Is oral 17-B-estradiol (estrogen) safe?

Safety Profile of Oral 17-β-estradiol

Oral 17-β-estradiol is not considered safe for general use due to increased risks of serious cardiovascular events, endometrial cancer, and other complications, with transdermal formulations being the preferred route of administration when estrogen therapy is indicated. 1, 2

Risks Associated with Oral 17-β-estradiol

Serious Boxed Warnings

• Increased risk of endometrial cancer requiring close clinical surveillance 1, 2
• Cardiovascular risks including:
  • Myocardial infarction
  • Stroke
  • Venous thromboembolism (VTE)
  • Deep vein thrombosis 1, 2
• Increased risk of invasive breast cancer 1, 2
• Increased risk of probable dementia in women over 65 years 1, 2

First-Pass Hepatic Effects

• Oral 17-β-estradiol undergoes significant first-pass metabolism in the liver, leading to:
  • Substantial increases in plasma estrone levels
  • Increased sex steroid binding protein (SBP)
  • Increased renin substrate
  • Increased VLDL levels
  • Decreased antithrombin activity 3

Preferred Alternative: Transdermal 17-β-estradiol

Advantages of Transdermal Route

• Avoids first-pass hepatic metabolism 4, 5
• Provides more physiological estradiol:estrone ratio 3
• Lower cardiovascular risk profile:
  • Lower rates of venous thromboembolism
  • Lower risk of stroke 4
• No measurable effects on hepatic markers of estrogen action 3
• Can maintain physiological levels with lower daily doses 5

Clinical Recommendations for Estrogen Therapy

Route Selection

• Transdermal estrogen formulations are strongly preferred over oral formulations 4
• Standard adult dose for transdermal estradiol patches is 50-100 μg/24 hours 4

Mandatory Endometrial Protection

• For women with an intact uterus, progestin must be administered alongside estrogen to reduce endometrial cancer risk 6, 4
• Progestin should be administered for 12-14 days every 28 days in a sequential regimen 4
• Micronized progesterone is preferred over medroxyprogesterone acetate due to lower VTE risk and lower rates of breast cancer 4

Absolute Contraindications

• History of hormonally mediated cancers 4
• History of breast cancer 4
• Undiagnosed vaginal bleeding 4
• Active thromboembolic disorders 4
• Current or history of arterial thrombotic disease 4

Monitoring and Follow-up

• Clinical review every 3-6 months initially, then annually 4
• Adequate diagnostic measures, including endometrial sampling when indicated, for any undiagnosed persistent or recurring abnormal vaginal bleeding 1, 2

Key Principles for Prescribing

• Use the lowest effective dose for the shortest duration consistent with treatment goals 1, 2
• Regular reassessment of risks and benefits 4
• Transdermal route should be first choice when estrogen therapy is indicated 6, 4