In a woman over 50 years old, what are the risks of hormone replacement therapy and when is its use appropriate?

HRT Risks in Women Over 50

For women over 50, hormone replacement therapy (HRT) carries specific risks that increase with age and time since menopause, but when initiated within 10 years of menopause onset (typically before age 60), the benefits for moderate-to-severe vasomotor symptoms generally outweigh the risks—use is appropriate only for symptom management at the lowest effective dose for the shortest duration, never for chronic disease prevention. 1, 2

Age-Dependent Risk Profile

Women Under 60 or Within 10 Years of Menopause

• The risk-benefit profile is most favorable in this window, with potential cardiovascular benefits (HR 0.59 for coronary heart disease in women aged 50-59) and lower absolute risks of adverse events. 1, 3
• Per 10,000 women taking combined estrogen-progestin for one year, expect 7 additional coronary events, 8 additional strokes, 8 additional pulmonary emboli, and 8 additional invasive breast cancers, balanced against 6 fewer colorectal cancers, 5 fewer hip fractures, and 75% reduction in vasomotor symptoms. 1, 2

Women Over 60 or More Than 10 Years Post-Menopause

• Oral estrogen-containing HRT carries excess stroke risk (Class III, Level A recommendation against use) with stroke incidence rising to 33 versus 25 per 10,000 women-years. 3
• The Women's Health Initiative Memory Study demonstrated significantly increased dementia risk in women aged 65-79 years (HR 2.05 for combined therapy, HR 1.38 for estrogen-alone). 3
• Initiating HRT after age 65 is explicitly contraindicated for chronic disease prevention due to increased morbidity and mortality. 3

Specific Risks by Organ System

Cardiovascular and Thromboembolic

• Stroke risk increases by 8 additional events per 10,000 women-years with combined therapy, though transdermal estradiol is not associated with increased stroke risk (RR 0.95; 95% CI 0.75-1.20) unlike oral formulations. 2, 1
• Venous thromboembolism risk increases by 8 additional pulmonary emboli per 10,000 women-years with oral therapy, but transdermal estradiol shows no increased VTE risk (OR 0.9; 95% CI 0.4-2.1). 2, 1
• Coronary heart disease events increase by 7 additional cases per 10,000 women-years, occurring principally in older women years beyond menopause. 2, 4

Breast Cancer

• Combined estrogen-progestin therapy increases breast cancer risk with HR 1.26, translating to 8 additional invasive breast cancers per 10,000 women-years. 2, 1
• The progestin component drives this risk, not estrogen alone—unopposed estrogen in women with hysterectomy shows no increased risk and may be protective (HR 0.80). 1, 2
• Risk does not manifest until after 4-5 years of continuous use and persists more than 10 years after discontinuation. 3, 1
• Micronized progesterone offers superior breast safety compared to synthetic progestins while maintaining endometrial protection. 1

Endometrial Cancer

• Unopposed estrogen dramatically increases endometrial cancer risk (RR 2.3 after one year, escalating to 9.5-fold after 10 years) in women with an intact uterus. 1, 5
• Adding progestin for 10-14 days monthly reduces this risk by approximately 90%. 1, 2
• Women without a uterus can safely use estrogen-alone therapy. 1

Other Risks

• Gallbladder disease risk increases with oral HRT (RR 1.48-1.8), though transdermal routes have lower impact. 1
• Ovarian cancer risk may increase with long-term use, though data remain inconsistent. 1

Absolute Contraindications

HRT must never be initiated in women with: 1, 2

• History of breast cancer or estrogen-dependent neoplasia
• Coronary heart disease or prior myocardial infarction
• Previous venous thromboembolic event or stroke
• Active liver disease
• Antiphospholipid syndrome or thrombophilic disorders
• Unexplained vaginal bleeding

When HRT Use Is Appropriate

Primary Indication

• HRT should be prescribed only for moderate-to-severe vasomotor symptoms (hot flashes, night sweats) or genitourinary syndrome of menopause, never for chronic disease prevention. 1, 4
• The U.S. Preventive Services Task Force assigns a Grade D recommendation (recommends against) using HRT solely for osteoporosis or cardiovascular disease prevention. 1, 3

Optimal Timing

• Initiate HRT at symptom onset, typically around age 51 (median menopause age), when the risk-benefit profile is most favorable. 1, 6
• Women with surgical menopause before age 45-50 should start HRT immediately post-surgery and continue at least until age 51, then reassess. 1, 2

Preferred Regimens

• Transdermal estradiol 50 μg patch twice weekly is first-line, as it bypasses hepatic first-pass metabolism and reduces cardiovascular and thromboembolic risks versus oral formulations. 1
• For women with intact uterus, add micronized progesterone 200 mg orally at bedtime (preferred) or medroxyprogesterone acetate 10 mg for 12-14 days monthly. 1
• For women post-hysterectomy, estrogen-alone therapy is appropriate and carries lower breast cancer risk. 1, 2

Risk Mitigation Strategies

• Use the lowest effective dose for the shortest duration necessary, with annual reassessment and attempts at discontinuation once symptoms are controlled. 1, 5, 4
• Strongly prefer transdermal over oral estrogen to minimize stroke and VTE risk. 1, 2
• Choose micronized progesterone over synthetic progestins when progestin is required. 1
• At age 65, mandatory reassessment with attempted discontinuation is required; if continuation is essential, reduce to lowest effective dose. 3

Critical Pitfalls to Avoid

• Never initiate HRT solely for chronic disease prevention—this increases morbidity and mortality. 1, 3
• Never prescribe estrogen-alone to women with intact uterus—this dramatically increases endometrial cancer risk. 1, 5
• Never initiate HRT after age 65—risks outweigh benefits except in rare cases of persistent severe symptoms started earlier. 3
• Do not assume all estrogen formulations carry equal risk—route of administration and progestin type significantly affect safety profile. 1, 2
• Smoking in women over 35 significantly amplifies cardiovascular and thrombotic risks with HRT. 1