What are the risks associated with Hormone Replacement Therapy (HRT)?

Risks Associated with Hormone Replacement Therapy (HRT)

HRT increases the risk of breast cancer, venous thromboembolism, stroke, and gallbladder disease, while its effects on cardiovascular disease vary by formulation and timing of initiation. 1, 2

Cardiovascular Risks

Heart Disease

• Combined estrogen-progestin therapy (CEE/MPA) increases coronary heart disease (CHD) risk:
  • 7 additional CHD events per 10,000 women-years 1
  • Risk appears highest in the first year of use 1
  • Women's Health Initiative (WHI) study showed a 26% increased incidence of CHD with combined HRT 1

Stroke

• Increased risk with both estrogen-alone and combined therapy:
  • 8 additional strokes per 10,000 women-years 1, 2
  • Risk persists throughout treatment duration 2

Venous Thromboembolism (VTE)

• 2-fold greater rate of VTE with combined HRT:
  • 34 vs 16 cases per 10,000 women-years compared to placebo 2
  • Risk highest in first year of use but persists throughout treatment 2
  • Risk increases with age, obesity, and genetic predisposition to thrombosis 1

Cancer Risks

Breast Cancer

• Combined HRT (estrogen plus progestin):

  • 26% increased risk (HR 1.26) 1
  • 8 additional cases per 10,000 women-years 1, 2
  • Cancers diagnosed at more advanced stages 2
  • Risk increases with duration of use and can persist for years after discontinuation 2

• Estrogen-alone therapy (in women with hysterectomy):

  • No significant increased risk observed in WHI study (HR 0.80) 1, 2
  • May increase mammographic breast density and abnormal mammograms 1

Endometrial Cancer

• Unopposed estrogen (without progestin) in women with intact uterus:

  • 2-12 fold increased risk 2
  • Risk increases with duration (15-24 fold for 5-10+ years of use) 2
  • Risk persists 8-15+ years after discontinuation 2

• Combined HRT (estrogen plus progestin):

  • No increased risk; may even decrease risk 1, 2

Ovarian Cancer

• WHI showed non-significant increased risk with combined HRT:
  • Relative risk 1.58 (95% CI, 0.77-3.24) 2
  • 1 additional case per 10,000 women-years 2
• Meta-analysis showed 41% increased risk with current HRT use 2

Other Risks

Gallbladder Disease

• 1.8-2.5 fold increased risk of cholecystitis 1
• 48% increased risk of biliary tract surgery 1

Dementia

• In women over 65 years:
  • 2-fold increased risk with combined HRT 2
  • 23 additional cases per 10,000 women-years 2

Risk Variations by Formulation and Patient Factors

Formulation Differences

• Estrogen-alone therapy has different risk profile than combined therapy:
  • Lower breast cancer risk
  • Still increases stroke and VTE risk
  • Increases endometrial cancer risk in women with intact uterus 1, 2

Route of Administration

• Transdermal estradiol may have lower VTE risk than oral formulations, especially in women with hypertension 1
• 17-β estradiol is preferred to ethinylestradiol or conjugated equine estrogens 1

Clinical Decision Making

Risk-Benefit Assessment

• For short-term menopausal symptom management:

  • Benefits may outweigh risks for severe symptoms
  • Use lowest effective dose for shortest duration 1

• For long-term chronic disease prevention:

  • Risks likely outweigh benefits for most women 1, 3
  • Not recommended solely for cardiovascular disease prevention 1

Special Populations

• Women with premature ovarian insufficiency (POI):
  • HRT recommended until average age of natural menopause
  • Benefits outweigh risks for cardiovascular and bone protection 1

Key Recommendations for Clinical Practice

1. Limit duration: Use HRT for shortest time possible to manage menopausal symptoms
2. Individualize therapy: Consider patient's age, time since menopause, and risk factors
3. Regular reassessment: Annual review of risks and benefits
4. Inform patients: Discuss both short-term risks (VTE, stroke) and long-term risks (breast cancer)
5. Consider alternatives: Non-hormonal options for osteoporosis prevention and symptom management

The absolute risk increase for an individual woman in a single year is small, but risks accumulate with longer-term use 1.