What are the risks and considerations for estrogen replacement therapy (ERT) in menopausal women?

Risks of Estrogen Replacement Therapy

Estrogen replacement therapy carries significant risks that increase with duration of use and age at initiation, including elevated risks of stroke, venous thromboembolism, breast cancer (when combined with progestin), and dementia in older women, though these risks must be weighed against benefits for symptom management in appropriately selected patients. 1, 2, 3

Cardiovascular and Thromboembolic Risks

The most immediate and concerning cardiovascular risks include:

• Stroke risk increases by 8 additional events per 10,000 women-years of combined estrogen-progestin therapy 1, 2
• Venous thromboembolism (VTE) risk increases by 8 additional pulmonary emboli per 10,000 women-years 1, 2
• Coronary heart disease events increase by 7 additional cases per 10,000 women-years with combined therapy 1, 2
• These cardiovascular risks appear within the first 1-2 years of therapy and are particularly elevated in women who initiate HRT more than 10 years after menopause 1, 2

Critical distinction: Transdermal estradiol has a more favorable cardiovascular and thrombotic risk profile compared to oral formulations because it bypasses hepatic first-pass metabolism 2

Breast Cancer Risk

The breast cancer risk profile differs dramatically based on whether progestin is added:

• 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 1, 2, 3
• The addition of synthetic progestins (particularly medroxyprogesterone acetate) drives the increased breast cancer risk, not estrogen alone 2
• Cancers diagnosed in women on combined therapy tend to be larger, more likely node-positive, and diagnosed at more advanced stages 2
• 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, 4
• Risk increases significantly with duration beyond 5 years 2

Endometrial Cancer Risk

• Unopposed estrogen dramatically increases endometrial cancer risk in women with an intact uterus 1, 3
• Adding progestin for 10-14 days monthly reduces endometrial cancer risk by approximately 90% 2
• This is why combined therapy is mandatory for women who have not had a hysterectomy 2, 3

Dementia and Cognitive Risks

• In women aged 65 and older, combined estrogen-progestin therapy doubles the risk of probable dementia (relative risk 2.05,95% CI 1.21-3.48) 3
• The absolute risk is 45 versus 22 cases per 10,000 women-years, representing 23 excess cases per 10,000 women-years 3
• It is unknown whether this finding applies to younger postmenopausal women or estrogen-alone therapy 3

Other Significant Risks

• Gallbladder disease requiring surgery increases 2- to 4-fold in postmenopausal women receiving estrogens 3
• Ovarian cancer risk may increase with long-term use, with a relative risk of 1.41 for current users, though this remains somewhat controversial 3
• Retinal vascular thrombosis can occur, requiring immediate discontinuation if visual symptoms develop 3

Age and Timing Considerations: The "Window of Opportunity"

The risk-benefit profile is critically dependent on timing:

• Women under 60 or within 10 years of menopause onset have the most favorable risk-benefit profile 2, 4
• Women who initiate HRT more than 10 years after menopause or after age 60 face substantially higher risks, particularly for cardiovascular events 2, 4
• For a 61-year-old woman who is 7+ years postmenopausal, the harmful effects likely exceed benefits 4

Special Population Considerations

Women with prior breast cancer:

• HRT is strongly contraindicated regardless of hormone receptor status of the tumor 1, 2, 5

Women with endometrial cancer history:

• Estrogen replacement remains controversial but may be reasonable in low-risk, early-stage disease after 6-12 months post-treatment 1
• Several retrospective trials show no increase in recurrence, but prospective data are lacking 1

Women with surgical menopause before age 45:

• Should receive HRT immediately to prevent long-term cardiovascular, bone, and cognitive consequences, continuing at least until age 51 2, 4

Absolute Contraindications to HRT

The following are absolute contraindications per current guidelines 2:

• History of breast cancer
• Coronary heart disease or prior myocardial infarction
• Previous venous thromboembolic event or stroke
• Active liver disease
• Antiphospholipid syndrome or positive antiphospholipid antibodies
• Known or suspected estrogen-dependent neoplasia
• Thrombophilic disorders

Risk Mitigation Strategies

To minimize risks when HRT is indicated:

• Use transdermal estradiol as first-line (50 μg daily patches changed twice weekly) rather than oral formulations to reduce VTE and stroke risk 2
• Use micronized progesterone (200 mg nightly) rather than medroxyprogesterone acetate to lower VTE and breast cancer risk 2
• Prescribe the lowest effective dose for the shortest duration necessary 1, 2, 3
• Reassess necessity annually and attempt discontinuation or dose reduction 2
• Never initiate HRT solely for chronic disease prevention 1, 2, 4

Common Pitfalls to Avoid

• Initiating HRT in women over 60 or more than 10 years past menopause without compelling symptomatic indications 2, 4
• Continuing HRT beyond symptom management needs, particularly beyond 5 years when breast cancer risk increases significantly 2
• Using oral estrogen when transdermal would be safer, especially in women with cardiovascular risk factors 2
• Failing to add progestin in women with an intact uterus, exposing them to endometrial cancer risk 1, 3
• Assuming all estrogen formulations carry equal breast cancer risk—the progestin component matters significantly 2