Patient Age and Treatment Timing May Affect Cardiovascular Risks of Menopausal Hormone Therapy

Some women experience vasomotor symptoms (hot flashes and night sweats) during menopause. These symptoms may persist for years and are often managed with individual strategies such as keeping the core body temperature cool and exercising regularly.[1]

When medication is necessary for severe symptoms, the Food and Drug Administration (FDA) has approved (and Public Citizen’s Health Research Group recommends)[2] menopausal hormone therapy. This therapy typically consists of estrogen only (such as conjugated estrogens [PREMARIN and generics[3]]) or combined estrogen and progestin (such as conjugated estrogens and medroxyprogesterone [PREMPHASE, PREMPRO[4]]). We do not recommend any other drug treatments for vasomotor symptoms.

Although effective,[5] the use of hormone therapy for menopause has been limited by concerns about an increased risk of cardiovascular adverse events such as heart attack, peripheral arterial disease and stroke. Recent data, however, suggest that hormone therapy may be safer and more effective for postmenopausal women in their fifties and those who start treatment within a decade of menopause onset, and less safe and less effective for older women and those who start treatment more than 10 years after menopause begins.

Published in the November 2024 issue of JAMA Internal Medicine, a new analysis of data from the Women’s Health Initiative trials lends support to the hypothesis that the safety and effectiveness of menopausal hormone therapy for vasomotor symptoms varies with the timing of administration.[6]

Background

Largely based on the results of the Women’s Health Initiative trials published in 2002 and 2004, the prescribing information for menopausal hormone therapy has included a boxed warning — the most prominent warning the FDA can require — about serious adverse effects associated with these medications, such as an increased risk of endometrial and breast cancer, dementia, and cardiovascular diseases.[7]

In November 2025 the FDA announced that it would remove the information in the boxed warning about cardiovascular risk as well as some other safety warnings, as discussed in the January issue of Worst Pills, Best Pills News.[8] A consideration in this decision was recent analyses of the trials’ data[9] as well as other studies[10] that suggested that the cardiovascular risk varies with patient age and the timing of treatment. The FDA requested that the updated drug label include information about treatment timing.[11]

The label changes should be made in 2026.

The Women’s Health Initiative trials

The Women’s Health Initiative trials were conducted in the 1990s. The trials included two studies that enrolled more than 27,000 postmenopausal women between the ages of 50 and 79 (with an average age of 63 years at the time of enrollment) to assess whether hormone therapy reduced the risk of coronary heart disease.[12]

The participants were randomized to receive either placebo or conjugated equine estrogens (estrogen only) if they had a hysterectomy (no longer have a uterus) or conjugated equine estrogens plus medroxyprogesterone acetate (combination therapy) if they still had their uterus. Using estrogen alone can increase the risk of endometrial cancer for women who have not had a hysterectomy,[13] which is why women with a uterus should take estrogen in combination with a progestin, whereas women who have had a hysterectomy do not need to add progestin.

Both trials were stopped early because compared with placebo, hormone therapy was associated with increased risks, including the risk of stroke, breast cancer and pulmonary embolism.[14] According to the researchers, these risks outweighed the observed benefits (such as reduced risks of fracture and colorectal cancer).

The new analysis

For the secondary analysis, researchers used data from the two Women’s Health Initiative hormone therapy trials.[15] The primary outcome was the effect of hormone therapy on atherosclerotic cardiovascular disease (including nonfatal heart attack, ischemic stroke and peripheral arterial disease [reduced blood flow to the extremities due to narrowed arteries]). The analysis also assessed the treatment’s efficacy for vasomotor symptoms.

Because the researchers were interested in whether these outcomes differed by age, they divided the participants into three age cohorts: participants between the ages of 50 and 59 years, 60 and 69 years, and 70 and 79 years.[16]

The analysis found that across both trials, women in their fifties had low cardiovascular risk due to hormone therapy and, compared with placebo, experienced an estimated 13 and six fewer atherosclerotic cardiovascular events per 10,000 person-years in the estrogen-only trial and combination-therapy trial, respectively.[17]

Women in their seventies were at high risk, with 217 and 382 excess events per 10,000 person-years compared with placebo in the estrogen-only and combination-therapy trials, respectively. These risks persisted even after adjusting for cardiovascular disease risk factors, such as body mass index and waist circumference.

The effects of hormone therapy for women in their sixties, however, were less certain: The cardiovascular risks were higher in one trial and lower in the other trial. Although there were no clear safety signals, the authors concluded that any increased risk is of concern because cardiovascular risks generally increase with age.[18]

The analysis also found that hormone therapy across both trials effectively reduced vasomotor symptoms in younger women. However, symptom relief was diminished with increasing age, especially for those who received combination therapy.[19]

Important caveats

The new study has important limitations. The secondary analysis was not planned at the time the data were collected decades ago and can thus be difficult to interpret.[20] For example, the original trials were not designed to assess atherosclerotic cardiovascular risk as the primary outcome, or the efficacy of hormone therapy on vasomotor symptoms. For this reason, the number of participants whose data were analyzed was relatively small.

Additionally, the data are old — they were collected between 1993 and 1998 — and were reanalyzed between 2024 and 2025. Importantly, non-cardiovascular outcomes or newer doses and formulations of hormone therapy were not studied (for example, older hormone therapy regimens often were higher-dose, oral formulations).[21] Further evidence is needed to confirm these findings and to assess the long-term risks of newer hormone therapy formulations, such as lower-dose gels.[22]

Still, the findings generally align with the recommendations of medical societies,[23] such as the Menopause Society and the American College of Obstetricians and Gynecologists.[24] According to their guidelines, hormone therapy is recommended for women younger than 60 years or those within 10 years of menopause unless there are some contraindications (such as a history of breast cancer, active liver or gallbladder disease, or a high risk of atherosclerotic cardiovascular disease).

The guidelines also generally advise against hormone therapy in older women and women with high cardiovascular risk, as well as women who are 10 or more years past menopause onset.

What You Can Do

If you experience vasomotor symptoms related to menopause, speak to your clinician about how best to address them. If nondrug approaches fail and your hot flashes are severe enough to prevent you from working or carrying out other important activities, discuss with your clinician the risks and potential benefits of hormone replacement therapy.
 

References

[1] 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 Nov 1;185(11):1330-1339.

[2] Do not use fezolinetant (VEOZAH) for the treatment of hot flashes (vasomotor symptoms). Worst Pills, Best Pills News. May 2024. https://www.worstpills.org/newsletters/view/1595. Accessed January 5, 2026.

[3] Pfizer, Inc. Label: Conjugated estrogens (PREMARIN). April 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/004782s179lbl.pdf. Accessed January 8, 2026.

[4] Pfizer, Inc. Label: Conjugated estrogens plus medroxyprogesterone acetate (PREMPHASE). April 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/020527s067lbl.pdf. Accessed January 8, 2026.

[5] Do not use fezolinetant (VEOZAH) for the treatment of hot flashes (vasomotor symptoms). Worst Pills, Best Pills News. May 2024. https://www.worstpills.org/newsletters/view/1595. Accessed January 8, 2026.

[6] 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 Nov 1;185(11):1330-1339.

[7] The Food and Drug Administration. FDA requests labeling changes related to safety information to clarify the benefit/risk considerations for menopausal hormone therapies. November 10, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-labeling-changes-related-safety-information-clarify-benefitrisk-considerations?utm_medium=email&utm_source=govdelivery. Accessed January 8, 2026.

[8] FDA removes most of the boxed warning for menopausal hormone therapy. Worst Pills, Best Pills News. January 2026. https://www.worstpills.org/newsletters/view/1700. Accessed January 8, 2026.

[9] Manson JE, Crandall CJ, Rossouw JE, et al. The Women's Health Initiative randomized trials and clinical practice: A review. JAMA. 2024 May 28;331(20):1748-1760.

[10] Cho L, Kaunitz AM, Faubion SS, et al. Rethinking menopausal hormone therapy: For whom, what, when, and how long? Circulation. 2023 Feb 14;147(7):597-610.

[11] The Food and Drug Administration. FDA requests labeling changes related to safety information to clarify the benefit/risk considerations for menopausal hormone therapies. November 10, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-labeling-changes-related-safety-information-clarify-benefitrisk-considerations?utm_medium=email&utm_source=govdelivery. Accessed January 8, 2026.

[12] Manson JE, Crandall CJ, Rossouw JE, et al. The Women's Health Initiative randomized trials and clinical practice: A review. JAMA. 2024 May 28;331(20):1748-1760.

[13] Cho L, Kaunitz AM, Faubion SS, et al. Rethinking menopausal hormone therapy: For whom, what, when, and how long? Circulation. 2023 Feb 14;147(7):597-610.

[14] Manson JE, Crandall CJ, Rossouw JE, et al. The Women's Health Initiative randomized trials and clinical practice: A review. JAMA. 2024 May 28;331(20):1748-1760.

[15] 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 Nov 1;185(11):1330-1339.

[16] Grady D, Inouye SK, Rittenberg E. Hormone therapy for menopausal vasomotor symptoms - Better understanding cardiovascular risk. JAMA Intern Med. 2025 Nov 1;185(11):1340.

[17] 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 Nov 1;185(11):1330-1339.

[18] Grady D, Inouye SK, Rittenberg E. Hormone therapy for menopausal vasomotor symptoms-Better understanding cardiovascular risk. JAMA Intern Med. 2025 Nov 1;185(11):1340.

[19] 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 Nov 1;185(11):1330-1339.

[20] Ibid.

[21] Schweitzer K. New analysis of Women's Health Initiative data aims to "clear the air" over menopausal hormone therapy. JAMA. 2025 Oct 21;334(15):1318-1320.

[22] Cho L, Kaunitz AM, Faubion SS, et al. Rethinking menopausal hormone therapy: For whom, what, when, and how long? Circulation. 2023 Feb 14;147(7):597-610.

[23] 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 Nov 1;185(11):1330-1339.

[24] Cho L, Kaunitz AM, Faubion SS, et al. Rethinking menopausal hormone therapy: For whom, what, when, and how long? Circulation. 2023 Feb 14;147(7):597-610.