What are the side effects of estradiol (estrogen) therapy?

Side Effects of Estradiol Therapy

Estradiol therapy is associated with significant risks including stroke, gallbladder disease, urinary incontinence, deep vein thrombosis, and potentially dementia, which likely outweigh benefits for most women using it for chronic disease prevention. 1

Major Serious Side Effects

Estradiol therapy can cause several serious adverse effects that require careful consideration:

• Cardiovascular Effects:

  • Stroke (increased risk) 1, 2
  • Heart attack (particularly in combination with progestin) 1
  • Venous thromboembolism (VTE) including deep vein thrombosis and pulmonary embolism 1
  • Note: Transdermal estradiol has lower VTE risk compared to oral formulations 1, 3

• Cancer Risks:

  • Breast cancer (particularly with combined estrogen-progestin therapy) 1, 2
  • Endometrial cancer (when estrogen is used without progestin in women with intact uterus) 2
  • Ovarian cancer (recent evidence suggests increased risk with higher estradiol levels) 4

• Other Serious Side Effects:

  • Gallbladder disease 1, 2
  • Dementia (particularly in women over 65) 2
  • Liver problems 2

Common Side Effects

• Headache 2
• Breast pain/tenderness 2
• Irregular vaginal bleeding or spotting 2
• Stomach/abdominal cramps and bloating 2
• Nausea and vomiting 2
• Hair loss 2
• Fluid retention 2
• High blood pressure 2
• High blood sugar 2
• Enlargement of uterine fibroids 2
• Skin changes (spotty darkening, particularly on the face) 2
• Vaginal yeast infections 2
• Urinary incontinence (stress, mixed, or any type) 1

Different Formulations and Risk Profiles

The risk profile varies depending on the formulation and route of administration:

• Oral Estradiol:

  • Higher risk of VTE due to first-pass hepatic metabolism 3, 5
  • Greater impact on hepatic protein synthesis 5

• Transdermal Estradiol:

  • Lower risk of VTE compared to oral formulations 1, 3
  • Avoids first-pass hepatic metabolism 5
  • Local skin irritation at application site is common 5

• Combined Estrogen-Progestin Therapy:

  • Higher risk of breast cancer than estrogen-only therapy 1
  • Increased risk of coronary heart disease events 1

• Estrogen-Only Therapy:

  • Lower breast cancer risk (may even be slightly protective in some studies) 1
  • Still carries risks of stroke, DVT, and gallbladder disease 1

Risk Factors and Contraindications

Estradiol therapy is contraindicated in patients with:

• Unusual vaginal bleeding that has not been evaluated 2
• Current or history of certain cancers, particularly breast cancer 2
• Recent stroke or heart attack (within past year) 2
• Current or history of blood clots 2
• Liver problems 2
• Known hypersensitivity to estradiol 2
• Pregnancy 2

Warning Signs Requiring Immediate Medical Attention

Patients should be instructed to seek immediate medical attention if they experience:

• Breast lumps 2
• Unusual vaginal bleeding 2
• Dizziness and faintness 2
• Changes in speech 2
• Severe headaches 2
• Chest pain 2
• Shortness of breath 2
• Leg pain (possible DVT) 2
• Vision changes 2
• Vomiting 2
• Yellowing of skin or eyes (liver problems) 2
• Abdominal pain or swelling (possible gallbladder issues) 2

Risk Mitigation

To minimize risks associated with estradiol therapy:

1. Use the lowest effective dose for the shortest duration necessary 2
2. Regular follow-up with healthcare provider (at least annually) 2
3. For women with intact uterus, add progestin to prevent endometrial cancer 2
4. Regular breast exams and mammograms 2
5. Monitor for cardiovascular risk factors 2
6. Consider transdermal rather than oral formulations, especially in patients with higher VTE risk 1, 3

Special Populations

• Transgender Women/Transfeminine People: May experience increased risk of venous thromboembolism and potentially increased cardiovascular mortality 1

• Older Women (65+): Higher risk of dementia with hormone therapy, particularly with combined estrogen-progestin 2

• Women with Intact Uterus: Must use progestin with estrogen to prevent endometrial cancer 2