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

Risks Associated with Hormone Replacement Therapy (HRT)

Hormone replacement therapy carries significant risks including increased risk of breast cancer, venous thromboembolism, stroke, and cardiovascular events, particularly with combined estrogen-progestin formulations. 1, 2

Major Risks by Type of HRT

Combined Estrogen-Progestin Therapy

• Breast Cancer:

  • Increased risk with relative risk of 1.24 and absolute risk of 41 versus 33 cases per 10,000 women-years 2
  • Women taking estrogen and progestin for 1 year might experience 8 more invasive breast cancers per 10,000 women 1
  • Breast cancers in women on combined therapy were larger, more likely node-positive, and diagnosed at more advanced stages 2

• Cardiovascular Disease:

  • Increased risk of coronary heart disease (7 additional CHD events per 10,000 women-years) 3
  • Early increased risk of cardiovascular events in the first 1-2 years of therapy 1

• Venous Thromboembolism (VTE):

  • 2-fold greater rate of VTE (35 versus 17 per 10,000 women-years) 2
  • Increased risk for both deep vein thrombosis (26 versus 13 per 10,000 women-years) and pulmonary embolism (18 versus 8 per 10,000 women-years) 2
  • Risk appears during the first year and persists 2

• Stroke:

  • Increased risk (8 more strokes per 10,000 women-years) 3

Estrogen-Only Therapy

• Endometrial Cancer:

  • 2-12 times greater risk in women with an intact uterus using unopposed estrogen 2
  • Risk increases with duration of treatment (15-24 fold for 5-10+ years) 2
  • Risk persists for at least 8-15 years after discontinuation 2

• Venous Thromboembolism:

  • Increased risk, though lower than with combined therapy 1

• Stroke:

  • Increased risk, though data are less conclusive than for combined therapy 3

• Breast Cancer:

  • Estrogen-alone therapy shows smaller increased risk compared to combined therapy 2
  • In the WHI estrogen-alone substudy, no increased risk was observed (RR 0.80) 2

Additional Risks

• Ovarian Cancer:

  • Non-significant increased risk (relative risk 1.58,95% CI 0.77-3.24) 2
  • Some epidemiologic studies associate HRT use for 5+ years with increased risk 2

• Gallbladder Disease:

  • Increased risk of cholecystitis 3, 2

• Dementia:

  • In women 65-79 years, increased risk of probable dementia (37 versus 25 cases per 10,000 women-years) 2

Risk Factors That Increase HRT Dangers

• Age: Risk increases with age, particularly for women over 60 1
• Smoking: Creates synergistic risk for cardiovascular events 1
• Pre-existing conditions:
  • History of breast cancer
  • Recent venous thromboembolism
  • Active liver disease
  • Uncontrolled hypertension 1
• Duration of use: Risks of breast cancer increase with longer duration of use 2
• Genetic factors: Women with prothrombin variants may have significantly increased risk of MI when using HRT 3

Risk Mitigation Strategies

1. Formulation Selection:

   • Transdermal estradiol is preferred over oral formulations due to lower risk of venous thromboembolism, stroke, and gallbladder disease 1
   • Natural micronized progesterone has a more favorable safety profile than synthetic alternatives 1

2. Dosing Considerations:

   • Use lowest effective dose (starting with 25-50 μg/day transdermal estradiol) 1
   • Consider shorter duration of therapy (5 years or less) 4

3. Monitoring:

   • Annual clinical review with attention to compliance 1
   • Regular monitoring for signs of cardiovascular events, VTE, and breast changes 1
   • Annual gynecological assessment including pelvic examination 1

Special Populations

• Women with intact uterus: Must receive progestogen with estrogen to prevent endometrial cancer 1, 2
• Women with history of breast cancer: HRT is contraindicated 1
• Smokers over age 35: HRT should be prescribed with extreme caution due to significantly increased cardiovascular risks 1

In conclusion, while HRT can effectively manage menopausal symptoms, the significant risks associated with therapy must be carefully weighed against potential benefits. The decision to use HRT should prioritize mortality, morbidity, and quality of life outcomes, with careful consideration of individual risk factors and appropriate selection of formulation, dose, and duration.