Published in JAMA Internal Medicine, the investigation revisited data from the landmark Women’s Health Initiative (WHI) hormone therapy trials. Jacques E. Rossouw, MD, of the National Heart, Lung, and Blood Institute, and colleagues examined outcomes in 27,347 postmenopausal participants, aiming to clarify which women with moderate to severe VMS might safely benefit from hormone therapy (HT).
The analysis included women aged 50 to 79 years from 40 U.S. clinical centers who were followed for up to eight years. Participants received either daily conjugated equine estrogens (CEE) 0.625 mg alone, CEE combined with medroxyprogesterone acetate (MPA) 2.5 mg, or placebo. The primary focus was the incidence of atherosclerotic cardiovascular disease (ASCVD), encompassing nonfatal heart attack, angina requiring hospitalization, coronary revascularization, ischemic stroke, peripheral arterial disease, carotid artery disease, or cardiovascular death.
The following were the key findings of the study:
- Hormone therapy significantly relieved moderate or severe vasomotor symptoms (VMS) in women enrolled at baseline.
- CEE alone reduced VMS by about 41% across all age groups.
- The combination of CEE plus MPA showed the greatest benefit in younger women, with effectiveness declining with age.
- Relative risk reductions for VMS were 59% in women aged 50–59, 28% in women aged 60–69, and showed virtually no benefit in those aged 70–79.
- Cardiovascular outcomes demonstrated a clear age-related pattern.
- Women aged 50–59 with bothersome VMS had no significant change in atherosclerotic cardiovascular disease (ASCVD) risk with CEE alone (HR 0.85) or CEE plus MPA (HR 0.84).
- Women aged 60–69 showed a slight, non-significant increase in ASCVD risk with CEE alone (HR 1.31), while combination therapy remained neutral.
- Women aged 70 and older experienced marked risk increases: CEE alone nearly doubled ASCVD events (HR 1.95) and CEE plus MPA more than tripled them (HR 3.22), adding hundreds of cases per 10,000 person-years.
These findings reinforce current guidance that favors menopausal hormone therapy for healthy, recently postmenopausal women suffering moderate to severe hot flashes or night sweats, while advising caution after age 60 and recommending against initiation after age 70. The authors note that only oral CEE and MPA were tested, and some subgroups were small, but emphasize that new large trials in this population are unlikely.
"Overall, the WHI secondary analysis provides reassurance that hormone therapy can be a safe and effective option for symptom relief in younger postmenopausal women when carefully selected, while highlighting significant cardiovascular dangers in older women with ongoing vasomotor complaints," the authors concluded.
Reference:
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. Published online September 15, 2025. doi:10.1001/jamainternmed.2025.4510
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