What are the risks of hormone replacement therapy (HRT) in menopausal women?

Risks of Hormone Replacement Therapy in Menopausal Women

Hormone replacement therapy carries significant risks including increased cardiovascular events, venous thromboembolism (particularly in the first year), breast cancer with combined therapy, and endometrial cancer with unopposed estrogen—risks that must be weighed against benefits and minimized through careful formulation selection and duration limitation.

Cardiovascular and Thrombotic Risks

Stroke

• HRT increases stroke risk with a relative risk of 1.12 to 1.41, primarily thromboembolic strokes rather than hemorrhagic 1
• The absolute excess is approximately 8 additional strokes per 10,000 women-years 1

Venous Thromboembolism

• Risk doubles with HRT use (RR 2.14,95% CI 1.64-2.81), with the highest danger occurring within the first year of therapy (RR 3.49,95% CI 2.33-5.59) 1
• This includes both deep venous thrombosis and pulmonary embolism 1
• Transdermal estrogen formulations significantly reduce this risk compared to oral preparations (odds ratio 0.9 versus 4.2 for oral) 2, 3

Coronary Heart Disease

• Combined estrogen-progestin therapy increases CHD events by 29% (RH 1.29,95% CI 1.02-1.63) rather than providing the cardiovascular protection previously assumed 2, 4
• The absolute excess is approximately 7 additional CHD events per 10,000 women-years 1, 4
• Observational studies suggesting cardiovascular benefit were confounded by selection bias (healthier women choosing HRT) 1

Cancer Risks

Breast Cancer

• Combined estrogen-progestin therapy increases invasive breast cancer risk (RH 1.26,95% CI 1.00-1.59), with an absolute excess of 8 cases per 10,000 women-years 2, 4
• The risk is greater for estrogen receptor-positive and low-grade cancers 5
• After cessation of HRT, the increased breast cancer risk dissipates within 2 years, suggesting hormone-dependent tumors may regress when stimulation is removed 5

Endometrial Cancer

• Unopposed estrogen dramatically increases endometrial cancer risk (RR 2.3,95% CI 2.1-2.5), escalating to RR 9.5 with 10 years of use 1, 2
• The elevated risk persists for at least 5 years after discontinuation 2
• Combined continuous estrogen-progestin therapy actually reduces endometrial cancer risk (RR 0.71,95% CI 0.56-0.90) 6
• Cyclic combined therapy (progestagen added 10-14 days per month) shows no significant effect on endometrial cancer risk (RR 1.05) 6
• Women with an intact uterus must receive progestogen with estrogen to prevent endometrial hyperplasia and cancer 2, 7

Ovarian Cancer

• Long-term HRT use (10+ years) associates with increased ovarian cancer mortality (RR 1.8-2.2) 1, 2
• Evidence remains inconsistent, with some studies showing no effect 1

Gastrointestinal Risks

Cholecystitis

• Current HRT users face increased cholecystitis risk (RR 1.8,95% CI 1.6-2.0) 1
• Long-term users (>5 years) have even higher risk (RR 2.5,95% CI 2.0-2.9) 1
• Risk remains elevated among past users 1

Risk Mitigation Strategies

Formulation Selection

• Transdermal 17-β estradiol is strongly preferred over oral formulations, particularly for women with hypertension or elevated thrombotic risk, as it reduces venous thromboembolism risk by approximately 80% compared to oral preparations 2, 3, 8
• Natural estrogens (17-β estradiol) have a more physiological profile than synthetic ethinyl estradiol 8

Duration and Timing

• Use the lowest effective dose for the shortest duration needed for symptom control 1, 2
• Risks such as venous thromboembolism and CHD emerge within the first 1-2 years of therapy 1
• Breast cancer risk increases with longer-term use 1
• Timing of initiation matters: women aged 50-59 years show non-significant trends toward reduced CHD (HR 0.63) and overall mortality (HR 0.71) compared to older initiators 4

Monitoring Requirements

• Annual clinical reviews with mammography are essential for women using HRT 2
• Women with BRCA gene mutations require particular caution due to breast cancer risk 2, 3

Absolute Risk Context

For 10,000 women taking combined estrogen-progestin therapy for one year, expect 1, 4:

• 7 additional CHD events
• 8 additional strokes
• 10 additional pulmonary emboli
• 8 additional invasive breast cancers
• 6 fewer colorectal cancers
• 5 fewer hip fractures

Critical Clinical Pitfalls

• Never prescribe unopposed estrogen to women with an intact uterus—the endometrial cancer risk is unacceptable 1, 2
• The first year of therapy carries the highest thrombotic risk; counsel patients about DVT/PE symptoms before initiation 1, 2
• Oral estrogen formulations carry substantially higher thrombotic risk than transdermal; default to transdermal unless contraindicated 2, 3, 8
• HRT should not be used for chronic disease prevention given the unfavorable risk-benefit profile for this indication 1