Commercially Available Biosimilar Estrogen Products
Currently available biosimilar estrogen products include estradiol valerate, estradiol hemihydrate, and 17β-estradiol formulations, which offer more physiological alternatives to synthetic ethinyl estradiol with potentially improved safety profiles. 1
Types of Biosimilar Estrogens
Natural Estrogen Formulations
- 17β-estradiol (17βE) - A natural estrogen that provides more physiological effects compared to synthetic estrogens 1
- Estradiol valerate (E2V) - A prodrug of estradiol that has been developed as an alternative to ethinyl estradiol 1
- Estradiol hemihydrate - Another estradiol formulation shown to be therapeutically equivalent to estradiol valerate in clinical settings 2
Commercial Products
- Estradiol valerate/dienogest (Qlaira®/Natazia®) - An approved combined oral contraceptive containing natural estrogen 3
- Estradiol valerate/cyproterone acetate (Femilar®) - Approved in Finland for women >40 years or women 35-40 years for whom ethinyl estradiol is not appropriate 3
- Estradiol-Depot 10 mg® and Progynon Depot-10® - Injectable estradiol valerate depot formulations that have demonstrated bioequivalence 4
Advantages of Biosimilar Estrogens
Improved Safety Profile
- Natural estrogens like 17βE appear to have a milder impact on hemostasis, fibrinolysis markers, and lipid profiles compared to synthetic ethinyl estradiol 1
- Transdermal estradiol formulations significantly reduce the risk of venous thromboembolism (VTE) compared to oral administration (OR 0.9 vs 4.2) 1
- Lower risk of cardiovascular events, particularly beneficial for individuals over age 45, smokers, and those with cardiovascular risk factors 5
Physiological Effects
- More physiological estradiol:estrone ratio when administered transdermally 5
- Avoidance of first-pass hepatic metabolism with transdermal formulations 5
- Twenty micrograms of ethinyl estradiol are approximately equivalent to 2 mg of 17βE valerate 1
Administration Routes and Formulations
Transdermal
- Patches - Available in different dosages (typically 50-100 μg/24 hours for menopausal symptoms) 5
- Preferred over oral formulations due to lower cardiovascular risk profile 5
- Neutral effect on Sex Hormone Binding Protein (SHBP) levels, unlike oral formulations 1
Oral
- Tablets available in various strengths, including generic formulations that have demonstrated bioequivalence 6
- Can be taken with or without food, as bioequivalence has been demonstrated under both fasting and fed conditions 6
Injectable
- Depot formulations for intramuscular administration 4
- Provide sustained release of estradiol over time
Clinical Considerations
Venous Thromboembolism Risk
- The risk of VTE is significantly lower with transdermal estradiol compared to oral ethinyl estradiol 1
- Oral 17βE (2 mg) and oral ethinyl estradiol (20 μg) both increase SHBP levels, a marker for VTE risk 1
- Route of administration is crucial - transdermal administration has an OR for VTE of 0.9 (95% CI, 0.4–2.1) compared to 4.2 (95% CI, 1.5–11.6) for oral administration 1
Contraindications
- History of hormonally mediated cancers
- Active thromboembolic disorders
- Current or history of arterial thrombotic disease 5
Monitoring Recommendations
- Initial evaluation at 3-6 months after starting therapy
- Annual clinical reviews thereafter
- Monitor serum estradiol levels, liver function, lipid profile, and blood pressure 5
Common Pitfalls
- Assuming all estrogen formulations carry the same risk profile
- Overlooking the importance of administration route on safety outcomes
- Failing to consider individual cardiovascular risk factors when selecting an estrogen formulation
- Not recognizing that compounded "bioidentical" hormones lack well-controlled studies examining safety and efficacy compared to FDA-approved biosimilar products 7
When selecting a biosimilar estrogen product, the transdermal route should be prioritized for patients with cardiovascular risk factors, while oral formulations may be suitable for those without such risks. The specific choice should be guided by the individual's medical history, risk factors, and treatment goals.