A decade-by-decade secondary analysis of two randomized Women’s Health Initiative (WHI) trials supports current guidelines for treating vasomotor symptoms (VMS) with hormone therapy (HT). It reports that HT safely reduces VSM without raising the risk for atherosclerotic cardiovascular disease (ASCVD) in women aged 50-59 years but urges caution in using it for those aged 60-69 years and recommends avoidance in women aged 70 years or older.

Reporting in JAMA Internal Medicine, Jacques E. Rossouw, MD, WHI head in the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute in Bethesda, and colleagues revisited data tracking the cardiovascular and other health effects of HT in more than 27,000 women aged 50-70 years recruited from 40 sites during November 1993 to September 2012. The WHI addressed whether HT with conjugated equine estrogens (CEE) alone or combined with medroxyprogesterone acetate (MPA) could reduce the risk for coronary heart disease (CHD) in older women. (The trials were not specifically designed to assess efficacy for VMS).

“This reanalysis was prompted by suggestive earlier findings for CHD but it contributes definitive knowledge about treatment effects specifically in women with VMS,” Rossouw told Medscape Medical News.

The evidence of CHD harm, especially in older users, led to early termination of the WHI trials and prompted many women to abandon HT, which was associated with an increased risk for CHD in the oldest women that was not found in younger women. However, the small numbers of CHD events in subgroup analyses had wide CI and were inconclusive, so Rossouw and associates reanalyzed the data by age decade during December 2024 to May 2025.

Instead of CHD alone, the 2025 reanalysis was a multi-outcome composite to define ASCVD: nonfatal myocardial infarction, hospitalization for angina, coronary revascularization, ischemic stroke, peripheral arterial disease, carotid artery disease, or cardiovascular death. The median follow-up times were 7.2 years and 5.6 years for the CEE alone trial and the CEE plus MPA trial, respectively.

The review found that CEE alone reduced VMS by 41% across all age groups but with combination therapy VMS reduction diminished with age. Significantly, CEE alone or with MPA had neutral effects on ASCVD in women with moderate or severe VMS aged 50-59 years. For CEE alone, the hazard ratio (HR) was 0.85 (95% CI, 0.53-1.35) and for combination HT, the HR was 0.84 (95% CI, 0.44-1.57). While the estimated risk was higher for HT in women aged 60-69 years, no clear signal of harm emerged (CEE alone: HR, 1.31; 95% CI, 0.90-1.90; CEE plus MPA: HR, 0.84; 95% CI, 0.51-1.39).

Notably, however, in those 70 years or older, ASCVD risk rose significantly with HT. For CEE, the HR was 1.95 (95% CI, 1.06-3.59), translating to 217 excess events per 10,000 person-years (interaction P for trend = .03). For combined therapy, the HR was 3.22 (95% CI, 1.36-7.63) amounting to 382 excess events per 10,000 person-years (interaction P for trend = .02).

Explaining the age differential, Rossouw told Medscape Medical News, “Estrogen likely destabilizes existing vulnerable arterial plaques, which together with prothombotic changes then leads to thrombosis and arterial occlusion. Older women have more atherosclerotic plaques and therefore show more adverse effects than younger women. Younger women are not immune but because they have fewer plaques their risks of adverse effects are much lower.” It is not known why VMS persists in some women well past the usual age of menopause into their 70s.

According to Rossouw, “The new analysis is more robust because it has much larger numbers of outcomes.” In addition, it examined the trials separately rather than in combination. “One unexpected and unexplained finding was that women with VMS had a lower risk of venous thromboembolism due to HT than women without VMS,” he noted.

But if the WHI were done today with newer HT formulations and finer-tuned dosages, would ASCVD risks likely be lower? “We don’t know because similar large-scale trials with other HT formulations have not been performed and are unlikely to be performed, so this is likely to remain the best available evidence,” Rossouw said. “But since transdermal estradiol does not undergo first-pass hepatic circulation and therefore does not perturb hemostatic factors, it is likely to be a safer alternative to oral HT with regard to ASCVD risk.”

While clonidine and paroxetil relieve VMS in some women, the most promising option is a new class of drugs targeting the hypothalamic heat system dysregulation, which seems to underlie hot flashes and night sweats. “Fezolinetant is the first of these to be approved by the Food and Drug Administration. Aside from the adverse effects of HT on ASCVD, women are also concerned about the potential for increasing the risk of breast cancer. These newer drugs are unlikely to have that risk,” he said.

Commenting on the updated analysis, Stephanie S. Faubion, MD, MBA, director of the Mayo Clinic Center for Women's Health and medical director of the Menopause Society, called the findings very reassuring. “Hopefully, [these results] will help inform decision-making for clinicians and women who are considering hormone therapy for management of menopause symptoms.”

Faubion added that we don’t know whether the risks of initiating HT in women in their 60s or 70s would be different if those same women had started HT around the time of menopause in their 50s and continued it until their 60s or 70s. “The WHI will never be able to tell us that it’s safe to start hormone therapy in a woman in her 70s. That would require a new trial and one that had a woman starting hormone therapy in her 50s and continuing it into her 70s, which will never happen.”

Therefore, she said, this recommendation still stands: “the best candidate for HT is a woman with bothersome symptoms, no contraindications, and is under age 60 years or within 10 years of menopause onset — understanding that decision-making in clinical practice is often nuanced and also takes into account patient preferences.”

In an accompanying editorial, Deborah Grady, MD, MPH, professor emerita of epidemiology and biostatistics at University of California San Francisco, and colleagues noted several limitations of the reanalysis. First, the data are from trials initiated in the 1990s, and formulations and doses of HT have changed. “Moreover, we should keep in mind that these analyses were post hoc, and multiple comparisons increased the likelihood of chance findings,” Grady and associates wrote. “Moreover, after stratification to subgroups by presence of VMS, age, and treatment, the sample sizes were modest, resulting in broad confidence intervals.”

Still, the study provides the best available evidence that HT for women in their 50s does not increase ASCVD risk, while its use by women in their 70s substantially increases it. For women in the middle decade, the risk is unclear. “A somewhat elevated risk estimate for ASCVD among this age group (OR [odds ratio], 1.32 for estrogen alone), while not statistically significant, is a signal for concern,” they cautioned. Nevertheless, “These new analyses from the WHI offer valuable guidance for understanding the impact on cardiovascular risk of menopausal HT for treatment of VMS in women over time.”

The WHI program is funded by the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the US Department of Health and Human Services. Study pills were donated by Wyeth Ayerst. Rossouw disclosed no competing interests. Several coauthors reported grants from US government research funding agencies, and others disclosed financial support from companies in the private sector. Faubion had no relevant conflicts of interest. Grady and associates had no relevant conflicts of interest but serve in editorial capacities for JAMA Internal Medicine.