Can estradiol (Estrogen) vaginal insert increase the risk of Deep Vein Thrombosis (DVT)?

From the Guidelines

Estradiol vaginal inserts can potentially increase the risk of deep vein thrombosis (DVT), though the risk is generally considered lower than with oral estrogen therapy. Estradiol vaginal inserts, such as Vagifem (10 mcg) or Imvexxy (4-10 mcg), are primarily used to treat vaginal atrophy symptoms in postmenopausal women. While these products are designed for local vaginal effects with minimal systemic absorption, some estrogen does enter the bloodstream. The risk of DVT is dose-dependent and related to systemic estrogen exposure, as demonstrated by studies showing that oral estrogen preparations have a higher risk of venous thromboembolism compared to transdermal or transvaginal routes 1.

Key points to consider:

• Patients with personal or family history of blood clots, smoking, obesity, or other thrombotic risk factors should use particular caution when using estradiol vaginal inserts.
• Women should watch for symptoms of DVT including leg pain, swelling, warmth, or redness, and seek immediate medical attention if these occur.
• The lowest effective dose should be used for the shortest duration needed to control symptoms.
• For women with significant risk factors for thrombosis, non-hormonal vaginal moisturizers or lubricants might be safer alternatives to consider.
• A study published in 2021 found that transdermal estrogens had a neutral effect on Sex Hormone Binding Protein (SHBP) levels, a marker of VTE, while oral estrogens increased its levels 1.

It is essential to weigh the benefits and risks of estradiol vaginal inserts and consider individual patient factors when making treatment decisions, prioritizing morbidity, mortality, and quality of life as the primary outcomes.

From the FDA Drug Label

Estrogens and progestins should not be used for the prevention of cardiovascular disease. 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.

The estradiol vaginal insert may increase the risk of Deep Vein Thrombosis (DVT), as the drug label mentions that estrogens increase the risk of DVT, although this specific information is based on a study using oral conjugated estrogens, not the vaginal insert form 2.

• The label does mention that other combinations and dosage forms of estrogens should be assumed to have similar risks in the absence of comparable data.
• However, it does not directly state that the estradiol vaginal insert has this risk.
• Therefore, a conservative clinical decision would be to assume a potential increased risk of DVT.

From the Research

Estradiol Vaginal Insert and DVT Risk

• The use of estradiol vaginal inserts has been studied in various contexts, but the specific question of whether they increase the risk of Deep Vein Thrombosis (DVT) requires examination of the available evidence.
• A study from 2008 3 focused on the efficacy of ultra-low-dose estradiol vaginal tablets for treating vaginal atrophy, but it did not directly address the risk of DVT.
• However, research on estrogen and thrombosis 4 suggests that estrogen can increase the risk of both arterial and venous thrombosis, with venous thromboembolism (VTE) being a common clinical presentation.
• The risk of VTE associated with hormone therapy, including local and systemic use, has been assessed in several studies 5, 6, indicating that systemic hormone therapy is associated with an increased risk of VTE, whereas local estrogen therapy may not confer the same level of risk.
• Specifically, a study from 2016 6 found that local estrogen use was not associated with an increased risk of VTE, suggesting that estradiol vaginal inserts might not significantly increase DVT risk.
• Another study from 2010 5 compared the risk of VTE between oral and transdermal estrogen therapy, concluding that transdermal estrogens may be safer in terms of VTE risk, which could imply a similar safety profile for local estrogen therapies like vaginal inserts.
• It's essential to consider that while these studies provide insights into the relationship between estrogen therapy and thrombosis risk, the specific context of estradiol vaginal inserts and DVT risk may require more direct investigation to fully understand the potential risks involved.