What are alternative estrogen drugs?

Alternative Estrogen Drugs: Options and Considerations

Transdermal 17β-estradiol is the preferred alternative estrogen formulation due to its more physiological effects and lower risk profile compared to oral formulations, particularly for patients with thrombotic risk factors. 1

Types of Estrogen Alternatives

1. Different Formulations of Estrogen

• 17β-estradiol (17βE)

  • Transdermal delivery: Available as patches, gels, or sprays
    • Provides more physiological serum estradiol concentrations
    • Avoids hepatic first-pass effect
    • Minimizes impact on hemostatic factors
    • More beneficial profile on lipids, inflammation markers, and blood pressure 1
  • Oral delivery: 1-2 mg daily dosing
    • Higher risk of thromboembolism compared to transdermal route
    • OR for venous thromboembolism: 4.2 (95% CI, 1.5-11.6) 1

• Conjugated Equine Estrogens (CEE)

  • Oral dosing: 0.625-1.25 mg daily
  • Complex formulation containing multiple estrogens
  • Contains components not secreted by human ovaries 2
  • Higher risk of cardiovascular events in WHI study 3, 4

2. Selective Estrogen Receptor Modulators (SERMs)

• Tamoxifen

  • Blocks estrogen's effects in breast tissue but has estrogenic effects in other tissues
  • Used for breast cancer prevention and treatment 5
  • May be an attractive option for hormone replacement therapy 1
  • Can be used in patients with contraindications to traditional estrogen therapy

• Raloxifene

  • FDA approved for prevention and treatment of osteoporosis in postmenopausal women
  • Decreases incidence of vertebral fracture
  • No documented benefit against non-vertebral or hip fractures
  • Associated with increased risk of fatal stroke (HR 1.49) and venous thromboembolism (HR 1.44) 1

Clinical Considerations for Selecting Estrogen Alternatives

Thrombotic Risk Assessment

• Route of administration matters:

  • Transdermal estrogens: OR for VTE 0.9 (95% CI, 0.4-2.1)
  • Oral estrogens: OR for VTE 4.2 (95% CI, 1.5-11.6) 1
  • Patients with thrombotic risk factors should avoid oral estrogens 6

• Estrogen formulation impacts risk:

  • 17βE appears to have milder impact on hemostasis and fibrinolysis markers compared to ethinylestradiol (EE) 1
  • 20 μg of EE is approximately equivalent to 2 mg of 17βE valerate 1

Breast Cancer Considerations

• For patients with history of breast cancer:

  • Traditional estrogen therapy has been contraindicated due to fear of recurrence
  • Consider non-hormonal alternatives for symptom management:
    • Vitamin E, clonidine, selective serotonin reuptake inhibitors 7
  • For bone health: bisphosphonates, diet, exercise 7
  • For cardiovascular health: diet, exercise, statins 7

• For breast cancer prevention:

  • Aromatase inhibitors are recommended as initial adjuvant therapy for 5 years (category 1) in postmenopausal patients 1
  • Tamoxifen for 2-3 years followed by aromatase inhibitor to complete 5 years (category 1) 1

Endometrial Cancer Risk

• Unopposed estrogen increases risk:

  • 20% incidence of endometrial hyperplasia with conjugated estrogens alone 8
  • ≤1% incidence with combined estrogen/progestin therapy 8

• After endometrial cancer treatment:

  • Estrogen replacement therapy remains controversial
  • May be reasonable for patients at low risk for tumor recurrence
  • 6-12 month waiting period recommended before initiation 1

Special Populations

Patients with Hereditary Angioedema

• Contraindicated options:
  • Estrogen-containing contraceptives should be avoided (evidence level III)
  • Estrogen replacement therapy must not be used for menopause
  • Phytoestrogens cannot be recommended due to their estrogenic potencies 1

Patients with Premature Ovarian Insufficiency

• Hormone replacement options:
  • Transdermal 17βE is preferred route of administration
  • For those needing contraception, progestin-only pills are safer than combined oral contraceptives 1, 6
  • Intrauterine devices (copper or levonorgestrel) have no increased thrombotic risk 6

Common Pitfalls and Caveats

1. Assuming all estrogens have identical risk profiles

   • Different estrogen formulations and delivery routes have significantly different safety profiles
   • Transdermal delivery substantially reduces thrombotic risk compared to oral administration

2. Overlooking the need for progestogen in women with intact uterus

   • Unopposed estrogen significantly increases endometrial hyperplasia risk
   • Progestogen should be administered continuously or sequentially with estrogen 1

3. Failing to consider patient-specific risk factors

   • History of thromboembolism, breast cancer, or angioedema requires careful selection
   • Transdermal 17β-estradiol offers the most favorable risk-benefit profile for most patients with cardiovascular risk factors

4. Assuming SERMs are equivalent to estrogen therapy

   • SERMs like raloxifene are less potent than bisphosphonates for bone protection
   • They have different tissue-specific effects than traditional estrogen therapy

In conclusion, when selecting an alternative estrogen therapy, transdermal 17β-estradiol provides the most physiological effects with the lowest risk profile, particularly for patients with cardiovascular or thrombotic risk factors. For patients with contraindications to estrogen therapy, SERMs or non-hormonal alternatives should be considered based on the specific symptoms requiring treatment.