Does Supplemental Estrogen Increase Risk of Breast Cancer?
The answer depends critically on whether estrogen is used alone or combined with progestin: estrogen-plus-progestin therapy clearly increases breast cancer risk by approximately 26%, while estrogen-alone therapy in women who have had hysterectomies does not significantly increase risk and may even reduce it. 1, 2
Combined Estrogen-Progestin Therapy
Combined hormone therapy definitively increases breast cancer risk and should be avoided for breast cancer risk reduction.
- The Women's Health Initiative (WHI) trial demonstrated a 26% increased incidence of breast cancer with estrogen-plus-progestin therapy (HR 1.26; 95% CI, 1.00-1.59) 1, 2
- More concerning, breast cancers diagnosed in women on combined therapy were more advanced stage than in the placebo group 1
- The risk increases with duration: each year of estrogen-progestin use increases relative risk by 0.08 (95% CI, 0.02-0.16) among recent users 3
- The Nurses' Health Study confirmed increased risk with combined therapy (RR 1.41; 95% CI, 1.15-1.74) 4
- The NCCN recommends against HRT use for women taking tamoxifen or raloxifene outside clinical trials 1, 2
Estrogen-Alone Therapy
Estrogen-alone therapy in women who have had hysterectomies does not significantly increase breast cancer risk based on the highest quality randomized trial data.
- The WHI estrogen-only arm showed no significant increase in breast cancer incidence after 7.1 years of follow-up (HR 0.80; 95% CI, 0.62-1.04; P = 0.09) 1, 2
- The breast cancer rate was actually lower in the estrogen group compared to placebo, though not statistically significant 1
Important Caveat on Duration
However, large observational studies suggest long-term estrogen-alone use (≥10-20 years) may increase risk, creating a nuanced picture:
- The Million Women Study showed increased risk with current estrogen-only use (RR 1.30; 95% CI, 1.21-1.40; P < 0.0001) 1, 2
- The Nurses' Health Study demonstrated significantly increased risk after ≥20 years of estrogen-alone use (RR 1.42; 95% CI, 1.13-1.77) 1, 2
- The Black Women's Health Study showed a trend toward increased risk with ≥10 years of use (RR 1.41; 95% CI, 0.95-2.10), though not statistically significant 1
Critical Distinctions in the Evidence
The apparent contradiction between WHI randomized trial data and observational studies likely reflects differences in timing and duration of exposure:
- WHI participants often started HRT years after menopause and had shorter exposure periods 1
- Observational study participants typically initiated HRT at menopause and continued for longer durations 1
- One hypothesis suggests short-term estrogen after estrogen deprivation may induce apoptosis of occult tumors, while long-term use may promote new tumor growth 1
Body Mass Index Matters
The breast cancer risk from hormone therapy is modified by body weight:
- Among women with BMI ≤24.4 kg/m², the risk increase per year of estrogen-progestin use was 0.12 (95% CI, 0.02-0.25) 3
- Risk in heavier women did not increase with either estrogen-only or estrogen-progestin therapy 3
Additional Considerations
Beyond breast cancer incidence, estrogen therapy affects breast cancer detection:
- Both estrogen-alone and estrogen-progestin therapy significantly increase mammographic breast density 1
- This leads to increased rates of abnormal mammograms and may interfere with cancer detection 1
- Estrogen-alone therapy doubled the risk of benign proliferative breast disease 1
Clinical Bottom Line
For women with intact uteri: Combined estrogen-progestin therapy increases breast cancer risk and should be used only when benefits clearly outweigh risks, at the lowest effective dose for the shortest duration needed 1, 2
For women who have had hysterectomies: Estrogen-alone therapy does not significantly increase breast cancer risk in the short-to-medium term (up to 7 years), though very long-term use (≥20 years) may carry some increased risk based on observational data 1, 2