Research Summary

Long-Term Hormone Therapy Shows Regimen-Specific Risks, Benefits in Menopausal Women

Edited by:
Anthony Calabro, MA

Key Highlights

  • Combined continuous hormone therapy probably increased breast cancer risk and may have increased stroke and venous thromboembolism risks.
  • Estrogen-only therapy probably increased stroke and gallbladder disease risks but made little or no difference in coronary events or breast cancer.
  • Both hormone therapy regimens probably reduced the risk of clinical fractures.
  • Most evidence came from older trials of oral hormone therapy, limiting applicability to formulations currently used in clinical practice.

Long-term health outcomes associated with menopausal hormone therapy varied according to whether women received combined estrogen-progestogen therapy or estrogen alone, according to an updated review published in the Cochrane Database of Systematic Reviews. Both regimens probably reduced fracture risk, but their effects on vascular disease, cancer, and gallbladder disease differed.

The systematic review included 24 randomized, double-blind trials involving 45,660 perimenopausal or postmenopausal women who received hormone therapy or placebo for at least 1 year. Two reviewers independently selected studies, assessed risk of bias, and extracted data. The investigators calculated risk ratios (RRs) with 95% CIs and evaluated evidence certainty using GRADE. Hormone therapy for menopausal symptom control was outside the review’s scope.

Nearly 70% of the evidence came from the Heart and Estrogen/progestin Replacement Study and Women’s Health Initiative research program. Most participants were postmenopausal US women with 1 or more comorbidities, and mean age exceeded 60 years in most studies. The principal outcome estimates summarized in the review came from the Women’s Health Initiative, which evaluated oral conjugated equine estrogen regimens.

Study Findings (Note: In accordance with GRADE terminology, “probably” indicates moderate-certainty evidence, whereas “may” indicates low-certainty evidence.)

Among 16,608 postmenopausal women with an intact uterus followed for an average of 5.6 years, combined continuous conjugated equine estrogen and medroxyprogesterone acetate probably made little or no difference in coronary events versus placebo (RR, 1.17; 95% CI, 0.95-1.44; moderate-certainty evidence). It probably increased breast cancer risk (RR, 1.27; 95% CI, 1.03-1.56) and reduced clinical fracture risk (RR, 0.78; 95% CI, 0.71-0.86), both with moderate-certainty evidence.

Combined therapy may also have increased stroke (RR, 1.39; 95% CI, 1.09-2.09), venous thromboembolism (RR, 2.03; 95% CI, 1.55-6.64), and gallbladder disease requiring surgery (RR, 1.64; 95% CI, 1.30-2.06), based on low-certainty evidence.

Among 10,739 postmenopausal women with previous hysterectomy followed for an average of 7 years, estrogen-only therapy probably increased stroke (RR, 1.33; 95% CI, 1.06-1.67) and gallbladder disease requiring surgery (RR, 1.78; 95% CI, 1.42-2.24). It probably reduced clinical fractures (RR, 0.73; 95% CI, 0.65-0.80) while making little or no difference in coronary events or breast cancer, based on moderate-certainty evidence.

Clinical Implications

According to the review authors, long-term hormone therapy risk profiles differ between combined therapy and estrogen-only therapy. The findings require cautious interpretation because the principal evidence involved older oral regimens that may not represent hormone therapy currently used in clinical practice.

Only approximately 30% of participants were aged 50 to 59 years at baseline, the population most likely to consider hormone therapy for vasomotor symptoms, and only 1 study focused on perimenopausal women. Most data came from studies of predominantly postmenopausal US women, further limiting applicability to younger patients and contemporary hormone formulations.

Expert Commentary

“These results should be interpreted with caution as they are based on one study using oral hormone therapy, which may not represent the risks of the hormone therapy currently used in clinical practice,” the researchers concluded.

Reference
Bofill Rodriguez M, Yong LN, Mirkov S, et al. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. Published September 4, 2026. doi:10.1002/14651858.CD004143.pub