What are the risks of Hormone Replacement Therapy (HRT) for postmenopausal women, particularly regarding heart attacks, blood clots, and certain cancers?

HRT Statistics: Heart Attacks, Blood Clots, and Cancers

For postmenopausal women taking combined estrogen-progestin therapy, the absolute risks are modest but measurable: for every 10,000 women treated for one year, expect 7 additional coronary heart disease events, 8 additional strokes, 8 additional pulmonary emboli, and 8 additional invasive breast cancers. 1

Cardiovascular Risks

Heart Attacks (Coronary Heart Disease)

• Combined estrogen-progestin therapy increases CHD events with a hazard ratio of 1.29 (95% CI, 1.02 to 1.63), evident shortly after initiation 1
• This translates to 7 additional CHD events per 10,000 women-years 1, 2
• CHD mortality was not significantly increased (RH 1.18; 95% CI, 0.70 to 1.97) 1
• HRT does not reduce cardiovascular risk and may actually increase it, contradicting earlier observational studies that suggested benefit 1

The critical distinction here is that observational studies showing cardiovascular benefit were confounded by socioeconomic factors—when controlled for social class, education, or income, no benefit was seen (RH 0.97; 95% CI, 0.82 to 1.16) 1. The Women's Health Initiative randomized trial data supersedes these earlier observations.

Stroke

• Meta-analysis shows HRT increases stroke incidence with RR 1.12 (95% CI, 1.01 to 1.23), primarily thromboembolic stroke (RR 1.20; 95% CI, 1.01 to 1.40) 1
• WHI data confirms increased stroke with RH 1.41 (95% CI, 0.86 to 2.31) 1
• This represents 8 additional strokes per 10,000 women-years 1, 2
• Fair evidence that HRT increases stroke risk per USPSTF conclusions 1

Blood Clot Risks (Venous Thromboembolism)

Deep Venous Thrombosis and Pulmonary Embolism

• Meta-analysis of 12 studies shows HRT increases VTE risk with RR 2.14 (95% CI, 1.64 to 2.81) 1
• WHI confirms twofold increased rate: RH 2.11 (95% CI, 1.26 to 3.55) 1
• This translates to 8 additional pulmonary emboli per 10,000 women-years 1, 2
• Risk is highest within the first year of use with RR 3.49 (95% CI, 2.33 to 5.59) 1
• Good evidence that HRT increases VTE risk per USPSTF conclusions 1

The timing is critical—the VTE risk emerges within the first 1-2 years of therapy, unlike breast cancer risk which doesn't appear until after 4-5 years 2.

Cancer Risks

Breast Cancer

• Combined estrogen-progestin increases breast cancer with RR 1.26 (95% CI, 1.00 to 1.59) 2
• This represents 8 additional invasive breast cancers per 10,000 women-years 1, 2
• Risk increases with duration, particularly beyond 5 years (RR 1.23-1.35 for long-term users) 2
• Risk does not appear until after 4-5 years of combined therapy use 2
• Cancers diagnosed in the estrogen-progestin group were larger, more likely node-positive, and diagnosed at more advanced stages 2

Critical distinction: Unopposed estrogen (in women with hysterectomy) showed NO increase in breast cancer risk after 5-7 years, with some evidence suggesting a small reduction (RR 0.80) 2. The progestin component drives the breast cancer risk, not estrogen alone 2.

Endometrial Cancer

• Unopposed estrogen dramatically increases endometrial cancer risk with RR 2.3 (95% CI, 2.1 to 2.5) 1
• Risk escalates to 9.5-fold after 10 years of unopposed estrogen use 1
• Risk remains elevated 5 or more years after discontinuation 1
• Combined estrogen-progestin therapy does NOT increase endometrial cancer risk (RH 0.83; 95% CI, 0.29 to 2.32 in WHI) 1
• Adding progestin reduces endometrial cancer risk by approximately 90% compared to unopposed estrogen 2

This is why women with an intact uterus must receive progestin with estrogen—it's not optional 2.

Ovarian Cancer

• Data are inconsistent across studies 1
• Two cohort studies reported increased risks (RR 1.8 to 2.2) for ovarian cancer among women taking HRT for 10 years or more 1
• One study suggested higher risk with unopposed estrogen than with estrogen-progestin 1
• Evidence insufficient to determine effect of HRT on ovarian cancer per USPSTF 1

Colorectal Cancer (Protective Effect)

• Combined estrogen-progestin reduces colorectal cancer risk 2
• 6 fewer colorectal cancers per 10,000 women-years 2

Balancing Benefits Against Risks

The calculus has fundamentally changed from earlier assumptions 1. While HRT effectively treats menopausal symptoms (75% reduction in vasomotor symptoms) and prevents osteoporosis (5 fewer hip fractures per 10,000 women-years), it does not reduce and may actually increase cardiovascular disease risk 1, 2.

Risk-Benefit Profile Summary (per 10,000 women-years):

Harms:

• 7 additional CHD events 1, 2
• 8 additional strokes 1, 2
• 8 additional pulmonary emboli 1, 2
• 8 additional invasive breast cancers 1, 2

Benefits:

• 6 fewer colorectal cancers 2
• 5 fewer hip fractures 2
• 75% reduction in vasomotor symptoms 2

Critical Clinical Implications

The USPSTF recommends against routine use of HRT for chronic disease prevention (Grade D recommendation) because harmful effects likely exceed benefits in most women, particularly those many years past menopause 2. Major medical organizations including the American College of Obstetricians and Gynecologists, North American Menopause Society, and American Heart Association now recommend against HRT for primary or secondary prevention of cardiovascular disease 1.

Common Pitfalls to Avoid:

• Never initiate HRT solely for chronic disease prevention (osteoporosis, cardiovascular disease) without considering individual risk factors 1, 2
• Do not assume all HRT regimens carry equal risk—the progestin component and route of administration significantly affect the risk profile 2
• Recognize that VTE risk emerges within the first year, while breast cancer risk doesn't appear until after 4-5 years 2
• Understand that observational studies showing cardiovascular benefit were confounded—randomized trial data supersedes these findings 1

The evidence supports using HRT for menopausal symptom management at the lowest effective dose for the shortest duration, but not for routine prevention of chronic conditions 1, 2.