Hormone therapy and the risk of stroke: Perspectives ten years after the Women’s Health Initiative trials Original paper

What was studied?

This study reviews the relationship between hormone therapy (HT) and the risk of stroke, with particular emphasis on postmenopausal women who use estrogen-based treatments. It evaluates data from large clinical trials like the Women’s Health Initiative (WHI), focusing on the risks associated with estrogen and progestogen therapies, including both oral and transdermal forms. The paper explores how estrogen therapy affects ischemic stroke risk, outlining the differences between estrogen alone and estrogen-progestogen combinations, as well as the dose-dependent effects on stroke. The study provides a comprehensive look at stroke mechanisms, estrogen’s impact on the cardiovascular system, and how these therapies influence hemostasis and vascular health.

Who was studied?

The review primarily examines postmenopausal women from large clinical trials, including those enrolled in the Women’s Health Initiative (WHI), which consisted of women aged 50 to 79 years at baseline. The study also includes data from observational studies and other clinical trials, such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Estrogen for Stroke Trial (WEST). It focuses on healthy women who were using hormonal therapies for menopause symptom management and those who participated in trials investigating the cardiovascular outcomes of these therapies. The paper also considers the impact of hormone therapy on women with specific risks for stroke, such as those with cardiovascular disease, and the potential for transdermal estrogen as a safer alternative in high-risk groups.

Most important findings

The study reveals estrogen therapy increases the risk of ischemic stroke by about one-third, a finding consistent across multiple clinical trials, including the WHI. The risk appears to be more pronounced in oral estrogen therapies, likely due to first-pass metabolism in the liver, which can alter coagulation pathways and increase thrombosis risk. In contrast, transdermal estrogen does not carry the same degree of risk, likely because it bypasses the liver. The estrogen-progestogen combination therapy showed a similar risk profile to unopposed estrogen in terms of stroke risk, with the addition of progestogen not offering additional protective benefits.

The study suggests that the timing of therapy initiation does not significantly alter stroke risk; both younger women starting hormone therapy soon after menopause and older women starting therapy later have similar stroke risk profiles. Furthermore, lower doses of estrogen, such as those used in transdermal estradiol (≤50μg/day) or low-dose oral conjugated estrogens (0.3 mg/day), were found to have no significant increase in stroke risk. However, the study highlights that stroke risk increases significantly with age, particularly for women aged 60 and older.

Key implications

Clinicians should recognize that while hormone therapy is effective for managing menopausal symptoms, particularly vasomotor symptoms, it also carries an increased risk of ischemic stroke. Transdermal estrogen may be a safer option, especially for women with cardiovascular risk factors, due to its lower association with thrombotic events. The study suggests that oral estrogen therapy should be used cautiously, particularly in older women or those with existing cardiovascular disease. For women aged under 60 or within 10 years of menopause, the absolute risk of stroke is low, but clinicians must still weigh the benefits of symptom relief against the small but real risk of stroke. The study further emphasizes that individualized therapy is critical, considering a patient’s age, cardiovascular health, and genetic predisposition to thrombosis when prescribing hormonal therapies.