A 34-study meta-analysis splits hormone therapy's breast cancer signal by regimen

Menopausal hormone therapy's relationship to breast cancer risk has been debated for two decades, complicated by the fact that "hormone therapy" describes several distinct regimens with different risk profiles. A meta-analysis published this month in Annals of Medicine, pooling 34 studies, tries to resolve some of that ambiguity by splitting the analysis by regimen type rather than treating hormone therapy as one exposure [s1].

The design

Researchers searched four databases — CNKI, Wanfang, PubMed, and Web of Science — from inception through August 2024, screening studies that examined breast cancer risk following menopausal hormone therapy [s1]. Thirty-four studies were ultimately included and pooled under a random-effects model, following PRISMA reporting guidelines [s1].

The headline number, and why it's misleading on its own

Across all 34 studies pooled together, hormone therapy was associated with a modest but statistically significant increase in breast cancer risk: odds ratio 1.15 (95% CI 1.09–1.22) [s1]. But that pooled estimate came with very high heterogeneity — a statistical measure (I² = 92.4%) indicating the individual studies disagreed with each other substantially, which is a signal that averaging them into one number obscures more than it reveals [s1].

Splitting by regimen resolved most of that disagreement

When the researchers stratified by hormone type, use status, and region, much of the heterogeneity resolved [s1]. The risk turned out to be concentrated almost entirely in estrogen-progestin therapy (EPT): odds ratio 1.44 (95% CI 1.26–1.64) [s1]. Estrogen-only therapy (ET) — typically used by women who have had a hysterectomy and don't need a progestin to protect the uterine lining — showed no overall association with breast cancer risk: odds ratio 1.00 (95% CI 0.91–1.10) [s1].

The estrogen-only finding split further by study design. Randomized controlled trials of estrogen-only therapy found a protective association — odds ratio 0.78 (95% CI 0.70–0.87) — while observational studies of the same regimen found a neutral one [s1]. That trial-versus-observational divergence for estrogen-only therapy is itself a notable finding, since it suggests the two study designs are capturing something different, possibly related to when in life women started ET relative to menopause, healthy-user biases in observational cohorts, or other confounding the trials' randomization controls for.

Geography mattered too

The researchers found the estrogen-progestin association varied meaningfully by region [s1] — the paper describes region as a significant effect modifier alongside hormone type and study type, though the specific regional breakdown of estimates is not detailed in the abstract. Combined with the type-of-therapy split, the authors describe the overall picture as one where breast cancer risk from hormone therapy is "modified by regimen and regional factors" rather than a single figure applicable everywhere [s1].

What this means, and what it doesn't

This meta-analysis reinforces a distinction that has been part of the hormone therapy safety conversation since the Women's Health Initiative: that combined estrogen-progestin regimens and estrogen-only regimens are not interchangeable when it comes to breast cancer risk, and pooling them together — which some earlier, smaller analyses have done — can produce a misleading composite number. It does not establish causation on its own; meta-analyses inherit the limitations of the studies they pool, including differing populations, hormone formulations, dosing, and duration of use across 34 different studies spanning multiple countries and eras. The paper does not report how many of the 34 included studies were randomized trials versus observational cohorts overall, only that study type was a significant modifier within the estrogen-only subgroup specifically.

What to watch

Whether future analyses can further separate risk by specific hormone formulations, doses, and duration of use — factors this pooled analysis groups under broader regimen categories. This article is not medical advice; hormone therapy decisions weigh breast cancer risk against therapy's effects on menopausal symptoms and other health outcomes, a balance that depends on individual history and should be discussed with a clinician.

Sources

1. Relationship between menopausal hormone therapy and incidence risk of breast cancer: systematic review and meta-analysis — Annals of Medicine, 10 March 2026