What are the risks and considerations for Hormone Replacement Therapy (HRT) now that the FDA black box warning has been removed?

FDA Black Box Warning and HRT: Current Risk-Benefit Profile

The FDA black box warning on HRT products remains in place and should guide prescribing decisions—HRT is approved only for menopausal symptom management and osteoporosis prevention, not for chronic disease prevention, and must be prescribed at the lowest effective dose for the shortest duration. 1

Current FDA Black Box Warning Status

The black box warning has not been removed from HRT products. The FDA-approved indications remain limited to:

• Treatment of menopausal symptoms (vasomotor and genitourinary)
• Prevention of osteoporosis

The warning explicitly states that estrogen with or without progestin should be prescribed at the lowest effective dose and for the shortest duration consistent with treatment goals. 1

Critical Cardiovascular and Thrombotic Risks

Immediate Risks (First 1-2 Years)

• Venous thromboembolism risk doubles (35 vs 17 per 10,000 women-years for combined estrogen-progestin) 1
• Deep vein thrombosis increases from 13 to 26 per 10,000 women-years 1
• Pulmonary embolism increases from 8 to 18 per 10,000 women-years 1
• Stroke risk increases (33 vs 25 per 10,000 women-years) 2, 1
• CHD events show increased relative risk in year 1, particularly in women with established heart disease 1

Long-Term Risks

• Breast cancer risk increases with duration of use, becoming apparent after several years and persisting >10 years after discontinuation 1
• Invasive breast cancers in HRT users are larger, more likely node-positive, and diagnosed at more advanced stages 1

Absolute Risk Quantification

For every 10,000 women taking estrogen-progestin for 1 year:

• 7 additional CHD events
• 8 additional strokes
• 8 additional pulmonary emboli
• 8 additional invasive breast cancers
• 6 fewer colorectal cancers
• 5 fewer hip fractures 2

Evidence-Based Prescribing Algorithm

Step 1: Determine Appropriateness

HRT is appropriate ONLY for:

• Moderate to severe vasomotor symptoms (hot flashes, night sweats) 3, 4
• Genitourinary symptoms of menopause 3, 4
• Women under age 60 OR within 10 years of menopause onset 3, 4

HRT is NOT appropriate for:

• Primary or secondary prevention of cardiovascular disease 4
• Routine prevention of osteoporosis (use alternatives: bisphosphonates, weight-bearing exercise) 2
• Women over age 60 or >10 years past menopause 3

Step 2: Screen for Absolute Contraindications

Do not prescribe HRT if patient has:

• History of breast cancer or hormone-sensitive cancers 3
• Coronary heart disease 3
• Previous venous thromboembolic event or stroke 3
• Active liver disease 3
• Antiphospholipid syndrome or positive antiphospholipid antibodies 3

Step 3: Assess Relative Contraindications

Exercise extreme caution with:

• History of gallbladder disease (RR 1.8-2.5 for cholecystitis) 2, 4
• Risk factors for arterial disease (hypertension, diabetes, tobacco use, hypercholesterolemia, obesity) 1
• Risk factors for VTE (personal/family history, obesity, systemic lupus erythematosus) 1

Step 4: Select Appropriate Formulation

For women with intact uterus:

• Must use combined estrogen-progestin to prevent endometrial cancer (unopposed estrogen increases risk 2.3-fold, up to 9.5-fold with 10 years use) 2, 4
• First-line: Transdermal estradiol 50 μg daily + micronized progesterone 200 mg daily 3
• Transdermal route preferred—avoids first-pass hepatic metabolism, reducing cardiovascular and thrombotic risks 3

For women post-hysterectomy:

• Estrogen-alone therapy can be used 2
• Evidence remains insufficient to determine if benefits outweigh harms in this population 2

Step 5: Prescribe Lowest Effective Dose

• Start with transdermal estradiol patches 50 μg (0.05 mg/day), applied twice weekly 3
• For oral formulations, conjugated estrogens 0.3 mg are as effective as 0.625 mg with fewer side effects 5
• Use lowest dose that controls symptoms 2

Step 6: Plan for Shortest Duration

• Reassess necessity at regular intervals (at minimum annually) 3, 6
• Attempt discontinuation or dose reduction periodically 3
• Risks increase with duration, particularly breast cancer risk 2, 1

Critical Clinical Pitfalls to Avoid

Never initiate HRT:

• In women over 65 for chronic disease prevention—this increases morbidity and mortality 3
• Solely for osteoporosis or cardiovascular disease prevention 2, 4
• In women with hormone-sensitive cancers 3

Never use unopposed estrogen:

• In women with intact uterus—endometrial cancer risk increases 2.3-fold, reaching 9.5-fold with 10 years of use 2, 4

Never continue HRT indefinitely:

• Breast cancer risk persists >10 years after discontinuation 1
• Cardiovascular risks remain elevated throughout use 1

Special Considerations for Specific Populations

Women with premature ovarian insufficiency:

• HRT should be initiated at diagnosis to prevent long-term health consequences 3
• May continue until average age of menopause (51 years), then reassess 3

Women with non-hormone-sensitive cancers:

• HRT may be considered for severe vasomotor symptoms 3
• Transdermal routes preferred 3

Women already on HRT at age 65:

• Reassess necessity and attempt discontinuation 3
• If continuation deemed essential, reduce to lowest effective dose 3

Shared Decision-Making Framework

Clinicians must discuss with patients:

• Early risks (VTE, CHD, stroke) occur within first 1-2 years 2
• Late risks (breast cancer) increase with longer-term use 2
• Alternative strategies for osteoporosis (bisphosphonates, calcitonin, weight-bearing exercise) 2
• Alternative strategies for cardiovascular disease prevention (lipid management, blood pressure control, smoking cessation) 2

The absolute increase in risk is modest but real—individual risk characteristics and personal preferences must guide the final decision, but only within the framework of appropriate indications and contraindications. 2

Monitoring Requirements

All women on HRT require:

• Yearly breast examinations by healthcare provider 1
• Monthly breast self-examinations 1
• Mammography based on age and risk factors 1
• Evaluation for undiagnosed persistent or recurrent abnormal genital bleeding (endometrial sampling when indicated) 1

Discontinue HRT immediately if:

• VTE occurs or is suspected 1
• Stroke occurs or is suspected 1
• Myocardial infarction occurs 1

Discontinue HRT 4-6 weeks before:

• Surgery associated with increased thromboembolism risk 1
• Periods of prolonged immobilization 1