News from the WHI Study

February 2026 | Former WHI DSMB Members publish a Viewpoint in JAMA: Menopausal Hormone Labels Should Rely on Evidence, Not Opinion

See full article here: https://jamanetwork.com/journals/jama/fullarticle/2844960

January 2026 | PharmedOut publishes opinion piece in STATNews: The 30-year itch: Hormone promotion is back with a vengeance

Uninformed influencers and physicians peddling products are trivializing the risks of menopausal hormones. See full article here: https://www.statnews.com/2026/01/08/hormone-therapy-menopause-history-hype/

December 2025 | Commentary: Gold standard science versus Disinformation

Jacques Rossouw, MD | Private
The article by Makary et al evokes the pre-Women’s Health Initiative (WHI) era, when small observational studies promised manifold benefits associated with menopausal hormone therapy (MHT).¹ Widespread adoption of MHT for cardiovascular disease (CVD) prevention in older women ultimately necessitated randomized clinical trials to test the hypothesis in the interest of public health. Unexpectedly, these landmark clinical trials provided definitive evidence that oral MHT should not be used for CVD prevention.² The trials also showed that older women with vasomotor symptoms (VMS) were at particularly high risk of CVD due to MHT.³ The post-hoc timing hypothesis postulates that MHT started at a younger age when risks are low and continued into older ages will translate into CVD benefit as women and their arteries age. Clinical trials to test the timing hypothesis are not feasible and observational studies of self-selected long-term users are fraught with confounding and bias from survivors and healthy users; thus, it remains but a hypothesis.⁴ The WHI trials included 8833 women aged 50-59 years, among whom MHT reduced VMS without elevating the risk of overall CVD, and for coronary heart disease specifically more favorable findings for estrogen-alone.^2,3 However, for estrogen plus progestin the increased risk of invasive breast cancer was similar at all ages, reaching statistical significance during postintervention follow-up in younger women.² Overall breast cancer risk was cumulative, with risks increasing by duration of exposure and significant over the full trial period, persisted during postintervention follow-up, and breast cancer mortality reached statistical significance at 11 years .² The findings for breast cancer due to estrogen plus progestin and the uncertainty about effects of long-term MHT use on CVD generally support a cautious approach that MHT should be used at the lowest dose and shortest duration needed to treat VMS in younger women. The WHI trials also showed reductions in fracture and diabetes risk, increased risks of gallbladder disease and urinary incontinence, and no protection from dementia.² Medroxyprogesterone acetate abrogated the risk of endometrial cancer.² The Food and Drug Administration is not meeting its obligation to provide reliable information to health care providers and to women. Other MHT formulations and routes of administration lack the comprehensive information available from clinical trials of conjugated equine estrogens with or without medroxyprogesterone acetate. Hopefully, experts writing practice guidelines will continue to follow the tenets of evidence-based medicine and prioritize information from clinical trials rather than from flawed observational studies.

¹ Makary MA, Nguyen CP, Høeg TB, Tidmarsh GF. Updated Labeling for Menopausal Hormone Therapy. JAMA. Published online November 10, 2025. doi:10.1001/jama.2025.22259.

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.

³ Rossouw JE, Aragaki AK, Manson JE, et al. Menopausal Hormone Therapy and Cardiovascular Diseases in Women With Vasomotor Symptoms: A Secondary Analysis of the Women’s Health Initiative Randomized Clinical Trials. JAMA Intern Med. 2025;185(11):1330–1339.

⁴ Rossouw JE. Reconciling the divergent findings from clinical trials and observational studies of menopausal hormone therapy for prevention of coronary heart disease.

November 2025 | FDA announced changes to the FDA labeling for Menopausal Hormone Therapy¹

WHI does not have a position on the black box warning for menopausal hormone therapy

We note that in the years since the results of the WHI were published there has been no new information from similarly large randomized trials that would change the balance of known overall risks versus benefits for oral menopausal hormone therapy. WHI did not test other forms (transdermal or vaginal) of hormone therapy.

The gold standard WHI trials showed that oral hormone therapy increased risks of stroke and blood clots and did not prevent heart attacks in women aged 50-79. In fact, during the first few years the risk of heart attacks was increased. In addition, combination estrogen plus progestin increased the risk of breast cancer irrespective of age and this risk became more significant over time in the trial and with longer duration of follow-up. Oral hormone therapy reduced diabetes and fracture risk, but increased risks of gallbladder disease, urinary incontinence and dementia in women over 65 years of age.

For younger women, the benefit of vasomotor symptom reduction may outweigh the small cardiovascular risks, but it is uncertain whether any cardiovascular benefit seen in younger ages with estrogen alone will carry over into older ages as women and their arteries age.

Our original conclusions still stands: oral menopausal hormone therapy should not be used for chronic disease prevention. Using menopausal hormone therapy for relief of moderate to severe vasomotor symptoms is reasonable but it should be limited to the lowest dose for the shortest time needed for this indication.

Irrespective of whether the black box warning for oral hormone therapy remains or is removed, it is essential that that women be fully informed about the overall risks versus benefits. This information should be based on the most rigorous science rather than anecdotes. There are no large, randomized trials to inform decision-making about non-oral (transdermal or intra-vaginal) menopausal hormone therapies and this too should be made transparent.

¹ Makary MA, Nguyen CP, Høeg TB, Tidmarsh GF. Updated Labeling for Menopausal Hormone Therapy. JAMA. Published online November 10, 2025. doi:10.1001/jama.2025.22259

See WHI response to the FDA Expert Panet on MHT use in July of 2025 here: https://www.whi.org/doc/banner/WHI_response_to_FDA_Expert_Panel_on_MHT_use_09.19.2025.pdf