Does hormone replacement therapy (HRT) increase the risk of cancer in individuals, particularly those with a history of cancer or at high risk for cancer?

Does HRT Cause Cancer?

Yes, hormone replacement therapy increases the risk of certain cancers, but the specific risk depends critically on the formulation used: combined estrogen-progestin therapy increases breast cancer risk (8 additional cases per 10,000 women-years), while unopposed estrogen dramatically increases endometrial cancer risk (RR 2.3, escalating to 9.5 after 10 years), though estrogen-only therapy in women post-hysterectomy actually reduces breast cancer risk. 1

Breast Cancer Risk: Formulation Matters

Combined estrogen-progestin therapy increases invasive breast cancer with a relative risk of 1.26 (95% CI 1.00-1.59), resulting in 8 additional invasive breast cancers per 10,000 women-years. 1 This finding from the Women's Health Initiative led to early termination of the combined therapy arm. 2

Conversely, estrogen-only therapy decreases invasive breast cancer risk, with 8 fewer invasive breast cancers per 10,000 women-years (HR 0.77,95% CI 0.62-0.95). 1 This protective effect makes estrogen-only therapy the preferred option for women who have undergone hysterectomy. 1

Duration and Timing Effects

• Current users of HRT show increased breast cancer risk that rises by a factor of 1.023 for each year of use, reaching RR 1.35 for 5+ years of use. 3
• The breast cancer risk disappears within 5 years after discontinuation of HRT. 2, 3
• Women who start HRT between ages 45-49 may have lower breast cancer risk (adjusted HR 0.54,95% CI 0.40-0.72) compared to the general population, though this may reflect selection bias. 4

Endometrial Cancer Risk: The Critical Distinction

Unopposed estrogen therapy poses the most significant 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. 2, 1 This elevated risk persists for at least 5 years after discontinuation. 2, 5

For women with an intact uterus, combined estrogen-progestin therapy protects against endometrial cancer (RR 0.71,95% CI 0.56-0.90). 1, 6 The protective effect is greater with continuous combined therapy (progestogen added daily) compared to cyclic regimens. 6

Absolute Risk Context

• The cumulative excess incidence of endometrial cancer in 1000 women using unopposed estrogen for 10 years starting at age 50 is approximately 42 cases. 7
• Combined estrogen-progestin therapy reduces this risk below baseline in women with intact uteri. 6

Ovarian Cancer Risk

Long-term HRT use (10+ years) increases ovarian cancer mortality with relative risks of 1.8-2.2. 2, 1 The evidence suggests higher risk with unopposed estrogen than with estrogen-progestin therapy, though data remain insufficient to definitively resolve formulation-specific effects. 2

Clinical Decision Algorithm

For Women with Intact Uterus:

1. Never prescribe unopposed estrogen due to unacceptable endometrial cancer risk (RR 2.3, escalating to 9.5). 1, 8
2. Use combined estrogen-progestin therapy if HRT is indicated for symptom control. 1
3. Accept the increased breast cancer risk (8 additional cases per 10,000 women-years) as the trade-off for endometrial protection. 1

For Women Post-Hysterectomy:

1. Estrogen-only therapy is strongly preferred as it reduces breast cancer risk while eliminating endometrial concerns. 1
2. This formulation provides 8 fewer breast cancers per 10,000 women-years compared to no treatment. 1

Route of Administration:

Prescribe transdermal 17-β estradiol over oral preparations whenever possible, particularly for women with cardiovascular risk factors, as transdermal formulations significantly reduce 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. 1
• Ensure annual mammography for all women using HRT. 1
• Recognize that venous thromboembolism risk peaks in the first year of use (RR 3.49). 1, 8
• Never use HRT for chronic disease prevention, as cardiovascular and cancer risks outweigh benefits for this indication. 1, 8

Absolute Risk Context for Shared Decision-Making

For every 10,000 women taking combined estrogen-progestin therapy for one year: 1, 8

• Harms: 8 additional invasive breast cancers, 8 additional strokes, 10 additional pulmonary emboli, 20 additional cases of gallbladder disease
• Benefits: 6 fewer hip fractures, 46 fewer total fractures

Special Populations

Women with BRCA gene mutations require particular caution regarding HRT use due to amplified breast cancer risk. 1, 5 These women should consider non-hormonal alternatives for menopausal symptom management whenever feasible.