Long-term hormone therapy for perimenopausal and postmenopausal women.
Level 1 - systematic review of randomized trials
Systematic review of randomized double-blind controlled trials
PubMed 41307293 · doi:10.1002/14651858.CD004143.pub6
What was done
This updated Cochrane systematic review evaluated randomized, double-blind trials comparing hormone therapy (various estrogen formulations with or without progestogens) to placebo for at least one year in perimenopausal or postmenopausal women. Searches were updated through September 26, 2024. Reviewers assessed long-term clinical endpoints—including cardiovascular events, cancer, gallbladder disease, fractures, and mortality—and evaluated risk of bias and evidence certainty using GRADE. Menopausal symptom management was excluded.
What was found
The review included 24 studies (45,660 participants), with approximately 70% of data derived from the WHI and HERS trials. In the WHI combined continuous hormone therapy arm (CEE + MPA vs. placebo, average 5.6 years follow-up, n = 16,608): - Coronary events: RR 1.17 (95% CI 0.95 to 1.44; moderate certainty) - Stroke: RR 1.39 (95% CI 1.09 to 2.09; low certainty) - Venous thromboembolism: RR 2.03 (95% CI 1.55 to 6.64; low certainty) - Breast cancer: RR 1.27 (95% CI 1.03 to 1.56; moderate certainty) - Lung cancer: RR 1.06 (95% CI 0.77 to 1.46; moderate certainty) - Gallbladder disease requiring surgery: RR 1.64 (95% CI 1.30 to 2.06; n = 14,203; low certainty) - Clinical fractures: RR 0.78 (95% CI 0.71 to 0.86; moderate certainty) In the WHI estrogen-only arm (CEE vs. placebo in women with prior hysterectomy, average 7.0 years follow-up, n = 10,739): - Coronary events: RR 0.94 (95% CI 0.78 to 1.13; moderate certainty) - Venous thromboembolism: RR 1.32 (95% CI 1.00 to 1.74; moderate certainty) - Breast cancer: RR 0.79 (95% CI 0.61 to 1.01; moderate certainty) - Lung cancer: RR 1.04 (95% CI 0.73 to 1.48; low certainty) - Stroke: RR 1.33 (95% CI 1.06 to 1.67; moderate certainty) - Gallbladder disease requiring surgery: RR 1.78 (95% CI 1.42 to 2.24; moderate certainty) - Clinical fractures: RR 0.73 (95% CI 0.65 to 0.80; moderate certainty)
Why it matters
Long-term hormone therapy reliably prevents clinical fractures but carries distinct harms: both estrogen-alone and combined therapies increase stroke and surgical gallbladder disease, while combined therapy additionally elevates risks of venous thromboembolism and breast cancer.
Limits
Findings rely heavily on two large trials testing specific oral formulations (conjugated equine estrogens with or without medroxyprogesterone acetate) that may not generalize to transdermal or lower-dose regimens. Participants were predominantly postmenopausal women over age 60 with existing comorbidities, only ~30% were aged 50–59 years, and only one small trial examined perimenopausal women.