What are the side effects of estrogen in women, particularly in those of reproductive age and postmenopausal women?

Side Effects of Estrogen

Estrogen therapy carries significant risks including increased stroke, venous thromboembolism, breast cancer (when combined with progestin), and gallbladder disease, with the risk-benefit profile varying dramatically based on timing of initiation, formulation, and patient age. 1, 2

Cardiovascular and Thrombotic Risks

Stroke and Thromboembolism:

• Estrogen therapy increases stroke risk by approximately 8 additional strokes per 10,000 women-years of use 1, 2
• Venous thromboembolism (deep vein thrombosis and pulmonary embolism) risk increases significantly, with 8 additional pulmonary emboli per 10,000 women-years 1, 2
• Combined estrogen-progestin therapy increases coronary heart disease events by 7 additional cases per 10,000 women-years 1, 2
• The cardiovascular risks are particularly elevated in women over 60 or those more than 10 years past menopause 1, 2

Timing-Dependent Cardiovascular Effects:

• Women who initiate estrogen therapy more than 10 years after menopause have substantially increased probability of cardiovascular harm 2
• Oral estrogen formulations carry higher cardiovascular and thrombotic risks compared to transdermal preparations due to first-pass hepatic metabolism 2

Cancer Risks

Breast Cancer:

• Combined estrogen-progestin therapy increases breast cancer risk with 8 additional invasive breast cancers per 10,000 women-years (hazard ratio 1.26) 1, 2, 3
• The breast cancer risk does not appear until after 4-5 years of combined therapy use 1
• Cancers diagnosed in estrogen-progestin users tend to be larger, more likely node-positive, and diagnosed at more advanced stages 1
• Critically, estrogen-alone therapy (in women without a uterus) shows NO increase in breast cancer risk and may even be protective (RR 0.80) 1, 2

Endometrial Cancer:

• Unopposed estrogen (without progestin) increases endometrial cancer risk 10- to 30-fold if continued for 5 years or more 1
• This risk persists for years after discontinuation 1
• Adding progestin reduces endometrial cancer risk by approximately 90% 1

Other Cancers:

• Estrogen therapy reduces colorectal cancer risk by 6 fewer cases per 10,000 women-years 1, 2
• Some studies suggest increased risk of cervical intraepithelial neoplasia, though causality remains controversial 4
• Ovarian cancer risk may increase with long-term use, though data are inconsistent 1

Gastrointestinal and Hepatobiliary Effects

• Cholecystitis (gallbladder inflammation) risk increases significantly 1, 2, 3
• Gallbladder disease risk increases with relative risk of 1.48-1.8, particularly with oral formulations 1
• Cholestatic jaundice may occur 4
• Active liver disease is an absolute contraindication to estrogen therapy 1, 2

Common Treatment-Related Side Effects

Breast and Gynecologic Symptoms:

• Breast tenderness occurs in 9.3% of previously asymptomatic women on estrogen-progestin versus 2.4% on placebo 5
• Vaginal bleeding is reported by 51% of women on estrogen-progestin at 6 months (mostly spotting) 5
• Vaginal discharge develops in 4.1% versus 1.0% on placebo 5
• Vaginal irritation occurs in 4.2% versus 2.8% on placebo 5
• Increased rates of gynecologic surgery including hysterectomy (3.1% versus 2.5%) and dilation and curettage (5.4% versus 2.4%) 5

Neurologic and Mood Effects:

• Headaches develop in 5.8% of previously asymptomatic women versus 4.7% on placebo 5
• Migraine may occur or worsen 4
• Mental depression is reported 4
• Nervousness and dizziness may occur 4

Metabolic and Endocrine Effects:

• Reduced tolerance to carbohydrates 4
• Changes in appetite 4
• Weight changes (increase or decrease) 4
• Changes in libido 4

Other Common Side Effects:

• Nausea and abdominal cramps/bloating (primarily estrogen-dose related) 4, 6
• Changes in cervical erosion and secretion 4
• Vaginal candidiasis 4
• Change in corneal curvature and intolerance to contact lenses 4
• Allergic reactions including rash, urticaria, and angioedema 4

Rare but Serious Adverse Effects

• Budd-Chiari Syndrome (hepatic vein thrombosis) 4
• Hemolytic uremic syndrome 4
• Impaired renal function 4
• Porphyria 4
• Erythema multiforme and erythema nodosum 4

Critical Pitfalls to Avoid

Never initiate estrogen therapy solely for chronic disease prevention (osteoporosis, cardiovascular disease) in asymptomatic women—the U.S. Preventive Services Task Force gives this a Grade D recommendation (recommends against) 1, 2, 3

Do not prescribe estrogen-alone to women with an intact uterus—this dramatically increases endometrial cancer risk and requires concurrent progestin 1, 2

Avoid initiating estrogen in women over 60 or more than 10 years past menopause—the risk-benefit profile becomes unfavorable with increased cardiovascular and cancer risks 1, 2

Do not overlook absolute contraindications: history of breast cancer, coronary heart disease, previous venous thromboembolism or stroke, active liver disease, and antiphospholipid syndrome 1, 2

Risk Mitigation Strategies

• Use the lowest effective dose for the shortest duration necessary 1, 2, 3
• Prefer transdermal over oral formulations to reduce cardiovascular and thrombotic risks 2
• Use micronized progesterone rather than synthetic progestins when progestin is needed, as it has lower breast cancer and thrombotic risks 2
• Initiate therapy within 10 years of menopause onset when the risk-benefit profile is most favorable 1, 2
• Conduct annual reassessment of necessity and attempt discontinuation once symptoms are controlled 2