Menopausal Hormone Therapy Linked With Breast Cancer Risk Only When Progestin Is Involved

Menopausal hormone therapy (MHT) is associated with a modest but statistically significant increase in breast cancer risk primarily driven by estrogen-progestin therapy (EPT), according to a meta-analysis of more than 4.5 million women.¹ However, this increased risk was not observed with estrogen-only therapy (ET), which instead showed a potential protective effect.

The study, published in Annals of Medicine, included an analysis of 34 studies and is a comprehensive examination on how specific MHT formulations affect breast cancer incidence. The researchers analyzed data from 10 randomized controlled trials, 9 cohort studies, and 15 case-control studies following PRISMA guidelines. Pooled odds ratios were calculated using a random-effects model, with extensive subgroup analyses by hormone type, use status, region, treatment duration, and cancer subtype.

Overall, MHT users had 15% higher odds of breast cancer compared with non-users (OR, 1.15; 95% CI, 1.09-1.22). However, there was a stark difference based on regimen, as EPT was associated with a 44% increased risk (OR, 1.44; 95% CI, 1.26-1.64). This association was strongest for invasive breast cancer and for long-term use of 5 or more years. Current EPT users faced a 62% higher risk (OR, 1.62). Past users, on the other hand, showed no significant elevation, suggesting risk attenuates after stopping.

When looking at ET, observational studies showed no association (OR, 1.00), while randomized controlled trials showed a statistically significant protective effect (OR, 0.78; 95% CI, 0.70-0.87), robust across all sensitivity analyses. The authors noted that "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."

Geography also mattered significantly. EPT risk was twice as high in European studies (OR, 2.02) as in North American ones. North American ET studies, by contrast, suggested a modest risk reduction (OR, 0.87).

The authors noted that the elevated risk with EPT is biologically grounded, as both estrogen and progesterone play well-established roles in breast tissue proliferation, and synthetic progestins appear to amplify estrogen's growth-promoting effects. Importantly, they noted that this risk is not permanent, as evidence consistently shows it declines after discontinuation—reinforcing the value of regularly reassessing the ongoing need for combined therapy.

The protective effect seen with ET in randomized controlled trials has a plausible mechanism as well. Women enrolled in trials years after menopause have experienced prolonged estrogen deprivation. Breast cancer cells that adapt to this low-estrogen state may actually undergo apoptosis when estrogen is reintroduced, rather than being stimulated to grow. This may explain why ET appeared protective, specifically in trial populations.

The authors also stressed that not all progestogens carry equal risk. Synthetic progestins such as medroxyprogesterone acetate and norethisterone are associated with significantly higher breast cancer risk than natural micronized progesterone. The authors noted that “an accurate assessment requires careful consideration of regimen characteristics—specifically, the use of estrogen alone or combined with a progestogen and the progestogen type—alongside individual patient factors.”

All in all, these findings offer further insight into a conversation that has long been contentious following the Women’s Health Initiative linking MHT to an increased risk of both cardiovascular disease and breast cancer.² This analysis shows that the type of hormone regimen, how long it is used, whether the patient is a current or past user, and even the region of the world where she is treated all meaningfully change the risk profile.

“Critically, the association exhibits marked geographical heterogeneity, underscoring that the risk profile of MHT is not uniform but is substantially modified by the specific hormone regimen used and regional factors,” the authors concluded.

References

1. Wu Q, Shen L, Hu S, et al. Relationship between menopausal hormone therapy and incidence risk of breast cancer: systematic review and meta-analysis. Ann Med. 2026;58(1):2640244. doi:10.1080/07853890.2026.2640244

2. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA. 2004;291(1):47-53. doi:10.1001/jama.291.1.47