What is estrogen used for in medical treatment?

Estrogen in Medical Treatment: Clinical Applications and Evidence

Primary FDA-Approved Indications

Estrogen therapy is FDA-approved for treating moderate to severe menopausal vasomotor symptoms (hot flashes), vulvovaginal atrophy, prevention of postmenopausal osteoporosis, and palliation of advanced breast and prostate cancers, but should NOT be used for primary prevention of chronic diseases due to significant cardiovascular and cancer risks that outweigh benefits. 1

Approved Treatment Uses

Menopausal Symptom Management:

• Estrogen effectively treats moderate to severe hot flashes and vulvovaginal atrophy in postmenopausal women 1
• Treatment should use the lowest effective dose (typically 1-2 mg daily estradiol) for the shortest duration necessary 1
• Therapy should be cyclic (3 weeks on, 1 week off) with reassessment every 3-6 months 1
• Women with an intact uterus must receive concurrent progestin to prevent endometrial cancer 1

Osteoporosis Prevention:

• Estrogen reduces fractures by approximately 56 per 10,000 woman-years when used alone 2
• Combined estrogen-progestin prevents about 46 fractures per 10,000 woman-years 2
• Should only be considered for women at significant osteoporosis risk when non-estrogen medications are inappropriate 1

Cancer Palliation:

• For metastatic breast cancer: 10 mg three times daily for at least 3 months in appropriately selected patients 1
• For advanced androgen-dependent prostate cancer: 1-2 mg three times daily 1

Hypoestrogenism Treatment:

• Initial dose of 1-2 mg daily for hypogonadism, castration, or primary ovarian failure 1
• Dose adjusted to control symptoms with maintenance determined by titration 1

Critical Safety Considerations and Contraindications

The U.S. Preventive Services Task Force recommends AGAINST using hormone therapy for primary prevention of chronic conditions in postmenopausal women due to unfavorable risk-benefit profile. 2

Major Harms with Combined Estrogen-Progestin:

• Increased stroke risk (8 additional cases per 10,000 woman-years) 2
• Increased invasive breast cancer (8 additional cases per 10,000 woman-years) 2
• Increased dementia (22 additional cases per 10,000 woman-years) 2
• Increased venous thromboembolism (DVT: 8 more, PE: 8 more per 10,000 woman-years) 2
• Increased gallbladder disease (20 additional cases per 10,000 woman-years) 2
• Increased urinary incontinence (872 additional cases per 10,000 woman-years) 2
• Does NOT reduce coronary heart disease risk (HR 1.22,95% CI 0.99-1.51) 2

Major Harms with Estrogen Alone:

• Increased stroke (11 additional cases per 10,000 woman-years) 2
• Increased DVT (7 additional cases per 10,000 woman-years) 2
• Increased gallbladder disease (33 additional cases per 10,000 woman-years) 2
• Increased urinary incontinence (1,271 additional cases per 10,000 woman-years) 2
• Does NOT reduce CHD risk (HR 0.95% CI 0.78-1.15) 2

Modest Benefits with Estrogen Alone:

• Small reduction in invasive breast cancer (8 fewer cases per 10,000 woman-years) 2
• Small reduction in breast cancer mortality (2 fewer deaths per 10,000 woman-years) 2
• The biological mechanism for this protective effect versus the harmful effect of combined therapy remains unclear 2

Mechanism of Action

Cardiovascular Effects:

• Estrogen binds to estrogen receptors (ER-α and ER-β) in cardiovascular tissues, acting as transcription factors 2
• Produces rapid vasodilation via ER-α-mediated activation of endothelial nitric oxide synthase 2
• Modulates endothelium-derived factors including nitric oxide, prostacyclin, and endothelin-1 2
• Improves lipid profiles: reduces LDL cholesterol and lipoprotein(a), increases HDL cholesterol 2
• However, increases triglycerides by approximately 20% 2
• Also increases coagulation proteins and decreases fibrinolytic proteins, explaining thrombotic risks 2

Neuroprotective Effects (Experimental Only):

• Over 50 rodent studies showed estrogen reduces histological damage in cerebral ischemia 2
• 22 in vitro neuronal studies demonstrated benefit (versus 0 showing no benefit) 2
• Critical caveat: Despite extensive preclinical evidence, estrogen has NEVER been evaluated in humans for acute stroke treatment 2

Special Populations and Considerations

Breast Cancer Survivors:

• Systemic estrogen is contraindicated in estrogen receptor-positive breast cancer 2
• Vaginal estrogen preparations containing estriol may be preferable to estradiol for vaginal atrophy in aromatase inhibitor users 2
• Safety of vaginal estrogens remains unestablished; patients should be counseled about potential risks 2

Women Under Age 50 with Surgical Menopause:

• USPSTF recommendations do not apply to this population 2
• These women may have different risk-benefit considerations 2

Micronized Progesterone Preference:

• When progestin is needed for endometrial protection, micronized progesterone has a more favorable breast cancer and venous thromboembolism risk profile compared to medroxyprogesterone acetate 3

Clinical Decision Algorithm

1. Determine indication: Is this for menopausal symptoms or chronic disease prevention?

   • If chronic disease prevention → Do NOT prescribe 2
   • If menopausal symptoms → Proceed to step 2

2. Assess contraindications: History of breast cancer, stroke, DVT/PE, active liver disease, unexplained vaginal bleeding?

   • If yes → Do NOT prescribe estrogen
   • If no → Proceed to step 3

3. Evaluate uterine status:

   • Intact uterus → Prescribe estrogen PLUS progestin (preferably micronized progesterone) 3, 1
   • Post-hysterectomy → Prescribe estrogen alone 1

4. Initiate lowest effective dose:

   • Start 1-2 mg daily estradiol 1
   • Use cyclic regimen (3 weeks on, 1 week off) 1

5. Reassess every 3-6 months:

   • Attempt discontinuation or tapering 1
   • Continue only if symptoms persist and benefits outweigh risks 1

Common Pitfalls to Avoid

• Never prescribe estrogen for cardiovascular disease prevention - despite favorable lipid effects and preclinical vascular data, clinical trials show no CHD benefit and increased stroke risk 2
• Never use unopposed estrogen in women with intact uterus - increases endometrial cancer risk 2, 1
• Never continue therapy indefinitely - reassess necessity every 3-6 months 1
• Never assume younger age at initiation is safer - post hoc analyses suggest harm increases with age, but this is not statistically significant and should not guide prescribing 2

2, 3, 1