI), which tested one oral estrogen product, alone or with a progestin, in women whose average age was 63.^[5] Each result says who was studied.

What the WHI tested

The WHI ran two randomized trials of oral hormones. Participants averaged about 63 years old at enrollment, across both trials.^[5] FDA’s November 2025 release describes that average age as over a decade past the average age of menopause.^[9]

Estrogen plus progestin. The trial enrolled 16,608 women aged 50 to 79 with a uterus. They took conjugated equine estrogens plus medroxyprogesterone, or placebo, and the trial stopped at a mean 5.2 years. Per 10,000 women per year, the hormone group had 7 more coronary heart disease events, 8 more strokes, 8 more pulmonary emboli (blood clots in the lungs) and 8 more invasive breast cancers. It had 6 fewer colorectal cancers and 5 fewer hip fractures. All-cause mortality did not differ.^[1] Dementia was also more common in women who started estrogen plus progestin at 65 or older than in women on placebo.^[4]

A hazard ratio compares risk on hormones with risk on placebo. 1.0 means no difference. The range in parentheses is the 95% confidence interval (CI), where the true value probably falls; “nominal” is explained under “What we checked” below.

Estrogen alone. 10,739 women aged 50 to 79 who had had a hysterectomy took conjugated equine estrogens, on average 6.8 years. Stroke was higher (hazard ratio 1.39, 1.10 to 1.77) and hip fracture lower (0.61, 0.41 to 0.91). Heart disease was not clearly different (0.91, 0.75 to 1.12). Per 10,000 women per year: 12 more strokes, 6 fewer hip fractures.^[2]

That is the oral regimen the WHI tested. FDA’s release notes it is no longer in common use.^[9]

What we checked, and what we didn’t. The figures in this section come from the abstracts (the short summaries printed at the top of each paper) of the 2002 and 2004 WHI papers. We couldn’t open the full papers. The 2002 abstract calls its confidence intervals “nominal,” which means standard intervals that are not adjusted for the many outcomes the trial tracked. The full paper may report a second, adjusted set. We haven’t seen it, so we make no claim about whether each result holds up under it.^[1][2] The timing and stroke figures (see “Does timing matter?”) come from the abstract of the 2007 Rossouw analysis. The dementia and breast cancer findings come from the abstracts of the 2013 and 2020 WHI follow-up papers. We couldn’t open these in full either.^[3][4][5]

Breast cancer: the results conflict

With 20 years of follow-up, women who took estrogen plus progestin had more breast cancer (hazard ratio 1.28, 1.13 to 1.45). Breast cancer deaths were also higher in that group (1.35), but that result was not statistically significant. In the WHI trial, women who took estrogen alone had less breast cancer (0.78, 0.65 to 0.93) and fewer breast cancer deaths (0.60, 0.37 to 0.97).^[5] The estrogen-alone result applies to women who have had a hysterectomy.

Observational data point the other way for estrogen alone. A pooled analysis of 108,647 breast cancers found excess risk with every type of hormone therapy except vaginal estrogen, rising with years of use. Current users in years 5 to 14: relative risk 2.08 for estrogen plus progestogen and 1.33 for estrogen alone. If the link is causal, the authors estimate 5 years of use from age 50 adds about 1 breast cancer per 50 users (estrogen plus daily progestogen), 1 per 70 (intermittent progestogen) or 1 per 200 (estrogen alone), over ages 50 to 69.^[7]

Contested. A randomized trial and an observational pool disagree on estrogen alone. They differ in design, participants and formulations. Neither cancels the other. We don’t merge them into one number.

Does timing matter?

A pooled analysis of both WHI trials asked whether heart risk changes with time since menopause. For coronary heart disease, the hazard ratio was 0.76 in women under 10 years past menopause, 1.10 at 10 to 19 years and 1.28 at 20 or more years. The trend across those groups had a P value of .02 (the lower the P value, the less often chance alone would produce a pattern like this), which the authors said did not meet their criterion for statistical significance. Grouping the same women by age instead, the trend was not statistically significant (P = .16).^[3] In the same pooled analysis, stroke risk was higher overall (hazard ratio 1.32) and did not vary significantly by age or time since menopause.^[3] This 2007 paper has a published correction to one number, which we don’t use here. The figures above come from the paper’s corrected abstract, and we haven’t read the correction itself.^[3]

Contested. For women under 10 years past menopause, the confidence interval (0.50 to 1.16) takes in both a benefit and a harm, so it doesn’t show a benefit.^[3] This is a secondary analysis, not the trials’ main question. The ELITE trial (643 healthy women) found estradiol slowed thickening of the carotid artery wall in women within 6 years of menopause but not in women 10 or more years out. Cardiac CT measures did not differ in either group. That is an imaging result, not a heart attack result.^[6] Treat the timing idea as a hypothesis with mixed support, not a proven rule.

What the Menopause Society says

The Menopause Society’s 2022 position statement calls hormone therapy the most effective treatment for hot flashes and night sweats and for the vaginal and urinary symptoms of menopause (genitourinary symptoms), and says it prevents bone loss and fracture. For women under 60 or within 10 years of menopause onset with no contraindications, it calls the benefit-risk balance favorable for bothersome hot flashes and bone-loss prevention. For starting later, it calls the balance less favorable because the absolute risks of heart disease, stroke, venous clots and dementia are greater. Risk depends on type, dose, duration, route, timing and whether a progestogen is used. When vaginal or urinary symptoms are the only problem and over-the-counter products don’t help, it recommends low-dose vaginal estrogen or other treatments.^[8]

The WHI authors’ conclusion and the Society’s statement address different things. The WHI conclusion was about preventing chronic disease in trial participants who averaged 63. The Society’s statement is about symptomatic women under 60 or within 10 years of menopause.^[4][8]

What FDA changed, and what it didn’t

• November 2025. FDA said it was starting to remove broad boxed warnings on menopausal hormone therapy, covering cardiovascular disease, breast cancer and probable dementia. The boxed warning on endometrial cancer for systemic estrogen-alone products stays.^[9]
• February 2026. FDA approved labeling changes for the first six products. 29 drug companies had submitted proposed changes.^[10]
• Not universal. One estrogen-plus-progestin label we checked, updated April 2026, still opens with a boxed warning for cardiovascular disorders, breast cancer, endometrial cancer and probable dementia. We didn’t confirm whether that product was among the first six.^[12]

FDA says it acted after a review of the scientific literature, an expert panel and a public comment period; the announcements do not report a new trial.^[9][10] FDA’s November 2025 release also gave percentage reductions in heart disease, Alzheimer’s disease and fractures. We couldn’t match those percentages to the trial reports we cite (the WHI does report lower hip fracture, above), so we don’t use them.^[9] The Menopause Society agreed with removing the boxed warning on low-dose vaginal estrogen and said systemic estrogen still carries potential risks for some people.^[11]

What the evidence doesn’t cover

• The WHI tested oral conjugated estrogens and medroxyprogesterone. Route, dose and progestogen type change risk.^[8]
• This post has no trial data on transdermal estradiol with micronized progesterone. That is a gap in our sources, not evidence of safety or harm.
• We found no source in this review for claims about “bioidentical” hormones or anti-aging protocols, so we make none.

Questions for your clinician

• Does having a uterus, or not, change which hormones I’d take?
• How do the years since my last period change the risk picture?
• If my symptoms are vaginal or urinary, would low-dose vaginal estrogen cover them?
• Does my history of clots, stroke or breast cancer change the options?
• Which route and dose, how long, and when do we reassess?

Estrogen alone raises endometrial cancer risk in women with a uterus, which is why FDA kept that warning.^[9] Ask about this if you still have a uterus. If you have a personal or family history of breast cancer, a prior clot or stroke, that history belongs in the first conversation. If you already take hormone therapy, talk with your prescriber before you stop or change it.

This is a summary of trials and position statements. It can’t tell you whether hormone therapy fits your body. Your clinician can, with your history in front of them.

Read next

• Menopause Symptoms: Only 37% of Women Feel Informed: How much women say they know about menopause and its treatment options, from a 2026 Gallup survey.
• Menopause Age and Brain Health: What a New Study Found: What a large US study of older women found about age at menopause and brain health.
• Perimenopause Is Not Just Hot Flashes: The symptoms before menopause, including the ones that are easy to miss.

References

The hazard ratios, confidence intervals and other figures from the journal papers cited here come from their abstracts: Rossouw 2002 [1], Anderson 2004 [2], Rossouw 2007 [3], Manson 2013 [4], Chlebowski 2020 [5], Hodis 2016 [6] and the Collaborative Group 2019 pooled analysis [7]. The Menopause Society statement [8] is cited from its abstract. The web pages [9] to [12] were read as published.

[1] Rossouw JE, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288(3):321-333. DOI: 10.1001/jama.288.3.321. Finding: 16,608 women, conjugated equine estrogens 0.625 mg/d plus medroxyprogesterone acetate 2.5 mg/d vs placebo, stopped at mean 5.2 years; hazard ratios and absolute excess risks as printed in the abstract (the abstract labels its 95% intervals “nominal”; the full paper was not accessed, so any adjusted intervals were not checked); the authors state the regimen should not be initiated or continued for primary prevention of coronary heart disease. ↑︎

[2] Anderson GL, et al; WHI Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA. 2004;291(14):1701-1712. DOI: 10.1001/jama.291.14.1701. Finding: 10,739 women, mean 6.8 years; stroke HR 1.39, hip fracture HR 0.61, coronary heart disease HR 0.91; the authors state estrogen should not be recommended for chronic disease prevention. ↑︎

[3] Rossouw JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297(13):1465-1477. DOI: 10.1001/jama.297.13.1465. Finding: coronary heart disease hazard ratios by years since menopause (under 10 years, hazard ratio 0.76, 95% CI 0.50 to 1.16; P for trend .02) and by age (P for trend .16, not significant); stroke raised overall (hazard ratio 1.32, 95% CI 1.12 to 1.56) and not significantly varying by age or time since menopause. Secondary analysis of pooled WHI trials. A correction titled “Incorrect Number” was published (JAMA. 2008;299(12):1426; DOI: 10.1001/jama.299.12.1426-a). The corrected abstract flags one placebo case count as corrected; that count is not used here. Figures are from the corrected abstract (PubMed 17405972); we did not review the correction’s text. ↑︎

[4] Manson JE, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368. DOI: 10.1001/jama.2013.278040. Finding: the results do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women; estrogen plus progestin raised dementia incidence in women 65 and older; neither regimen affected all-cause mortality. ↑︎

[5] Chlebowski RT, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;324(4):369-380. DOI: 10.1001/jama.2020.9482. Finding: estrogen alone, breast cancer HR 0.78 and mortality HR 0.60; estrogen plus progestin, incidence HR 1.28 and mortality HR 1.35 (not statistically significant); baseline mean age 63.4 years. ↑︎

[6] Hodis HN, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221-1231. DOI: 10.1056/NEJMoa1505241. Finding: 643 healthy women; carotid artery wall thickness progressed less with estradiol in women under 6 years from menopause (0.0044 vs 0.0078 mm/year, P = .008), not in women 10 or more years out (P = .29); cardiac CT measures did not differ. ↑︎

[7] Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019;394(10204):1159-1168. DOI: 10.1016/S0140-6736(19)31709-X. Finding: observational pool of 108,647 breast cancers; current users in years 5 to 14, relative risk 2.08 (estrogen-progestagen) and 1.33 (estrogen-only); estimated excess of about 1 per 50, 1 per 70 and 1 per 200 users over 5 years of use from age 50, if causal. ↑︎

[8] The 2022 hormone therapy position statement of The North American Menopause Society Advisory Panel (now The Menopause Society). Menopause. 2022;29(7):767-794. DOI: 10.1097/GME.0000000000002028. Finding: hormone therapy is the most effective treatment for vasomotor symptoms and genitourinary syndrome of menopause and prevents bone loss and fracture; benefit-risk favorable under age 60 or within 10 years of menopause onset for bothersome vasomotor symptoms and bone loss, less favorable later; low-dose vaginal estrogen or other therapies for genitourinary symptoms alone not relieved by over-the-counter products. ↑︎

[9] U.S. Food and Drug Administration. HHS advances women’s health, removes misleading FDA warnings on hormone replacement therapy. Press announcement, 2025-11-10 (read 2026-10-26). www.fda.gov/news-events/press-announcements/hhs-advances-womens-health-removes-misleading-fda-warnings-hormone-replacement-therapy. Finding: FDA is initiating removal of broad boxed warnings on cardiovascular disease, breast cancer and probable dementia; the endometrial cancer boxed warning for systemic estrogen-alone products is not being removed; the release says it follows a review of the scientific literature, an expert panel and a public comment period; it describes WHI participants as averaging 63 years, over a decade past the average age of menopause, and the WHI formulation as no longer in common use; it also gives percentage reductions for cardiovascular disease, Alzheimer’s disease and fractures, which we could not match to the trial reports cited and do not reproduce. ↑︎

[10] U.S. Food and Drug Administration. FDA approves labeling changes for menopausal hormone therapy products. Press announcement, 2026-02-12 (read 2026-10-26). www.fda.gov/news-events/press-announcements/fda-approves-labeling-changes-menopausal-hormone-therapy-products. Finding: six products approved across four categories with cardiovascular, breast cancer and probable dementia risk statements removed from the boxed warning; 29 drug companies have submitted proposed labeling changes at FDA’s request; the release cites a comprehensive review of the scientific literature. ↑︎

[11] The Menopause Society. The Menopause Society comments on the FDA announcement on hormone therapy. 2025-11-10 (read 2026-10-26). menopause.org/press-releases/the-menopause-society-comments-on-the-fda-announcement-on-hormone-therapy. Finding: agrees with removing the boxed warning on low-dose vaginal estrogen; systemic estrogen still comes with potential risks in certain individuals. ↑︎

[12] U.S. National Library of Medicine. DailyMed prescribing information for Prempro/Premphase (label update 2026-04-28; read 2026-10-26). dailymed.nlm.nih.gov (Prempro/Premphase). Finding: the label is headed “WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA.” ↑︎

Kurt Greiner

Kurt is a digital strategist and IT professional blending emerging technology with practical application, exploring how individuals can leverage modern tools to navigate the second half of life with purpose.