Estrogen Replacement Therapy and Stroke Risk

BRIEF COMMUNICATION

Hormone replacement therapy after menopause is not a simple topic. Among other health implications, the risk of stroke events in postmenopausal women with or without hormone replacement therapy (HRT) is not clear. Efforts have been made to assess the risks and benefits of hormone replacement therapy after menopause. The most well-defined benefits are related to prevention of osteoporosis and bone fractures as well as the reduction of menopausal and post-menopausal symptoms. Risks of HRT include malignancy (especially breast cancer) and cardiovascular events (eg, myocardial infarction, stroke, venous thromboembolism).

Carrasquilla and colleagues¹ used pooled data from 5 population-based cohort studies that included a total of 88,914 women. This observational study concluded that the number of years between menopause and the initiation of HRT had a strong impact on the incidence of stroke. Women who began taking HRT within 5 years of menopause experienced no change in the stroke-free period compared with women who did not receive HRT. Likewise, initiation of HRT more than 5 years after menopause increased the risk of ischemic and hemorrhagic stroke.¹

Researchers in another study in Denmark examined stroke and stroke sub-type incidence based on the route of administration of hormone therapy.² Using 5 national registries, a total of 980,003 women were included. The results demonstrated that there was an increased risk of ischemic stroke with oral HRT, but not with a transdermal mode of delivery, and that there was, interestingly, a decreased risk of stroke with vaginal estrogen use.

The mechanism by which HRT could increase the risk of stroke had been extensively studied, and there are some answers-but there are some unanswered questions as well. Before the onset of menopause, women have a lower incidence of stroke than men of the same age. Because women experience a higher stroke rate than age-matched men after menopause, estrogen, the most obvious physiological change in women after menopause, could have an influence on this incidence. Yet, estrogen replacement therapy has been noted to increase the incidence of cardiac events and stroke. And that is where the question of mechanism gets more complicated.

Several studies show that estrogen receptors may become less sensitive to estrogen after a period of time, during which there has been lower exposure to estrogen. This diminished response has been hypothesized to be an explanation for the fact that women who begin HRT later do not experience a protective effect. But it does not explain the increased incidence of stroke that is sometimes observed with HRT.

Patient care implications after stroke

The 2017 Hormone Therapy Position Statement of The North American Menopause Society (NAMS)³ recommends that doctors follow a patient-specific and tailored approach to HRT decision-making. NAMS recommends initiating treatment within 10 years of menopause for women who have a low risk of adverse effects and who have a high risk of bone loss or bone fracture or who have bothersome vasomotor symptoms (eg, “hot flashes”). Women who experience the vasomotor symptoms of menopause are generally started on low-dose, non-systemic estrogen therapy before trying systemic therapy to maintain a lower stroke risk.

While neurologists do not initiate or make decisions about HRT, stroke risk plays a role in the decision-making process. Neurologists could be asked to assess stroke risk when physicians who prescribe HRT are making risk/benefit decisions.

References:

1. Carrasquilla GD, Frumento P, Berglund A, et al. Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies. PLoS Med. 2017;14:e1002445.

2. Løkkegaard E, Nielsen LH, Keiding N. Risk of Stroke With Various Types of Menopausal Hormone Therapies: A National Cohort Study. Stroke. 2017;48:2266-2269.

3. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753.