Does oral estradiol (estrogen) increase the risk of thrombosis (blood clots)?

From the Guidelines

Oral estradiol does increase the risk of thrombosis, with a significantly higher odds ratio for venous thromboembolism compared to transdermal estrogen preparations. According to the Estrogen and Thromboembolism Risk (ESTHER) study, the odds ratio for venous thromboembolism in women using oral estrogen preparations was 4.2 (95% CI, 1.5-11.6), whereas transdermal estrogens had an odds ratio of 0.9 (95% CI, 0.4-2.1) 1. This increased risk is attributed to the first-pass metabolism of oral estradiol through the liver, which leads to increased production of clotting factors and reduced production of anticoagulant proteins.

Key points to consider:

• The risk of venous thromboembolism is higher with oral estrogen compared to transdermal or transvaginal routes 1
• Transdermal estradiol is generally considered safer regarding clot risk because it bypasses the first-pass effect, delivering estrogen directly into the bloodstream
• The clot risk from oral estradiol is most pronounced during the first year of use and decreases somewhat with continued use, though it remains elevated compared to baseline
• Patients with additional risk factors, such as smoking, obesity, personal or family history of clots, or certain genetic conditions, should be cautious when using oral estradiol

In terms of alternative options, transdermal estradiol formulations are often recommended for patients concerned about clot risk but requiring estrogen therapy. These formulations have been shown to have a neutral effect on Sex Hormone Binding Protein (SHBP) levels, a marker of VTE, whereas oral estradiol preparations increase SHBP levels independently of the progestin used 1. Overall, the choice of estrogen formulation should be individualized based on a patient's specific risk factors and medical history.

From the FDA Drug Label

Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2. 5 mg) relative to placebo.

• Oral estradiol increases the risk of thrombosis (blood clots): The FDA drug label warns that estrogen therapy is associated with an increased risk of venous thrombosis and pulmonary embolism.
• Key risks:
  • Venous thrombosis
  • Pulmonary embolism
  • Deep vein thrombosis
  • Myocardial infarction
  • Stroke 2, 2, 2

From the Research

Risk of Thrombosis with Oral Estradiol

The use of oral estradiol (estrogen) has been associated with an increased risk of thrombosis (blood clots) in various studies 3, 4, 5, 6, 7.

Key Findings

• Oral estrogen therapy increases the risk of both arterial and venous thrombosis, with the most common clinical presentation being venous thromboembolism (VTE) of the deep veins of the legs or pulmonary vessels 3.
• Transdermal estrogens may be safer than oral estrogens, with minimal effects on hemostatic variables and no increased risk of VTE 4, 7.
• The risk of thrombosis associated with oral estrogen is dose and medication dependent, and increases with age, congenital and/or acquired predisposition to thrombosis, and mode of administration 5.
• Combined estrogen and progestin contraceptives increase the risk of both venous and arterial thrombosis, and are contraindicated in women with a history of thrombosis or at high risk for thrombosis 6.

Comparison of Oral and Transdermal Estrogen

• Oral estrogens can increase thrombin generation and induce a resistance to activated protein C, whereas transdermal estrogens have minimal effects on hemostatic variables 4.
• The difference in VTE risk between oral and transdermal estrogen users is supported by biological data, with transdermal estrogens improving the benefit/risk ratio of postmenopausal hormone therapy 4, 7.

Recommendations for Women at High Risk of Thrombosis

• Women at high risk of thrombosis need careful evaluation and counseling for contraception, pregnancy, menopausal hormonal therapy, and other estrogen-related conditions or treatments to lower the risk of thromboses 3, 6.
• Progestin-only contraceptives are generally considered safe for women at high risk of thrombosis, and long-acting reversible contraception may offer additional noncontraceptive benefits for women on anticoagulant therapy 6.