What are the risks associated with Hormonal Replacement Therapy (HRT) for women?

Risks of Hormone Replacement Therapy for Women

Hormone replacement therapy carries significant cardiovascular, thrombotic, and cancer risks that increase with age, duration of use, and time since menopause, with combined estrogen-progestin therapy posing greater risks than estrogen alone. 1

Cardiovascular and Thrombotic Risks

Combined estrogen-progestin therapy increases the risk of coronary heart disease, stroke, and venous thromboembolism, particularly in the first 1-2 years of therapy. 1

• For every 10,000 women taking estrogen-progestin for 1 year, expect 7 additional coronary heart disease events, 8 more strokes, and 8 more pulmonary emboli 1, 2
• The rate of venous thromboembolism doubles with combined therapy: 34 per 10,000 women-years versus 16 per 10,000 in placebo groups 3
• VTE risk is highest during the first year of therapy and persists throughout use 3
• Transdermal estradiol has lower thrombotic risk than oral formulations because it bypasses hepatic first-pass metabolism 2

Breast Cancer Risk

The addition of progestin to estrogen is what drives increased breast cancer risk, not estrogen alone. 3

• Combined estrogen-progestin therapy increases invasive breast cancer risk with a relative risk of 1.24, translating to 8 additional cases per 10,000 women-years 1, 3
• Among women with prior hormone therapy use, the relative risk increases to 1.86 (46 versus 25 cases per 10,000 women-years) 3
• Breast cancers diagnosed in women on combined therapy are larger, more likely node-positive, and diagnosed at more advanced stages 3
• Estrogen-alone therapy in women without a uterus shows NO increased breast cancer risk after 5-7 years (RR 0.80), and may even be protective 2, 3
• Risk increases significantly with duration beyond 5 years and can persist for more than 10 years after discontinuation 3

Endometrial Cancer Risk

Unopposed estrogen in women with an intact uterus dramatically increases endometrial cancer risk. 3

• Endometrial cancer risk is 2- to 12-fold greater in unopposed estrogen users compared to non-users 3
• Risk increases to 15- to 24-fold with 5-10 years of use and persists 8-15 years after discontinuation 3
• Adding progestin to estrogen therapy reduces endometrial hyperplasia risk by approximately 90% 2, 3
• Women with an intact uterus must receive combined estrogen-progestin therapy, never estrogen alone 2, 4

Other Malignancy Risks

• Ovarian cancer risk increases with HRT use (RR 1.41), with no difference between short-term (<5 years) and long-term (>5 years) use 3
• The absolute risk for ovarian cancer is 4 versus 3 cases per 10,000 women-years for combined therapy versus placebo 3
• Colorectal cancer risk decreases by 6 cases per 10,000 women-years with combined therapy 1

Cognitive and Neurological Risks

HRT initiated in women 65 years or older doubles the risk of probable dementia. 3

• The relative risk for dementia with combined therapy is 2.05 (95% CI 1.21-3.48) 3
• Absolute risk is 45 versus 22 cases per 10,000 women-years (23 excess cases per 10,000 women-years) 3
• It is unknown whether these findings apply to younger postmenopausal women or estrogen-alone therapy 3

Gallbladder Disease

• HRT increases gallbladder disease requiring surgery by 2- to 4-fold in postmenopausal women 3
• The relative risk ranges from 1.48 to 1.8 2
• Oral HRT carries higher risk than transdermal formulations 1

Timing-Dependent Risk Profile

The risk-benefit balance of HRT is critically dependent on timing of initiation relative to menopause. 2, 5

• Women under 60 or within 10 years of menopause have the most favorable risk-benefit profile 1, 2
• Women starting HRT more than 10 years after menopause face substantially increased cardiovascular risks 2, 5
• The U.S. Preventive Services Task Force recommends against routine use of HRT for chronic disease prevention in postmenopausal women (Grade D recommendation) 5

Absolute Contraindications to HRT

The following conditions represent absolute contraindications where HRT must be avoided: 1, 2

• History of breast cancer
• Active or history of coronary heart disease
• Previous venous thromboembolism or stroke
• Active liver disease
• Antiphospholipid syndrome or positive antiphospholipid antibodies
• Known or suspected estrogen-dependent neoplasia
• Thrombophilic disorders

Benefits That May Offset Risks

While risks are substantial, HRT does provide certain benefits: 1, 5

• Reduction of 5 hip fractures per 10,000 women-years
• Reduction of 6 colorectal cancer cases per 10,000 women-years
• 75% reduction in vasomotor symptom frequency 2
• 60-80% improvement in genitourinary symptoms with low-dose vaginal estrogen 2

Critical Clinical Pitfalls to Avoid

• Never initiate HRT solely for chronic disease prevention (osteoporosis, cardiovascular disease) without bothersome menopausal symptoms 1, 2
• Never initiate HRT in women over 65 years for any indication other than severe, refractory symptoms 2
• Never use unopposed estrogen in women with an intact uterus 3
• Never continue HRT beyond symptom management needs—risks increase substantially with duration beyond 5 years 2, 3
• Never assume all estrogen formulations carry equal risk—transdermal has lower thrombotic risk than oral 2
• Never ignore the distinction between estrogen-alone and estrogen-progestin therapy—breast cancer risk profiles differ dramatically 3

Risk Minimization Strategy

When HRT is indicated for symptom management: 1, 2

• Use the lowest effective dose
• Plan for the shortest possible duration
• Prefer transdermal over oral estradiol (lower VTE and stroke risk)
• Use micronized progesterone over medroxyprogesterone acetate (lower VTE and breast cancer risk)
• Reassess necessity annually and attempt discontinuation when symptoms resolve
• Discontinue 4-6 weeks before major surgery or prolonged immobilization