Highlights
- Long-term hormone therapy offers modest fracture protection but carries specific cardiovascular and cancer risks.
- Risk profiles differ substantially between combined estrogen-progestogen therapy and estrogen-only therapy.
- Combined therapy appears linked to increased breast cancer and venous thromboembolism risk.
- Evidence predominantly from oral hormone therapy; applicability to modern regimens is uncertain.
Background
Menopause and the perimenopausal transition often bring vasomotor symptoms, mood changes, and increased risk of osteoporosis. Historically, hormone therapy (HT) was widely prescribed not only for symptom relief but also for prevention of chronic disorders such as cardiovascular disease and dementia. However, pivotal trials from the late 1990s and early 2000s challenged the assumption that HT could safely confer long-term preventive benefits. This updated Cochrane review, first published in 2005, evaluates the long-term effects (≥1 year) of hormone therapy on critical outcomes including mortality, cardiovascular events, cancer, gallbladder disease, fractures, and cognition.
Study Design
The review included 24 randomized, double-blind trials, enrolling 45,660 peri- and postmenopausal women, with new data added from two recently conducted studies as of September 2024. Most participants were postmenopausal American women over 60 years old, with one or more comorbidities; only one study enrolled perimenopausal women. Trials tested oral estrogen formulations with or without progestogens against placebo, with follow-up spanning several years. Key data were derived from the Heart and Estrogen/progestin Replacement Study (HERS 1998) and the Women’s Health Initiative (WHI 1998), including estrogen-only and combined estrogen-progestogen arms dependent on uterus status.
Key Findings
Combined Continuous Hormone Therapy (CEE + MPA; intact uterus)
- Coronary events: Probably little to no difference (RR 1.17, 95% CI 0.95–1.44; moderate-certainty).
- Stroke: Possible increased risk (RR 1.39, 95% CI 1.09–2.09; low-certainty).
- Venous thromboembolism: Increased risk (RR 2.03, 95% CI 1.55–6.64; low-certainty).
- Breast cancer: Probable increased risk (RR 1.27, 95% CI 1.03–1.56; moderate-certainty).
- Lung cancer: Little to no difference (RR 1.06, 95% CI 0.77–1.46; moderate-certainty).
- Gallbladder disease requiring surgery: Increase (RR 1.64, 95% CI 1.30–2.06; low-certainty).
- Fractures: Probable reduction in risk (RR 0.78, 95% CI 0.71–0.86; moderate-certainty).
Estrogen-Only Therapy (CEE; post-hysterectomy)
- Coronary events: Probably little to no difference (RR 0.94, 95% CI 0.78–1.13; moderate-certainty).
- Stroke: Probable increased risk (RR 1.33, 95% CI 1.06–1.67; moderate-certainty).
- Venous thromboembolism: Possibly increased risk (RR 1.32, 95% CI 1.00–1.74; moderate-certainty).
- Breast cancer: Probably little to no difference (RR 0.79, 95% CI 0.61–1.01; moderate-certainty).
- Lung cancer: Little to no difference (RR 1.04, 95% CI 0.73–1.48; low-certainty).
- Gallbladder disease requiring surgery: Probable increased risk (RR 1.78, 95% CI 1.42–2.24; moderate-certainty).
- Fractures: Probable reduction (RR 0.73, 95% CI 0.65–0.80; moderate-certainty).
Expert Commentary
The findings reinforce that hormone therapy’s long-term benefit-risk balance is nuanced and must be individualized. While both combined and estrogen-only regimens confer meaningful fracture protection, cardiovascular and cancer risks differ between them. The increased incidence of stroke and gallbladder disease in both regimens is clinically significant. Particularly for combined therapy, the risk of venous thromboembolism and breast cancer must be carefully weighed, especially in older women or those with pre-existing risk factors.
Evidence predominantly comes from oral hormone therapy formulations used in the WHI era. Modern transdermal or lower-dose regimens may alter the risk profile but require robust randomized controlled data for confirmation. Notably, the study population was largely older women; results may not be fully applicable to women initiating therapy near menopause for short-term symptom control.
Conclusion
Long-term hormone therapy in menopausal women delivers consistent fracture protection but poses specific cardiometabolic and cancer risks that vary between combined and estrogen-only formulations. For women considering HT mainly for chronic disease prevention, these data argue against its routine use for cardiovascular benefit due to lack of clear protective effect and potential harm. Future research should address different administration routes, dosing strategies, and initiation timing relative to menopause onset, as well as gather safety data on contemporary hormone formulations.
Funding and Trial Registration
ClinicalTrials.gov Identifier: NCT05586724. The updated review was conducted by the Cochrane Gynaecology and Fertility Group.
References
Bofill Rodriguez M, Yong LN, Mirkov S, Bekos C, Lethaby A, Farquhar C. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2025 Nov 27;11(11):CD004143. doi: 10.1002/14651858.CD004143.pub6. PMID: 41307293; PMCID: PMC12658958.
