What are the potential side effects of estradiol (estrogen replacement therapy) in peri- or post-menopausal women, as well as in younger women or transgender individuals undergoing hormone therapy?

Side Effects of Estradiol

Estradiol therapy carries significant risks that vary by patient population, with the most serious adverse effects including increased venous thromboembolism, stroke, cardiovascular disease, and breast cancer (when combined with progestins), particularly in transgender women and postmenopausal women beyond 10 years of menopause. 1

Cardiovascular and Thromboembolic Risks

Major Cardiovascular Events

• Venous thromboembolism (VTE) represents the primary concern with estradiol therapy across all populations. 1
• In transgender women, estradiol increases VTE risk compared to both cisgender men and women, with this elevated risk persisting despite changes in dosing and preparations over time. 1
• For postmenopausal women taking combined estrogen-progestin therapy, expect 8 additional pulmonary emboli per 10,000 women-years. 2, 3
• Stroke risk increases by 8 additional events per 10,000 women-years with combined therapy. 2, 3
• Coronary heart disease events increase by 7 additional cases per 10,000 women-years. 2, 3

Population-Specific Cardiovascular Risks

• Transgender women on long-term estradiol therapy show elevated risk of ischemic stroke and myocardial infarction relative to cisgender women. 1
• The cardiovascular risk profile is critically dependent on timing—women under 60 or within 10 years of menopause have the most favorable risk-benefit profile, while those beyond this window face substantially higher risks. 2, 3
• Oral estrogen formulations carry higher cardiovascular and thrombotic risks than transdermal preparations due to first-pass hepatic metabolism. 1, 2

Cancer Risks

Breast Cancer

• Combined estrogen-progestin therapy increases breast cancer risk with a hazard ratio of 1.26, translating to 8 additional invasive breast cancers per 10,000 women-years. 2, 3, 4
• The addition of synthetic progestins (particularly medroxyprogesterone acetate) drives the increased breast cancer risk, not estrogen alone. 2, 3
• Critically, unopposed estrogen in women with hysterectomy shows NO increase in breast cancer risk after 5-7 years, with some evidence suggesting a small protective effect (RR 0.80). 2, 3
• Breast cancer risk increases with duration of use, particularly beyond 5 years (RR 1.23-1.35 for long-term users). 2
• Risk becomes apparent earlier with estrogen-plus-progestin therapy compared to estrogen-alone therapy. 4

Endometrial Cancer

• Unopposed estrogen dramatically increases endometrial cancer risk with a relative risk of 2.3 (95% CI 2.1-2.5), escalating to 9.5-fold after 10 years of use. 2, 4
• Adding progestin for 10-14 days monthly reduces endometrial cancer risk by approximately 90%. 2, 3
• This risk persists for 5 or more years even after discontinuing unopposed estrogen. 2

Ovarian Cancer

• The WHI estrogen-plus-progestin substudy reported a statistically non-significant increased risk of ovarian cancer (relative risk 1.58,95% CI 0.77-3.24). 4
• Meta-analysis of epidemiologic studies found women using hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer (relative risk 1.41,95% CI 1.32-1.50). 4

Metabolic and Body Composition Changes

Expected Physical Changes

• Estradiol induces increases in fat mass and reduction in muscle mass. 1
• Weight gain is a common adverse effect. 1
• Breast growth occurs as an expected feminizing effect. 1

Metabolic Effects

• Long-term estradiol use causes reduction in serum albumin, which increases free drug concentrations of highly protein-bound medications such as bupivacaine. 1
• Estradiol may cause potentially reduced plasma cholinesterases, resulting in prolonged block from suxamethonium. 1
• Gallbladder disease risk increases 2- to 4-fold in postmenopausal women receiving estrogens. 2, 3, 4

Bone and Skeletal Effects

• Compromised bone structure represents a paradoxical adverse effect in transgender women despite estrogen's protective effects in postmenopausal women. 1
• This occurs relative to both cisgender women and men in the transgender population. 1

Neurological and Cognitive Risks

Dementia Risk

• The Women's Health Initiative Memory Study (WHIMS) reported increased risk of developing probable dementia in postmenopausal women 65 years or older during combined estrogen-progestin therapy (relative risk 2.05,95% CI 1.21-3.48). 4
• The absolute risk was 45 versus 22 cases per 10,000 women-years for combined therapy versus placebo. 4
• It is unknown whether this finding applies to younger postmenopausal women or to estrogen-alone therapy. 4

Other Neurological Effects

• Severe headaches or vomiting, dizziness, and faintness may occur. 4
• Changes in speech, vision, or weakness/numbness of extremities warrant immediate evaluation for possible stroke. 4

Reproductive and Sexual Effects

• Decreased libido occurs as an expected effect. 1
• Reduced erectile function and decreased testicular size occur in transgender women. 1
• Infertility is a permanent adverse effect. 1
• Irregular vaginal bleeding or spotting is common. 4

Gastrointestinal Effects

• Nausea and vomiting are common side effects. 4
• Stomach/abdominal cramps and bloating occur frequently. 4
• Possible increased risk of postoperative nausea and vomiting. 1
• Pain, swelling, or tenderness in the abdomen may indicate gallbladder problems. 4

Dermatologic Effects

• Softening of the skin is an expected feminizing effect. 1
• Decreased body and facial hair occurs. 1
• A spotty darkening of the skin, particularly on the face, may develop. 4
• Hair loss can occur. 4

Other Adverse Effects

Hypercalcemia

• Estradiol administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. 4
• If hypercalcemia occurs, the drug should be stopped and appropriate measures taken to reduce serum calcium levels. 4

Visual Abnormalities

• Retinal vascular thrombosis has been reported. 4
• Sudden partial or complete loss of vision, sudden onset of proptosis, diplopia, or migraine warrant immediate discontinuation pending examination. 4

Hypertension

• High blood pressure may develop or worsen. 4
• Blood pressure levels may be higher with oral formulations compared to transdermal estradiol. 1

Other Common Effects

• Breast pain and tenderness are frequent. 4
• Fluid retention occurs. 4
• Enlargement of benign uterine tumors ("fibroids") may occur. 4
• Vaginal yeast infections are more common. 4
• High blood sugar may develop. 4
• Liver problems can occur, with yellowing of skin or eyes indicating possible liver dysfunction. 4

Critical Warnings and Absolute Contraindications

Absolute Contraindications (Do Not Use Estradiol If):

• History of breast cancer (except in special situations). 2, 3, 4
• Active or history of coronary heart disease or myocardial infarction. 2, 3, 4
• Active or history of venous thromboembolism or pulmonary embolism. 2, 3, 4
• Active or history of stroke. 2, 3, 4
• Active liver disease. 2, 4
• Undiagnosed abnormal vaginal bleeding. 4
• Known or suspected estrogen-dependent neoplasia. 2
• Thrombophilic disorders. 2, 4
• Pregnancy. 4

Relative Contraindications

• Smoking in women over age 35 significantly amplifies cardiovascular and thrombotic risks. 2
• History of gallbladder disease (increased risk with oral HRT). 2

Route-Specific Considerations

Transdermal vs. Oral Formulations

• Transdermal estradiol has a more favorable cardiovascular and thrombotic risk profile compared to oral formulations because it bypasses hepatic first-pass metabolism. 1, 2
• The ESTHER study showed odds ratio for VTE with transdermal estrogens was 0.9 (95% CI 0.4-2.1) compared to 4.2 (95% CI 1.5-11.6) with oral preparations. 1
• If using topical estradiol patches, ensure no localized heat from patient warming devices or pyrexia, which will increase transdermal uptake. 1

Drug Interactions

• Estrogen is bound by sugammadex, reducing serum concentration with unclear clinical effect. 1
• Estradiol tablets 2 mg contain tartrazine (FD&C Yellow No. 5), which may cause allergic-type reactions including bronchial asthma in susceptible individuals, particularly those with aspirin hypersensitivity. 4

Common Pitfalls to Avoid

• Never initiate estradiol solely for chronic disease prevention (osteoporosis, cardiovascular disease) in asymptomatic women—this is explicitly contraindicated and increases morbidity and mortality. 2, 5
• Do not assume all estrogen formulations carry equal breast cancer risk—the progestin component and type matters significantly. 2, 3
• Do not continue HRT beyond symptom management needs—breast cancer risk increases with duration, particularly beyond 5 years. 2, 3
• Never use estrogen-alone therapy in women with an intact uterus—this dramatically increases endometrial cancer risk. 2, 4
• Do not delay evaluation of abnormal vaginal bleeding—this can be a warning sign of endometrial cancer. 4