Does the combination of estrogen and progesterone (hormone therapy) increase the risk of thromboembolism (blood clots)?

Combined Estrogen and Progesterone Therapy Significantly Increases Blood Clot Risk

Yes, the combination of estrogen and progesterone in hormone therapy significantly increases the risk of blood clots (thromboembolism) by approximately 2-3 fold compared to non-users. 1

Evidence for Increased Thrombotic Risk

Venous Thromboembolism Risk

• Meta-analysis of 12 studies (including randomized controlled trials, case-control studies, and cohort studies) demonstrated that hormone replacement therapy (HRT) was associated with a more than doubled risk of venous thromboembolism (RR 2.14; 95% CI 1.64-2.81) 1
• The Women's Health Initiative (WHI) study confirmed this finding, showing a two-fold increased rate of venous thromboembolic disease (RH 2.11; 95% CI 1.26-3.55) in women taking combined estrogen-progestin therapy 1
• The Heart and Estrogen/progestin Replacement Study (HERS) found a relative hazard of 2.7 (95% CI 1.4-5.0) for venous thromboembolic events in women taking combined hormone therapy 2

Timing of Risk

• The risk of venous thromboembolism is highest within the first year of hormone therapy use (RR 3.49; 95% CI 2.33-5.59) 1
• This elevated risk persists throughout treatment but appears to be most pronounced during initial therapy 1

Stroke Risk

• Combined estrogen-progestin therapy is associated with increased stroke incidence (RH 1.41; 95% CI 0.86-2.31) 1
• The increased stroke risk is primarily due to thromboembolic stroke (RR 1.20; 95% CI 1.01-1.40) rather than hemorrhagic stroke 1

Mechanisms of Thrombosis

• Estrogen, with or without progestin, affects multiple hemostatic pathways in a prothrombotic direction 1:

  • Increases factor VII activity, D-dimer, and prothrombin F1.2 1
  • Decreases anti-thrombin III, tissue factor pathway inhibitor, and tissue plasminogen activator 1
  • Alters inflammatory markers including C-reactive protein 1

• The exact molecular mechanism of estrogen-related thrombosis is not fully understood, but the hemostatic changes create a prothrombotic environment 3

Risk Factors and Special Considerations

Route of Administration

• Oral estrogen administration carries a significantly higher thrombotic risk than transdermal administration 4, 5
• Transdermal estrogen combined with progesterone may have a lower thrombotic risk (OR ranging from 0.87 to 1.16) compared to oral formulations 5
• The American College of Rheumatology strongly recommends against combined estrogen-progestin contraceptives in women with positive antiphospholipid antibodies due to further increased thrombosis risk 1

Genetic Factors

• Prothrombotic genetic variants significantly increase thrombosis risk with hormone therapy 1:
  • Factor V Leiden carriers taking hormone therapy have significantly higher VTE risk compared to non-carriers taking placebo 1
  • Prothrombin 20210A variant in hormone therapy users with hypertension increases myocardial infarction risk 11-fold 1

Progestogen Type

• Different progestogens may confer different levels of thrombotic risk 4:
  • Norpregnanes are associated with increased thrombotic risk (HR 1.8; 95% CI 1.2-2.7) 4
  • Progesterone, pregnanes, and nortestosterones show no significant association with thrombotic risk 4

Clinical Implications

• The U.S. Preventive Services Task Force concluded there is good evidence that HRT increases the risk for venous thromboembolism 1
• For women requiring hormone therapy, transdermal estrogen formulations may be safer regarding thrombotic risk 4, 5
• Women with additional risk factors for thrombosis (history of VTE, known thrombophilia, obesity, smoking, immobility) should be particularly cautious about combined hormone therapy 6
• Local estrogen therapy (vaginal) does not appear to increase VTE risk (OR 0.69; 95% CI 0.43-1.10) 5

Monitoring and Prevention

• Women on combined hormone therapy should be educated about signs and symptoms of thromboembolism 6
• The risk of thrombosis should be carefully weighed against potential benefits of hormone therapy for each individual 1, 6
• Some medications may modify thrombotic risk in hormone therapy users:
  • Aspirin and statins may decrease the relative risk of VTE in hormone therapy users 2
  • However, this potential reduction in risk should not be relied upon as primary prevention 2