What are the contraindications to estrogen therapy?

Contraindications to Estrogen Therapy

Estrogen therapy is absolutely contraindicated in women with a history of breast cancer, coronary heart disease, previous venous thromboembolic events or stroke, active liver disease, and antiphospholipid syndrome. 1, 2

Absolute Contraindications

The following conditions represent absolute contraindications where estrogen should not be prescribed:

• History of breast cancer - Estrogen may stimulate residual cancer cells and increase recurrence risk 1, 2, 3
• Coronary heart disease (CHD) - Estrogen therapy does not reduce CHD risk and may increase events, particularly in women with established disease 1
• Previous venous thromboembolic event (deep vein thrombosis or pulmonary embolism) - Estrogen increases thrombotic risk 2-fold, with oral estrogen conferring 7-12 additional DVT/PE events per 10,000 woman-years 1
• History of stroke - Estrogen increases stroke risk by 9-11 additional events per 10,000 woman-years 1
• Active liver disease - Hepatic metabolism of estrogen is impaired, increasing toxicity risk 1
• Known or suspected estrogen-dependent neoplasia - This includes endometrial cancer in women with intact uterus taking unopposed estrogen 1
• Thrombophilic disorders - Inherited or acquired clotting disorders substantially amplify venous thromboembolism risk 1

Special Population: Antiphospholipid Antibody Syndrome

Women with antiphospholipid syndrome (APS) should never receive estrogen therapy due to dramatically increased thrombotic risk. 1

The strength of contraindication varies by APS status:

• Obstetric and/or thrombotic APS - Strongly contraindicated (absolute) 1
• APS on anticoagulation - Contraindicated even with anticoagulation therapy 1
• Asymptomatic antiphospholipid antibodies - Contraindicated due to potential thrombosis risk 1
• Previously positive aPL, now negative with no clinical APS - May consider with extreme caution only if severely symptomatic 1

Age and Timing Considerations

While not absolute contraindications, estrogen carries substantially increased risk in:

• Women ≥60 years of age - Stroke risk is elevated compared to younger women 1
• Women >10 years past menopause onset - Cardiovascular and stroke risks outweigh benefits 1, 2
• Women at elevated baseline cardiovascular or stroke risk - Pre-existing risk factors compound estrogen-related harms 1

Additional High-Risk Conditions

The following represent strong relative contraindications where risk typically exceeds benefit:

• Gallbladder disease - Estrogen increases gallbladder disease by 20-33 additional cases per 10,000 woman-years 1
• Dementia risk or cognitive impairment - Combined estrogen-progestin increases dementia by 22 additional cases per 10,000 woman-years in women ≥65 years 1
• Obesity - Increases baseline thrombotic risk, which is further amplified by estrogen 1
• Factor V Leiden or other inherited thrombophilias - Substantially increases venous thromboembolism risk with estrogen 1

Critical Clinical Pitfalls to Avoid

Do not prescribe estrogen for chronic disease prevention - The USPSTF explicitly recommends against using hormone therapy for primary prevention of conditions like osteoporosis or cardiovascular disease in asymptomatic women, as harms outweigh benefits 1, 2

Do not assume all estrogen formulations carry equal risk - While most data comes from oral conjugated equine estrogen, oral formulations specifically increase stroke risk, whereas transdermal preparations may have different risk profiles 1

Do not continue estrogen longer than necessary - Breast cancer risk increases with duration of use, and many risks persist during ongoing exposure 1

Do not forget endometrial protection - Women with intact uterus taking estrogen must receive concurrent progesterone to prevent endometrial hyperplasia and cancer 1, 2