Menopausal hormone therapy after the WHI: what the follow-up data changed

In July 2002, the Women's Health Initiative reported that combined estrogen plus progestin increased the risks of breast cancer, coronary events, stroke, and blood clots, and the trial arm was stopped early, after a mean of 5.2 years of follow-up [1]. Prescribing fell sharply worldwide within a year. Two decades of follow-up analysis have produced a more detailed picture, and the difference between the 2002 headline and the current reading comes down to who was studied and what they were given.

What the original trial tested

The WHI estrogen plus progestin trial randomized 16,608 postmenopausal women with a uterus to one regimen, oral conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg daily, or placebo. Mean age at enrollment was 63.3 years; about two-thirds of participants were over 60, and only about 11 percent were aged 50 to 54 [1]. The reported hazard ratios were 1.29 for coronary heart disease, 1.26 for invasive breast cancer, 1.41 for stroke, and 2.13 for pulmonary embolism, with the breast cancer interval reaching 1.00 and the coronary interval crossing 1 after adjustment for multiple comparisons [1]. These were relative increases applied to low absolute rates in that age group. The trial was designed as a chronic disease prevention study in older women, not a study of symptom treatment in women around 50. Its results were applied to both, and prescribing guidance for younger women was rewritten on data from older ones.

What later analysis added

Age and timing. The 2013 WHI report of 13 years of cumulative follow-up found that outcomes differed by age [2]. In the estrogen-alone trial, women aged 50 to 59 had a hazard ratio for coronary heart disease of 0.63 (95% CI 0.36 to 1.08) and a trend toward lower all-cause mortality, while women 60 and older showed no difference from placebo [2]. The 2017 WHI mortality analysis, covering 27,347 women across both trials over 18 years, found no overall difference in all-cause, cardiovascular, or cancer mortality with hormone therapy (HR 0.99, 95% CI 0.94 to 1.03); among women aged 50 to 59 during the intervention phase, all-cause mortality was lower with hormone therapy (HR 0.69, 95% CI 0.51 to 0.94), a pattern not seen in the older age groups [3]. This age-dependent pattern is what is usually meant by the timing hypothesis. The WHI investigators describe it as a trend consistent with the hypothesis, not proof of it, and they continue to state that the findings do not support hormone therapy for chronic disease prevention [2, 3].

Estrogen alone, in women who had a hysterectomy, did not increase breast cancer. During the intervention phase the hazard ratio was 0.79, and over 13 years of cumulative follow-up breast cancer incidence was significantly reduced in the estrogen-alone group [2]. The increase in breast cancer appeared in the combined regimen, which used medroxyprogesterone acetate. The WHI did not test other progestogens, so it cannot say whether a different progestogen would have produced a different result.

Route of administration. Oral estrogen passes through the liver before reaching the circulation, where it increases production of clotting factors. In the French ESTHER case-control study of 271 women with a first idiopathic venous thromboembolism and 610 matched controls, current oral estrogen use was associated with an odds ratio of 4.2 (95% CI 1.5 to 11.6) compared with nonusers, while transdermal estrogen was associated with an odds ratio of 0.9 (95% CI 0.4 to 2.1) [4]. A 2008 meta-analysis of eight observational studies and nine randomized trials by the same group found an odds ratio of 2.5 (95% CI 1.9 to 3.4) for oral estrogen and 1.2 (95% CI 0.9 to 1.7) for transdermal estrogen, with oral risk highest in the first year of use [5]. The transdermal finding rests on observational data; no randomized trial has tested transdermal estrogen against oral for venous thromboembolism [5]. Transdermal estradiol and oral micronized progesterone are chemically identical to the hormones the ovary makes, and neither was the regimen the WHI tested.

What progesterone is for. A woman with a uterus who takes systemic estrogen needs a progestogen to protect the uterine lining, because unopposed estrogen raises the risk of endometrial hyperplasia and cancer [6]. The FDA kept this risk in the boxed warning for systemic estrogen-alone products when it removed the other warnings in 2025 and 2026 [11, 12]. Micronized progesterone fills the protective role and has a measurable effect on sleep: in a crossover trial of 10 healthy postmenopausal women, 300 mg of oral micronized progesterone at night reduced time awake on sleep EEG from about 80 to about 54 minutes without impairing daytime cognition [7], and a 2021 meta-analysis of randomized trials found micronized progesterone shortened sleep onset latency, with inconsistent results for total sleep time and sleep efficiency and clearer effects at 200 to 300 mg than at 100 mg [8]. A levonorgestrel intrauterine device delivers progestogen to the lining with little systemic exposure. A 2011 meta-analysis of six randomized trials (518 women) found rates of proliferative endometrium with the device comparable to systemic progestogens, though the longest trial ran 24 months [9]. In the United States this use is off-label, and only 3 of 72 trials of endometrial protection reviewed at the 2025 Menopause Society meeting studied the hormonal IUD [10].

What the FDA changed

On November 10, 2025, HHS and the FDA announced that the boxed warning on menopausal hormone therapy, added in 2003 on the basis of the WHI, would lose its language on cardiovascular disease, breast cancer, and probable dementia, following a literature review, a July 2025 expert panel, and a public comment period; the endometrial cancer warning stays on systemic estrogen-alone products, and cardiovascular and breast cancer information remains elsewhere in the labeling [11]. On February 12, 2026, the FDA approved the first revised labels for six products (Prometrium, Divigel, Cenestin, Enjuvia, Estring, and Bijuva), with submissions from 29 manufacturers under review [12]. Critics, including Public Citizen's Worst Pills, Best Pills, argued the change rested on reinterpretation of existing data, not new safety data [11].

Where this leaves current practice

The WHI answered a narrow question: oral conjugated estrogen plus medroxyprogesterone, started at a mean age of 63, caused more harm than benefit as a prevention strategy. It did not test transdermal estradiol, micronized progesterone, or treatment started near menopause for symptoms. The 2022 Menopause Society position statement endorses hormone therapy for vasomotor symptoms and the genitourinary syndrome of menopause, notes that it prevents bone loss and fracture, and frames the decision around age, time since menopause, and individual risk, with periodic reassessment [6]. The follow-up data support that framing. They do not show that hormone therapy prevents chronic disease, and the WHI investigators still say so [2, 3].

Sources

1. Writing Group for the Women's Health Initiative Investigators (Rossouw JE, et al.). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333. https://jhanley.biostat.mcgill.ca/c609/material/hrtJama2002.pdf
2. Manson JE, Chlebowski RT, Stefanick ML, 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
3. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women's Health Initiative randomized trials. JAMA. 2017;318(10):927-938. https://menopause.org.au/hp/studies-published/menopausal-hormone-therapy-and-long-term-all-cause-and-cause-specific-mortality-the-whi-randomized-trials
4. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115(7):840-845. https://pubmed.ncbi.nlm.nih.gov/17309934/
5. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008;336(7655):1227-1231. https://www.bmj.com/content/336/7655/1227
6. The North American Menopause Society Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794. doi:10.1097/GME.0000000000002028. https://www.menopause.org/docs/default-source/professional/nams-2022-hormone-therapy-position-statement.pdf
7. Schüssler P, et al. Progesterone reduces wakefulness in sleep EEG and has no effect on cognition in healthy postmenopausal women. Psychoneuroendocrinology. 2008;33(8):1124-1131. https://pubmed.ncbi.nlm.nih.gov/18676087/
8. Nolan BJ, Liang B, Cheung AS. Efficacy of micronized progesterone for sleep: a systematic review and meta-analysis of randomized controlled trial data. Journal of Clinical Endocrinology and Metabolism. 2021;106(4):942-951. doi:10.1210/clinem/dgaa873
9. Somboonporn W, et al. Levonorgestrel intrauterine system versus systemic progestogens for endometrial protection in women using estrogen therapy: meta-analysis of randomized trials. Menopause. 2011. (Six trials, 518 participants.)
10. Contemporary OB/GYN. Michelle Wise, MD, discusses levonorgestrel IUD offering effective endometrial protection during hormone therapy. October 23, 2025. https://www.contemporaryobgyn.net/view/michelle-wise-md-discusses-levonorgestrel-iud-offering-effective-endometrial-protection-during-hormone-therapy
11. US Department of Health and Human Services and US Food and Drug Administration. HHS Advances Women's Health, Removes Misleading FDA Warnings on Hormone Replacement Therapy. Press announcement, November 10, 2025. https://www.fda.gov/news-events/press-announcements/hhs-advances-womens-health-removes-misleading-fda-warnings-hormone-replacement-therapy-0 ; critique: Worst Pills, Best Pills, https://www.worstpills.org/newsletters/view/1700
12. US Food and Drug Administration. FDA Approves Labeling Changes to Menopausal Hormone Therapy Products. Press announcement, February 12, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-labeling-changes-menopausal-hormone-therapy-products