What is the stroke risk associated with hormone replacement therapy (HRT), particularly oral estrogen, and how do age, route of administration, dose, and cardiovascular risk factors (hypertension, diabetes, smoking, hyperlipidaemia, prior thrombo‑embolic events) affect management recommendations?

HRT and Stroke Risk

Estrogen-containing hormone replacement therapy increases stroke risk by approximately 12-32%, and should be avoided in women ≥60 years of age, those >10 years past menopause, and anyone with cardiovascular risk factors including hypertension, diabetes, smoking, hyperlipidemia, or prior thromboembolic events. 1, 2

Age and Timing Considerations

Age ≥60 years or >10 years since menopause:

• Oral estrogen-containing HRT carries an excess stroke risk that must be weighed against clinical benefits 1
• The Women's Health Initiative demonstrated 36-41% increased stroke risk in women aged 50-79 years (mean age 67 years) taking estrogen alone or combined estrogen-progestin 1, 2
• Meta-analyses confirm 12-32% increased stroke incidence with HRT use, primarily ischemic strokes 1, 3, 4
• The absolute risk translates to 52-79 additional strokes per 10,000 women treated 1

Age <60 years and within 10 years of menopause:

• The absolute stroke risk remains low—approximately 2 additional strokes per 10,000 women per year 4, 5
• However, the relative risk increase persists regardless of age at initiation or proximity to menopause 4, 5
• The 2024 AHA/ASA guidelines state that even younger women experience increased stroke risk, though the absolute numbers are smaller 1

Route of Administration and Dose

Oral estrogen formulations:

• Standard-dose oral conjugated estrogens (0.625 mg) increase stroke risk by approximately one-third 4
• A strong dose-response relationship exists: 0.3 mg shows minimal risk (RR 0.93), while 0.625 mg (RR 1.54) and 1.25 mg (RR 1.62) show progressively higher risk 5
• Both estrogen-alone and estrogen-plus-progestin formulations carry similar stroke risk 1, 4

Transdermal estrogen:

• Low-dose transdermal estradiol (≤50 μg/day) may not increase stroke risk 1, 4
• The 2024 AHA/ASA guidelines note that transdermal formulations, especially low-dose, were not associated with clear stroke risk 1
• Transdermal routes avoid first-pass hepatic metabolism, potentially reducing prothrombotic effects 1

Vaginal estrogen:

• Low-dose vaginal estradiol 0.01% delivers local effects with minimal systemic absorption and does not increase stroke, VTE, or MI risk 3
• This formulation is appropriate even for women with prior stroke or cardiovascular disease when used solely for genitourinary symptoms 3

Cardiovascular Risk Factors

Absolute contraindications to estrogen-containing HRT:

• Prior stroke or transient ischemic attack 6, 2
• History of venous thromboembolism 1, 6, 2
• Active cardiovascular disease 3, 2

High-risk factors requiring HRT avoidance:

• Cigarette smoking dramatically compounds stroke risk with any hormonal therapy 1, 6
• Hypertension increases stroke risk in HRT users 1, 7
• Diabetes mellitus elevates stroke risk with HRT 1, 6
• Hyperlipidemia contributes to vascular risk 7
• Obesity is associated with increased stroke risk in HRT users 7

Timing of Risk

Early treatment period:

• Stroke risk increases 2-fold during the first 6 months of HRT initiation 8
• VTE risk is highest in the first year (RR 3.49) 3
• The WHI trial showed increased CHD events in year one that persisted 2

Long-term use:

• The increased stroke risk persists throughout HRT use and does not diminish with continued therapy 4, 5
• Risk was observed after the first year in the WHI trial and continued 2

Clinical Algorithm for HRT Decision-Making

Step 1: Screen for absolute contraindications

• History of stroke, TIA, VTE, MI, or active CVD → Do not prescribe systemic HRT 6, 3, 2
• Consider low-dose vaginal estrogen only for genitourinary symptoms 3

Step 2: Assess age and time since menopause

• Age ≥60 years OR >10 years past menopause → Avoid systemic HRT 1
• Age <60 years AND within 10 years of menopause → Proceed to Step 3 1

Step 3: Evaluate cardiovascular risk factors

• Presence of smoking, hypertension, diabetes, hyperlipidemia, or obesity → Avoid systemic HRT 1, 7
• Absence of risk factors → Proceed to Step 4 1

Step 4: Select appropriate formulation if HRT is indicated

• First choice: Low-dose transdermal estradiol (≤50 μg/day) with progestin if uterus intact 1, 4
• Avoid: Oral estrogen formulations, especially doses ≥0.625 mg 5
• Duration: Use lowest effective dose for shortest duration 2

Step 5: For genitourinary symptoms only

• Preferred: Low-dose vaginal estradiol 0.01% regardless of cardiovascular history 3
• This avoids systemic absorption and cardiovascular risks 3

Critical Pitfalls to Avoid

• Do not assume younger age or recent menopause eliminates stroke risk—the relative risk increase persists across all ages, though absolute risk is lower in younger women 4, 5
• Do not prescribe oral contraceptives to women with prior thromboembolic events—this is explicitly contraindicated by the AHA 1, 6
• Do not continue systemic HRT in women who develop cardiovascular risk factors—reassess and discontinue if hypertension, diabetes, or smoking develops 3, 2
• Do not confuse low-dose vaginal estrogen with systemic HRT—vaginal preparations lack cardiovascular risks and are safe even after stroke 3
• Do not overlook the first 6 months of therapy—this is the highest-risk period for both stroke and VTE 3, 8

Special Populations

Women with premature menopause (<40 years) or early menopause (<45 years):

• These women have 32% increased stroke risk from early menopause itself 1
• Evaluation and modification of vascular risk factors are recommended 1
• Data are lacking on whether HRT until average menopause age modifies this risk 1

Transgender women on gender-affirming estrogen:

• Evaluation and modification of stroke risk factors can be beneficial 1
• Studies suggest higher stroke incidence and prevalence in transfeminine individuals using HT 1