What is the risk of Venous Thromboembolism (VTE) with transdermal estrogen therapy?

Venous Thromboembolism Risk with Transdermal Estrogen

Transdermal estrogen therapy is associated with minimal to no increased risk of venous thromboembolism (VTE) compared to the significantly elevated risk seen with oral estrogen formulations. 1

Risk Comparison Between Routes of Administration

• Transdermal estrogen has an odds ratio (OR) of approximately 0.9 (95% CI: 0.4-2.1) for VTE risk, which represents no significant increase compared to non-users 1
• In contrast, oral estrogen significantly increases VTE risk with an OR of 4.2 (95% CI: 1.5-11.6) 1
• Meta-analysis data confirms this difference, with pooled risk ratios of 1.0 (95% CI: 0.9-1.1) for transdermal estrogen versus 1.9 (95% CI: 1.3-2.3) for oral estrogen 2

Biological Mechanism for Lower Risk

• Transdermal estrogen administration bypasses first-pass liver metabolism, resulting in:
  • Minimal effects on hemostatic variables 2
  • No significant increase in thrombin generation 2
  • No induction of resistance to activated protein C 2
  • Neutral effect on Sex Hormone Binding Protein (SHBP) levels, a marker of VTE risk 1

Special Populations and Risk Considerations

Women with Prothrombotic Mutations

• Women with Factor V Leiden or prothrombin G20210A mutations using transdermal estrogen do not have additional VTE risk beyond that conferred by the mutation alone (OR: 4.4; 95% CI: 2.0-9.9) 3
• In contrast, the combination of oral estrogen and prothrombotic mutations results in a 25-fold increased risk of VTE compared to non-users without mutations 3

Overweight and Obese Women

• Transdermal estrogen does not confer additional VTE risk in overweight women (OR: 2.9; 95% CI: 1.5-5.8) compared to non-users with increased BMI (OR: 2.7; 95% CI: 1.7-4.5) 4
• Similarly, obese women using transdermal estrogen (OR: 5.4; 95% CI: 2.1-14.1) have comparable risk to obese non-users (OR: 4.0; 95% CI: 2.1-7.8) 4
• In contrast, the combination of oral estrogen with overweight or obesity dramatically increases VTE risk (OR: 10.2 and 20.6, respectively) 4

Women with History of VTE

• Transdermal estrogen does not appear to increase the risk of recurrent VTE in women with prior VTE history 2
• This makes transdermal estrogen a potentially safer option for women with previous thrombotic events who require hormone therapy 2

Clinical Considerations and Contraindications

• Despite the improved safety profile of transdermal estrogen, it should still be used with caution in:
  • Women with antiphospholipid antibodies, as any estrogen therapy is contraindicated due to thrombosis risk 1
  • Patients with systemic lupus erythematosus (SLE), particularly those with moderate to severe disease activity 1
  • Women with multiple prothrombotic risk factors 1

Practical Recommendations

• For women requiring hormone therapy who have:

  • History of VTE or high VTE risk: Transdermal estrogen is the preferred route if estrogen therapy is necessary 1, 2
  • Obesity: Transdermal estrogen should be considered to avoid the multiplicative risk seen with oral formulations 4
  • Known thrombophilia: Transdermal estrogen is significantly safer than oral formulations 3
  • Antiphospholipid antibodies: Consider avoiding all estrogen therapy and using progestin-only or non-hormonal options 1

• When initiating transdermal estrogen therapy, use the lowest effective dose to further minimize any potential risk 1