What are the contraindications for estrogen replacement therapy (ERT)?

Contraindications for Estrogen Replacement Therapy

Estrogen replacement therapy is absolutely contraindicated in patients with undiagnosed abnormal genital bleeding, known or suspected breast cancer (except metastatic disease being treated), estrogen-dependent neoplasia, active or recent thromboembolic disease (DVT, PE, stroke, MI within the past year), active liver disease, and pregnancy. 1

Absolute Contraindications

The FDA-approved drug label provides the definitive list of absolute contraindications 1:

• Undiagnosed abnormal genital bleeding - must be evaluated before initiating therapy 1
• Known, suspected, or history of breast cancer - except in appropriately selected patients being treated for metastatic disease 1
• Known or suspected estrogen-dependent neoplasia 1
• Active deep vein thrombosis or pulmonary embolism, or history of these conditions 1
• Active or recent arterial thromboembolic disease - specifically within the past year, including stroke and myocardial infarction 1
• Active liver dysfunction or disease 1
• Known hypersensitivity to estradiol or its ingredients 1
• Known or suspected pregnancy 1

Cancer-Specific Contraindications

Gynecologic Malignancies

Hormone replacement therapy is contraindicated in specific gynecologic cancers based on hormonal sensitivity:

• Low-grade serous epithelial ovarian cancer - contraindicated due to hormonal dependence 2
• Granulosa cell tumors - contraindicated due to potential hormonal link 2
• Certain uterine sarcomas - specifically leiomyosarcoma and stromal sarcoma are contraindicated 2
• Advanced endometrioid uterine adenocarcinoma - contraindicated, though early-stage disease has favorable risk/benefit profile 2

Breast Cancer

HRT is generally contraindicated in breast cancer survivors 2. However, the evidence shows nuance:

• Retrospective studies have not demonstrated increased recurrence rates with estrogen use after early-stage breast cancer treatment 2
• A meta-analysis showed significantly increased recurrence risk specifically in Black American women, though this should be interpreted cautiously due to study limitations 2
• If adjuvant treatment is performed, wait 6-12 months before considering HRT 2

Non-Hormone Dependent Cancers

No contraindication exists for cervical, vaginal, or vulvar cancers - these are not hormone-dependent tumors 2

Favorable risk/benefit profile for most epithelial ovarian cancers - including high-grade, clear cell, and mucinous subtypes 2

Cardiovascular and Thromboembolic Contraindications

Existing cardiovascular and cerebrovascular disease represent relative contraindications 3:

• Active or recent (within past year) arterial thromboembolic events are absolute contraindications 1
• History of stroke or myocardial infarction beyond one year requires careful risk assessment 2
• Increased risks include venous thromboembolic events, particularly with oral formulations 2

Important caveat: Transdermal estradiol does not increase VTE risk in healthy women and may be preferred in those with cardiovascular risk factors 2

Antiphospholipid Syndrome and Lupus

Strong recommendations exist for patients with antiphospholipid antibodies:

• Avoid HRT completely in patients with obstetric and/or thrombotic APS 2
• Avoid HRT if current aPL titers are positive, even without APS diagnosis 2
• Avoid HRT in SLE patients on anticoagulation 2
• May consider HRT in aPL-negative SLE patients with stable, low-level disease activity 2

Special Populations

Premature Ovarian Insufficiency

Hypertension and migraine should NOT be considered contraindications to HRT in women with POI 2:

• Transdermal estradiol is preferred in hypertensive women with POI 2
• Migraine should not prevent HRT use, though consideration should be given to changing dose, route, or regimen if migraine worsens 2

BRCA Mutation Carriers

HRT is a treatment option for women carrying BRCA1/2 mutations without personal history of breast cancer after prophylactic bilateral salpingo-oophorectomy 2

Common Pitfalls to Avoid

• Do not deny HRT to young women with chemotherapy-induced premature menopause (except breast cancer patients) - replacement until normal menopause age is appropriate and does not carry the same risks as seen in older postmenopausal women 2
• Do not use unopposed estrogen in women with intact uterus - this increases endometrial cancer risk; always add progestogen for endometrial protection 2
• Do not assume all endometrial cancer survivors cannot use HRT - early-stage disease has favorable risk/benefit profile, though individualized discussion is required 2