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

Risks of Oral Hormone Replacement Therapy

Oral hormone replacement therapy (HRT) significantly increases the risk of venous thromboembolism (VTE), stroke, gallbladder disease, and in combined estrogen-progestin formulations, breast cancer. 1

General Risks of Oral HRT

Oral HRT carries several important risks that must be considered:

• Venous thromboembolism (VTE):

  • Oral HRT increases VTE risk approximately 2-fold 1
  • Risk is highest during the first year of use 2
  • The absolute risk is about 1 per 5000 users per year 3

• Stroke:

  • Fair evidence shows increased stroke risk with oral HRT 1
  • This risk appears to be route-dependent, with oral administration being riskier than transdermal 4

• Gallbladder disease:

  • Fair evidence demonstrates increased risk of cholecystitis 1

• Breast cancer:

  • Combined estrogen-progestin therapy increases breast cancer risk 1
  • Estrogen-only therapy may have a different risk profile 1

• Cardiovascular disease:

  • Combined estrogen-progestin therapy shows a trend toward increased cardiac events (HR 1.22) 1
  • Estrogen-only therapy does not reduce CHD risk 1

Risk Factors That Increase HRT Dangers

The risks of oral HRT are significantly higher in women with:

1. History of breast cancer 1
2. Coronary heart disease 1
3. Previous venous thromboembolism or stroke 1
4. Active liver disease 1
5. Positive antiphospholipid antibodies (aPL) 1
6. Systemic lupus erythematosus (SLE) with positive aPL 1
7. Antiphospholipid syndrome (APS) 1
8. Thrombophilia 5
9. Cigarette smoking - especially when combined with other risk factors 1
10. Hypertension 4
11. Diabetes 4

Specific Recommendations for Different Patient Groups

For Women Without Autoimmune Disorders:

• Women with no risk factors: Oral HRT still carries risks but may be considered for severe vasomotor symptoms 1
• Women with cardiovascular risk factors: Transdermal estradiol is safer than oral formulations 4

For Women With Autoimmune Disorders:

• SLE without positive aPL: Conditional recommendation for HRT if needed for severe vasomotor symptoms 1
• SLE with positive aPL: HRT should be avoided due to increased thrombosis risk 1
• Asymptomatic aPL: Conditional recommendation against HRT 1
• Obstetric and/or thrombotic APS: Strong recommendation against HRT use 1
• APS on anticoagulation: Conditional recommendation against HRT use 1

Safer Alternatives to Consider

1. Transdermal estradiol:

   • Does not increase VTE risk in healthy women 4, 5
   • Better option for women with diabetes, hypertension, and cardiovascular risk factors 4

2. Micronized progesterone (when progestin is needed):

   • More favorable cardiovascular profile than synthetic progestogens 4
   • May have less impact on breast cancer risk 4

Key Considerations for Clinical Decision-Making

1. Route of administration matters: Transdermal estradiol avoids first-pass liver metabolism and has less impact on clotting factors 4

2. Duration of use: Risk appears higher during the first year of use 2

3. Age and timing: Benefits may outweigh risks in younger women (under 60) within 10 years of menopause 1

4. Dose: Use lowest effective dose for shortest duration necessary 1

5. Type of progestogen: Natural progesterone may be safer than synthetic progestogens, particularly medroxyprogesterone acetate 4

The U.S. Preventive Services Task Force recommends against routine use of HRT for prevention of chronic conditions in postmenopausal women, as the harmful effects likely exceed chronic disease prevention benefits for most women 1.