What is the risk of stroke associated with estrogen replacement therapy (ERT) in postmenopausal women?

From the Guidelines

Estrogen replacement therapy in postmenopausal women is not recommended due to the increased risk of stroke, as evidenced by multiple randomized trials, including the Women’s Estrogen for Stroke Trial (WEST) and the Women’s Health Initiative (WHI) 1. When considering hormone therapy for menopausal symptoms, the following key points should be taken into account:

• The lowest effective dose should be used for the shortest duration possible, typically starting with preparations like oral estradiol (0.5-1 mg daily) or transdermal estradiol patches (0.025-0.05 mg/day) 1.
• Women with an intact uterus must also take progesterone to prevent endometrial cancer.
• The stroke risk is most pronounced with oral formulations, while transdermal delivery may carry less risk, as suggested by the differences in risk observed in various studies 1.
• The increased risk is most significant in women over 60 or those who start therapy more than 10 years after menopause, highlighting the importance of individualized risk assessment 1. Key factors to consider when evaluating the risk-benefit ratio of hormone therapy include:
• Existing cardiovascular disease
• History of stroke
• Uncontrolled hypertension
• Clotting disorders Women with these conditions should generally avoid hormone therapy altogether, and for those who require treatment for severe menopausal symptoms, a thorough discussion of individual risk factors with their healthcare provider is essential before starting therapy 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 stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years).

The use of estrogen replacement therapy in postmenopausal women is associated with an increased risk of stroke. The Women's Health Initiative study found that women receiving conjugated estrogens (CE) had a higher risk of stroke compared to those receiving placebo 2. Additionally, the CE/MPA substudy of WHI found that women receiving CE/MPA had an increased risk of stroke compared to those receiving placebo, with a rate of 29 vs 21 per 10,000 women-years 2. Therefore, estrogen replacement therapy should be used with caution in postmenopausal women, and the lowest effective dose should be prescribed for the shortest duration consistent with treatment goals and risks for the individual woman 2. Key points include:

• Increased risk of stroke associated with estrogen replacement therapy
• Use with caution in postmenopausal women
• Prescribe lowest effective dose for shortest duration consistent with treatment goals and risks.

From the Research

Estrogen Replacement Therapy and Stroke Risk

• Estrogen replacement therapy has been shown to increase the risk of stroke in postmenopausal women, with an approximate excess risk of 1 event per 1000 person-years 3.
• The risk of stroke associated with estrogen replacement therapy tends to persist over the years, and women should be made aware of this risk when considering hormone therapy 4.
• However, healthy women who begin hormone therapy soon after menopause may earn more benefit than harm from the treatment, including a reduction in cardiovascular risk and an increase in bone mineral density 4.
• Transdermal routes of hormone therapy administration may be preferred as they have the least impact on coagulation, which may help reduce the risk of stroke 4.

Factors Influencing Stroke Risk

• The timing of hormone therapy initiation may influence the risk of stroke, with early initiation (close to menopause) potentially having a more favorable risk-benefit profile 5.
• The dose and duration of hormone therapy may also impact the risk of stroke, with lower doses and shorter durations potentially having a lower risk 5.
• Individualized assessment of a woman's health status and risk factors is necessary to determine the best approach to hormone therapy and minimize the risk of stroke 6, 7.

Alternative Therapies

• Nonhormonal therapies, such as selective estrogen receptor modulators and bioidentical estrogens, may be considered for women who are not candidates for hormone therapy or who experience adverse effects 3.
• Alternative therapies, such as acupuncture and electroacupuncture, may also be effective in alleviating menopausal symptoms and reducing the risk of stroke 5.