What are the contraindications and dosage of Estradiol (Estrogen)

From the Guidelines

Estradiol is contraindicated in patients with a history of estrogen-dependent cancers, active or recent arterial thromboembolic disease, active venous thromboembolism, unexplained vaginal bleeding, liver dysfunction or disease, and known hypersensitivity to estradiol. The most recent and highest quality study, published in 2021 in Blood Reviews 1, provides guidance on the use of hormonal replacement therapy in adolescents and young women with chemo- or radio-induced premature ovarian insufficiency.

Key Considerations

• Dosing varies by formulation and indication, with oral estradiol typically starting at 1-2 mg daily, transdermal patches at 50-100 μg/24 hours, and vaginal estradiol at 0.5-1 mg daily.
• For menopausal symptoms, the lowest effective dose should be used for the shortest duration necessary to minimize risks.
• Regular monitoring is essential, including breast exams, pelvic exams, and blood pressure checks.
• Estradiol works by replacing declining estrogen levels, which helps alleviate symptoms by binding to estrogen receptors throughout the body, particularly in reproductive tissues, bone, and the central nervous system.

Important Recommendations

• The use of combined 17βE and progestin patches is recommended as a first choice for improving compliance to treatment.
• Progestins with an anti-androgenic effect should be avoided in patients with iatrogenic POI due to the risk of worsening hypoandrogenism.
• The dose of 17βE should be adjusted according to each woman's tolerance and feeling of wellbeing.
• HRT in cancer survivors with POI should be continued until the average age of spontaneous menopause (45-55 years). Some studies have reported that estrogen and progestin impart a small increase in the risks for developing and dying of breast cancer, whereas estrogen alone seems to slightly reduce these risks 1. However, the most recent study 1 provides the most up-to-date guidance on the use of estradiol, and its recommendations should be prioritized.

From the FDA Drug Label

Estrogens should not be used in individuals with any of the following conditions: Undiagnosed abnormal genital bleeding. Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Active deep vein thrombosis, pulmonary embolism or history of these conditions. Active or recent (e. g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction. Liver dysfunction or disease. The usual initial dosage range is 1 to 2 mg daily of estradiol adjusted as necessary to control presenting symptoms.

The contraindications for estradiol are:

• Undiagnosed abnormal genital bleeding
• Known, suspected or history of cancer of the breast
• Known or suspected estrogen-dependent neoplasia
• Active deep vein thrombosis, pulmonary embolism or history of these conditions
• Active or recent arterial thromboembolic disease
• Liver dysfunction or disease
• Known hypersensitivity to its ingredients
• Known or suspected pregnancy

The recommended dose of estradiol is 1 to 2 mg daily, adjusted as necessary to control presenting symptoms 2 2.

From the Research

Estradiol Contraindications

• Estradiol is contraindicated in women with a history of thrombosis or thrombophilia, as it increases the risk of venous thromboembolism (VTE) and arterial thrombosis 3, 4, 5
• Women with estrogen-dependent cancers, such as breast cancer, may be contraindicated for estradiol therapy, depending on the stage and estrogen-receptor status of the cancer 6
• Estradiol may also be contraindicated in women with a history of endometrial cancer, as tamoxifen therapy for breast cancer prevention has been associated with an increased risk of endometrial cancer in women under 50 years old 7

Estradiol Dose

• The dose of estradiol used in hormone replacement therapy (HRT) can affect the risk of venous thrombosis, with high-dose estrogen therapy associated with a greater increased risk than low-dose preparations 4
• Transdermal HRT may be associated with a lower risk of venous thrombosis compared to oral HRT, and may be a safer option for women at high risk of thrombosis 4, 5
• The optimal dose of estradiol for HRT in women with a history of thrombosis or thrombophilia is not well established, and individualized risk assessment and counseling are recommended 5