What are the cardiac side effects of Estradiol (Estrogen)?

From the Guidelines

Estradiol can cause several cardiac side effects, including an increased risk of blood clots, stroke, and heart attack, particularly in older women and those with existing cardiovascular disease, as evidenced by the Women's Health Initiative randomized, controlled trial 1. The most significant concerns with estradiol therapy include:

• Increased risk of cardiac ischemic events, such as nonfatal myocardial infarction, as shown in the Women's Health Initiative study 1
• Increased risk of stroke and venous thromboembolism, as reported in the 2011 ACCF/AHA guideline for coronary artery bypass graft surgery 1
• Potential to raise blood pressure and cause fluid retention, which may worsen heart failure symptoms in susceptible patients
• Risk of palpitations or irregular heartbeats These cardiovascular risks are more pronounced with oral estradiol compared to transdermal forms, such as patches or gels, because oral administration creates higher concentrations of estrogen in the liver, altering clotting factors and lipid metabolism 1. The risk of these cardiac effects is generally dose-dependent and increases with age, smoking, obesity, and pre-existing conditions like hypertension or diabetes. For this reason, if estradiol therapy is necessary, using the lowest effective dose for the shortest duration is recommended, and transdermal formulations may be safer for women with cardiovascular risk factors 1. It is essential to weigh the benefits and harms of estradiol therapy, considering the individual patient's risk factors and medical history, as emphasized by the U.S. Preventive Services Task Force recommendation statement 1.

From the FDA Drug Label

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 thrombosis and pulmonary embolism (venous thromboembolism or VTE). In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. 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). Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. Breast cancer Cancer of the uterus Stroke Heart attack Blood clots Dementia Gallbladder disease Ovarian cancer

The cardiac side effects of Estradiol (Estrogen) include:

• Myocardial infarction
• Stroke
• Venous thrombosis
• Pulmonary embolism
• Coronary heart disease (CHD) events
• Heart attack
• Blood clots These side effects are associated with an increased risk of cardiovascular events, and the risk may be higher in women with pre-existing risk factors, such as hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity 2.

From the Research

Cardiac Side Effects of Estradiol

The cardiac side effects of estradiol, a form of estrogen, have been studied in various research papers. The evidence suggests that:

• Estradiol may have a lower risk of cardiovascular events compared to other forms of hormone therapy, such as conjugated equine estrogens 3
• The risk of myocardial infarction, thrombotic stroke, and venous thromboembolism may be lower in users of estradiol/dydrogesterone compared to non-users of hormone therapy 4
• Transdermal estrogen patch use may have a protective effect on cardiovascular outcomes, with a decrease in the risk of stroke and no increase in the risk of coronary heart disease, death, or myocardial infarction 5
• The timing of initiation of estradiol therapy may affect its cardiovascular effects, with earlier initiation (within 6 years of menopause) associated with less progression of subclinical atherosclerosis compared to later initiation 6
• Estradiol-based postmenopausal hormone therapy may be associated with a reduced risk of death caused by coronary heart disease, stroke, or any disease, with risk reductions positively related to duration of exposure 7

Key Findings

• Estradiol may have a more favorable cardiovascular risk profile compared to other forms of hormone therapy
• The risk of cardiac side effects may vary depending on the timing of initiation and duration of estradiol therapy
• Transdermal estrogen patch use may be a safer alternative to oral hormone therapy in terms of cardiovascular risk
• Estradiol-based postmenopausal hormone therapy may be associated with a reduced risk of mortality from cardiovascular and all-cause mortality