Relationship between menopausal hormone therapy and incidence risk of breast cancer: systematic review and meta-analysis

Menopausal hormone therapy (MHT) is widely prescribed for alleviating menopausal symptoms. Prior studies have mainly focused on individual hormone therapy formulations. This meta-analysis comprehensively synthesized evidence across various regimens to systematically evaluate the association between MHT and breast cancer risk.
We systematically searched CNKI, Wanfang, PubMed, and Web of Science from inception through August 2024. Eligible studies examining breast cancer risk following MHT were independently screened and assessed by two reviewers. The review and meta-analysis followed PRISMA guidelines.
Thirty-four studies were included. The random-effects model showed a significant but heterogeneous overall association (OR = 1.15, 95% CI: 1.09–1.22; I² = 92.4%). Subgroup analysis identified hormone type, use status, and region as key determinants (P for interaction < 0.001). Stratification by hormone type resolved much of the heterogeneity, revealing risk confined to estrogen-progestin therapy (EPT; OR = 1.44, 95% CI: 1.26–1.64), while estrogen-only therapy (ET) showed no overall association (OR = 1.00, 95% CI: 0.91–1.10). Study type, region, and sample size were significant effect modifiers. For ET, randomized controlled trials demonstrated a protective effect (OR = 0.78, 95% CI: 0.70–0.87), contrasting with neutral findings from observational studies.
MHT is associated with a modest but significant increase in breast cancer risk, primarily driven by EPT. This risk was not observed with ET in observational studies, though trials suggested a protective effect. Crucially, the association shows marked geographical heterogeneity, indicating risk is modified by regimen and regional factors.

The increased breast cancer risk associated with MHT is mainly attributable to EPT, current user in Europe, with no overall risk observed for ET.
The apparent effect of ET is critically influenced by study design, with randomized trials suggesting a protective effect, in contrast to neutral findings from observational studies.
The association between MHT and breast cancer risk is not uniform but exhibits marked geographical heterogeneity, indicating that regional factors substantially modify the risk profile.

The increased breast cancer risk associated with MHT is mainly attributable to EPT, current user in Europe, with no overall risk observed for ET.
The apparent effect of ET is critically influenced by study design, with randomized trials suggesting a protective effect, in contrast to neutral findings from observational studies.
The association between MHT and breast cancer risk is not uniform but exhibits marked geographical heterogeneity, indicating that regional factors substantially modify the risk profile.