How does estrogen hormone replacement therapy (HRT) increase the risk of myocardial infarction (MI) and cerebrovascular accident (stroke)?

From the Guidelines

Estrogen hormone replacement therapy (HRT) increases the risk of myocardial infarction (MI) and stroke, with a statistically significant increased risk for stroke, as evidenced by the Women's Health Initiative (WHI) trials, which reported a hazard ratio (HR) of 1.36 for stroke with estrogen-only therapy and an HR of 1.22 for coronary heart disease (CHD) with combined estrogen and progestin therapy 1. The mechanism behind this increased risk involves estrogen's effects on blood clotting and vascular function, including the promotion of coagulation and reduction of fibrinolytic activity, leading to a prothrombotic state that can result in the formation of blood clots blocking coronary or cerebral arteries. Key factors that influence the risk include:

• The type of estrogen formulation, with oral formulations posing a higher risk due to first-pass metabolism through the liver
• The dose and duration of HRT, with higher doses and longer durations increasing the risk
• The timing of HRT initiation, with starting more than 10 years after menopause associated with a greater risk
• The presence of pre-existing cardiovascular risk factors, such as hypertension, diabetes, smoking, or obesity, which further elevate the risk For women requiring HRT for severe menopausal symptoms, using the lowest effective dose for the shortest duration possible, preferably with transdermal rather than oral administration, can help minimize these cardiovascular risks, as supported by guidelines and recommendations from various health organizations 1.

From the FDA Drug Label

An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thromboembolism and pulmonary embolism (venous thromboembolism or VTE). In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women years). In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years).

The estrogen hormone replacement therapy increases the risk of myocardial infarction (MI) and stroke by:

• Increasing the risk of thromboembolic events, such as deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Increasing the risk of cardiovascular events, such as coronary heart disease (CHD) events, including nonfatal myocardial infarction and CHD death
• Increasing the risk of stroke, including ischemic stroke The increased risk is observed in women receiving estrogen-alone therapy and estrogen plus progestin therapy, and is demonstrated in several studies, including the Women's Health Initiative (WHI) study 2, 2, and 3.

From the Research

Estrogen Hormone Replacement Therapy and Cardiovascular Risk

• Estrogen hormone replacement therapy (HRT) has been shown to have a complex relationship with cardiovascular risk, including the risk of myocardial infarction (MI) and stroke 4, 5, 6, 7, 8.
• Some studies have suggested that HRT may increase the risk of MI and stroke, particularly in the first year of treatment 4, 5.
• The Women's Health Initiative study found a small but significant increase in the risk of MI in postmenopausal women receiving combined HRT 8.
• Other studies have found that the risk of MI and stroke associated with HRT may be modified by factors such as duration of use, type of estrogen, and presence of prothrombotic mutations 6, 7.

Mechanisms of Increased Risk

• Estrogens are known to have prothrombotic effects, which may contribute to the increased risk of MI and stroke associated with HRT 7.
• The presence of prothrombotic mutations, such as the prothrombin 20210 G-->A variant, may also modify the association between HRT use and MI risk 7.
• The interaction between HRT and prothrombotic mutations may be more pronounced in certain subgroups of women, such as those with hypertension 7.

Clinical Implications

• The use of HRT should be carefully considered in women with a history of MI or stroke, or those with risk factors for these conditions 4, 5, 6, 7, 8.
• Women with prothrombotic mutations or other risk factors for thrombosis may need to be monitored more closely for signs of MI or stroke if they are taking HRT 7.
• Further studies are needed to fully understand the relationship between HRT and cardiovascular risk, and to identify subgroups of women who may be at increased risk 4, 5, 6, 7, 8.