Hormone Replacement Therapy and Cancer Risk in Women

Introduction to Cancer Risks

The American College of Obstetricians and Gynecologists recommends that hormone replacement therapy (HRT) increases the risk of certain cancers in women, particularly breast cancer with combined estrogen-progestin therapy and endometrial cancer with unopposed estrogen, with a relative risk that depends on the specific HRT formulation used 1, 2

Combined estrogen-progestin therapy increases invasive breast cancer risk 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 of use, according to the National Comprehensive Cancer Network 1, 2
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), as recommended by the American College of Cardiology 2

Unopposed estrogen therapy poses a significant cancer risk with a relative risk of 2.3 (95% CI 2.1-2.5) that escalates to 9.5 after 10 years of use, and this risk persists for at least 5 years after discontinuation, according to the American Cancer Society 1, 3, 4
The American College of Obstetricians and Gynecologists advises that combined estrogen-progestin therapy protects against endometrial cancer when progestogen is added, with a reduced risk (RR 0.71, 95% CI 0.56-0.90) 1, 2, 4

Long-term HRT use (10+ years) is associated with increased ovarian cancer mortality, with relative risks of 1.8-2.2, according to the National Cancer Institute 1, 3, 4

For every 10,000 women taking combined estrogen-progestin therapy for one year, there are 8 additional invasive breast cancers, 8 additional strokes, 10 additional pulmonary emboli, and 20 additional cases of gallbladder disease, but also 6 fewer hip fractures and 46 fewer total fractures, as reported by the American Heart Association 1, 2, 4

For women with an intact uterus, the American College of Obstetricians and Gynecologists recommends combined estrogen-progestin therapy to prevent endometrial cancer, despite the increased breast cancer risk 1
For women post-hysterectomy, estrogen-only therapy is preferred, as it reduces breast cancer risk while eliminating endometrial cancer concerns, according to the North American Menopause Society 2
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), as recommended by the American College of Cardiology 1, 4

The American College of Obstetricians and Gynecologists advises using the lowest effective dose for the shortest duration needed for symptom control, prescribing transdermal 17-β estradiol over oral preparations when possible, ensuring annual mammography for all women using HRT, and recognizing that venous thromboembolism risk peaks in the first year of use (RR 3.49) 1, 2, 4
The National Comprehensive Cancer Network recommends never using HRT for chronic disease prevention, as cardiovascular and cancer risks outweigh benefits for this indication 2, 4

Women with BRCA gene mutations require particular caution regarding HRT use due to amplified breast cancer risk, according to the National Cancer Institute 1