Does Hormone Replacement Therapy Cause Cancer in Women?
Yes, hormone replacement therapy increases the risk of certain cancers in women, particularly breast cancer with combined estrogen-progestin therapy and endometrial cancer with unopposed estrogen, though the magnitude and type of risk depends critically on the specific HRT formulation used. 1, 2
Breast Cancer Risk
Combined estrogen-progestin therapy definitively increases invasive breast cancer risk with a relative risk of 1.26 (95% CI 1.00-1.59), translating to 8 additional invasive breast cancers per 10,000 women-years of use. 1, 2 This risk is particularly elevated for estrogen receptor-positive and low-grade tumors. 3
Critically, estrogen-only therapy shows the opposite effect, with 8 fewer invasive breast cancers per 10,000 women-years (HR 0.77,95% CI 0.62-0.95). 2 This paradoxical protective effect makes formulation selection crucial.
The increased breast cancer risk with combined therapy dissipates rapidly after cessation, disappearing within 2 years, suggesting hormone-dependent tumors may regress when hormonal stimulation is removed. 3
Endometrial Cancer Risk - The Most Dramatic Effect
Unopposed estrogen therapy poses the most severe cancer risk, with a relative risk of 2.3 (95% CI 2.1-2.5) that escalates dramatically to 9.5 after 10 years of use. 4, 1, 5 This elevated risk persists for at least 5 years after discontinuation. 1
The critical clinical pitfall to avoid: Never prescribe unopposed estrogen to women with an intact uterus. 2, 5 This represents an unacceptable endometrial cancer risk.
Combined estrogen-progestin therapy protects against endometrial cancer when progestogen is added, with continuous combined regimens showing a reduced risk (RR 0.71,95% CI 0.56-0.90). 6 The protective effect increases with more days per month of progestogen use and is greatest in obese women. 6
Ovarian Cancer Risk
Long-term HRT use (10+ years) associates with increased ovarian cancer mortality, with relative risks of 1.8-2.2. 1, 5 Evidence suggests higher risk with unopposed estrogen than combined therapy, though data remain insufficient to definitively resolve effects of different formulations. 4
Risk-Benefit Context and Absolute Numbers
For every 10,000 women taking combined estrogen-progestin therapy for one year, expect:
- 8 additional invasive breast cancers 2
- 8 additional strokes 5
- 10 additional pulmonary emboli 5
- 20 additional cases of gallbladder disease 2
Against these risks, combined therapy provides:
Formulation-Specific Guidance
For women with an intact uterus: Combined estrogen-progestin therapy is mandatory to prevent endometrial cancer, accepting the increased breast cancer risk. 1 Continuous combined preparations (progestogen added daily) provide superior endometrial protection compared to cyclic regimens. 6
For women post-hysterectomy: Estrogen-only therapy is preferred, as it reduces breast cancer risk while eliminating endometrial cancer concerns. 2
Route of administration matters: Transdermal estradiol is strongly preferred over oral formulations, particularly for women with cardiovascular risk factors, as it significantly reduces thrombotic risk (odds ratio 0.9 vs 4.2 for oral). 1, 5
Essential Risk Mitigation Strategies
- Use the lowest effective dose for the shortest duration needed for symptom control 5
- Prescribe transdermal 17-β estradiol over oral preparations when possible 1, 5
- Ensure annual mammography for all women using HRT 1
- Recognize that venous thromboembolism risk peaks in the first year of use (RR 3.49) 2, 5
- Never use HRT for chronic disease prevention—cardiovascular and cancer risks outweigh benefits for this indication 2, 5
Special Populations
Women with BRCA gene mutations require particular caution regarding HRT use due to amplified breast cancer risk. 1
The overall cancer burden differs by formulation: when endometrial and breast cancers are combined, there is greater total cancer incidence with combined HRT (both continuous and cyclic) than with other therapies, despite the endometrial protection. 6