Primary Concerns for Long-Term Hormone Replacement Therapy
Long-term HRT use significantly increases risks of breast cancer, cardiovascular events, venous thromboembolism, stroke, and gallbladder disease, with most risks escalating with duration of use beyond 5 years. 1, 2
Cardiovascular and Thrombotic Complications
Stroke risk increases substantially with long-term HRT, with a relative risk of 1.12 to 1.41, translating to approximately 8-9 additional strokes per 10,000 women-years. 1, 2 The risk is primarily for thromboembolic strokes rather than hemorrhagic events. 1
Venous thromboembolism risk doubles with HRT use (relative risk 2.14), with the highest danger occurring within the first year of therapy. 1, 3 After 7 years of estrogen-only therapy, the absolute risk reaches 21 per 10,000 women-years. 4 Combined estrogen-progestin therapy carries 12 additional deep venous thromboses and 9 additional pulmonary emboli per 10,000 women-years. 2
Coronary heart disease events increase with combined estrogen-progestin therapy, particularly evident shortly after initiation (hazard ratio 1.29), with 7 additional coronary events per 10,000 women-years. 3, 2 This contradicts earlier observational studies that suggested cardiovascular protection, which were confounded by socioeconomic status and healthier user bias. 3
Cancer Risks
Breast cancer risk increases significantly with combined estrogen-progestin therapy, with a relative risk of 1.26 and an absolute excess of 8 cases per 10,000 women-years. 1, 2 This risk does not appear until after 4-5 years of use and continues to escalate with longer duration. 2, 4 Notably, estrogen-only therapy in women without a uterus shows no increased breast cancer risk and may even be protective (relative risk 0.77-0.80). 2, 3
Unopposed estrogen dramatically increases endometrial cancer risk with a relative risk of 2.3, escalating to 9.5-fold after 10 years of use. 1, 3 This risk remains elevated for 5 or more years even after discontinuation. 3 Adding progestin reduces this risk by approximately 90%. 1
Ovarian cancer mortality increases with long-term HRT use, with a relative risk of 1.8-2.2, though data are inconsistent across studies. 1, 5 After 5.6 years of combined therapy, the absolute risk is 4 cases per 10,000 women-years. 5
Lung cancer mortality increases after prolonged use, with 9 additional deaths per 10,000 women-years after 5.6 years of combined therapy plus 2.4 years of follow-up. 4
Gastrointestinal Complications
Gallbladder disease requiring surgery increases 2- to 4-fold in postmenopausal women receiving estrogens. 5 Current HRT users face a relative risk of 1.8 for cholecystitis, with 20-27 additional cases per 10,000 women-years after 5.6 years of combined therapy. 1, 2
Cognitive and Neurological Risks
Probable dementia risk increases in women over 65 years taking HRT. 5 Combined estrogen-progestin therapy carries a relative risk of 2.05, with 45 cases per 10,000 women-years compared to 22 in placebo groups. 5 Estrogen-alone therapy shows a relative risk of 1.49, with 37 cases per 10,000 women-years. 5 The pooled relative risk for probable dementia is 1.76. 5
Duration-Dependent Risk Escalation
Most serious risks increase substantially after 5 years of continuous use. 1, 4 Breast cancer risk becomes significant after 4-5 years, endometrial cancer risk with unopposed estrogen reaches 9.5-fold after 10 years, and cardiovascular risks emerge within the first 1-2 years. 2, 3
Venous thromboembolism risk is highest within the first year (relative risk 3.49), then remains elevated at approximately 2-fold throughout continued use. 1, 3
Age-Related Risk Amplification
Women over 60 or more than 10 years past menopause face substantially higher risks when initiating or continuing HRT. 5, 4 In the WHI study, women over 65 had higher relative risks of stroke and invasive breast cancer. 5
Critical Clinical Pitfalls to Avoid
Never prescribe unopposed estrogen to women with an intact uterus due to unacceptable endometrial cancer risk. 1, 2 This is an absolute contraindication that dramatically increases malignancy risk. 1
HRT should never be used for chronic disease prevention (osteoporosis, cardiovascular disease) in asymptomatic women, as the unfavorable risk-benefit profile increases morbidity and mortality for this indication. 1, 2
Do not continue HRT beyond symptom management needs, as risks including stroke, venous thromboembolism, and breast cancer increase with dose and duration. 1, 2
Avoid oral estrogen formulations when possible, as transdermal preparations significantly reduce venous thromboembolism risk compared to oral preparations. 1
Risk Mitigation Strategies
Use the lowest effective dose for the shortest duration needed for symptom control to minimize risks. 1, 2 This fundamental principle applies to all HRT prescribing.
Strongly prefer transdermal 17-β estradiol over oral formulations, particularly for women with hypertension or elevated thrombotic risk, as transdermal routes bypass hepatic first-pass metabolism and reduce cardiovascular and thromboembolic complications. 1
Reassess necessity annually and attempt discontinuation once symptoms are controlled, with mandatory reevaluation at age 65. 2