Hrt And Stroke: What's The Link?

Hormone replacement therapy (HRT) is a treatment option for postmenopausal women to relieve symptoms such as vasomotor symptoms, atrophic vaginitis, and osteoporosis. However, the use of HRT has been linked to an increased risk of stroke, particularly ischemic stroke, in postmenopausal women. This risk appears to be dependent on the timing of initiation, with women who start HRT within 5 years of menopause having a similar risk to those who never use HRT, while women who start HRT 10 or more years after menopause have an increased risk. The mechanism behind this increased risk is not fully understood but may be related to the effects of HRT on blood clotting and blood pressure. Overall, the absolute risk of stroke from HRT is low, but it is important for women considering HRT to be aware of this potential risk and discuss it with their doctor.

Hormone replacement therapy (HRT) and the risk of stroke in postmenopausal women

Hormone replacement therapy (HRT) is used to treat postmenopausal women for osteoporosis and bone fractures, as well as menopausal and post-menopausal symptoms. However, HRT has been linked to an increased risk of stroke in postmenopausal women.

The link between HRT and stroke

Several studies have shown a link between HRT and an increased risk of stroke in postmenopausal women. The Women's Health Initiative (WHI) clinical trials found that standard-dose HRT increased the risk of stroke in postmenopausal women by about a third. This risk was not modified by the age of hormone initiation or use, or the temporal proximity to menopause. The absolute risk of stroke from standard-dose HRT is about 2 additional strokes per 10,000 person-years of use for women under 60 years of age, and the risk is considerably greater for older women.

The Nurses' Health Study, which followed over 120,000 women aged 30 to 55, found a similar increase in the risk of stroke among current users of HRT compared to never-users. The risk was higher for estrogen plus progestogen (relative risk of 1.39) than for estrogen alone (relative risk of 1.3).

Another study that examined the relationship between age at menopause and stroke incidence found no significant relationship. However, it did find that a lifetime exposure to estrogen of less than 34 years was associated with an increased risk of ischemic stroke.

The Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Estrogen for Stroke Trial (WEST) found no overall difference in stroke risk between women taking HRT and those taking a placebo. However, WEST found a twofold increased risk of fatal or non-fatal stroke in the first 6 months after starting HRT.

Mechanisms behind the link

The mechanism behind the increased risk of stroke with HRT is not yet fully understood. One hypothesis is the timing hypothesis, which suggests that estrogen is protective against cardiovascular disease when women are younger and their vessels are healthy, but harmful after menopause or in the presence of early-onset atherosclerosis. Another hypothesis is the unified hypothesis, which proposes that combination HRT increases the risk of plaque erosion/rupture with early exposure but reduces plaque formation and antagonises the vasculoprotective effects of estrogens over the long term.

Patient care implications

The 2017 Hormone Therapy Position Statement of The North American Menopause Society (NAMS) recommends a patient-specific and tailored approach to HRT decision-making. It suggests that HRT should be initiated within 10 years of menopause for women with a low risk of adverse effects and a high risk of bone loss or bothersome vasomotor symptoms. For women experiencing vasomotor symptoms, low-dose, non-systemic estrogen therapy is generally recommended first to maintain a lower stroke risk.

HRT and stroke: the role of timing

Hormone replacement therapy (HRT) is used to treat menopausal and post-menopausal symptoms such as osteoporosis and bone fractures, as well as hot flashes and night sweats. However, HRT has been linked to an increased risk of stroke, with research indicating that standard-dose HRT increases the risk of stroke in postmenopausal women by about a third. The risk is similar for estrogen-only HRT and estrogen combined with progestogen.

The risk of stroke with HRT appears to be dependent on the timing of initiation relative to menopause. Some studies suggest that the risk of stroke is higher when HRT is initiated more than five years after menopause, while others suggest that the risk is higher when initiated within the first year of menopause. However, the majority of studies indicate that the timing of HRT initiation does not affect stroke risk.

The Impact of Timing on Stroke Risk

Several studies have investigated the impact of the timing of HRT initiation on stroke risk, with mixed results. Some studies suggest that the risk of stroke is higher when HRT is initiated further from the time of menopause. For example, a study by Carrasquilla et al. found that women who began taking HRT more than five years after menopause had an increased risk of ischemic and hemorrhagic stroke compared to women who did not receive HRT. Similarly, a Danish study found that oral HRT was associated with an increased risk of ischemic stroke, while vaginal estrogen use was associated with a decreased risk. This suggests that the route of administration may also play a role in stroke risk.

On the other hand, some studies suggest that the risk of stroke is higher when HRT is initiated closer to the time of menopause. For example, a study by Lokkegaard et al. found that the risk of stroke was highest during the first year of HRT use, regardless of the time since menopause. This may be due to immediate changes in hemostatic balance, leading to a prothrombotic state. However, this elevated risk appeared to decline after the first year of use.

The Critical Window Hypothesis

The critical window hypothesis posits that the effects of exogenous estrogens are modified by a woman's age or the temporal proximity to menopause. It predicts that HRT is more likely to be beneficial when initiated by younger women who are closer to menopause. However, this hypothesis has not been supported by studies investigating the link between HRT and stroke risk. Both the Women's Health Initiative (WHI) hormone therapy trials and the Nurses' Health Study found no evidence that stroke risk was modified by age or the timing of HRT use.

Absolute vs. Relative Risk

It is important to consider both the absolute and relative risk of stroke when evaluating the impact of HRT. While the relative risk of stroke may be increased with HRT, the absolute risk is still low, especially for women under 60 years of age. For example, the WHI trial found that HRT caused two additional strokes per 10,000 person-years for women aged 50 to 59, which is equivalent to one additional stroke among 1,000 women using HRT for five years. Therefore, while HRT may increase the risk of stroke, the absolute risk is relatively small.

Recommendations for HRT Use

Due to the potential increased risk of stroke and other cardiovascular events, HRT is not recommended for the primary or secondary prevention of cardiovascular disease. Current guidelines recommend a patient-specific and tailored approach to HRT decision-making, taking into account individual risk factors and the severity of menopausal symptoms. For women with bothersome vasomotor symptoms, low-dose, non-systemic estrogen therapy is recommended before trying systemic therapy to maintain a lower stroke risk. Additionally, HRT should be used at the lowest effective dose for the shortest duration necessary.

HRT and stroke risk: the impact of different types of hormones

Hormone replacement therapy (HRT) is a treatment option for women to relieve menopausal symptoms such as hot flashes, night sweats, and vaginal dryness. While HRT can be beneficial for some women, it is important to understand the potential risks associated with this treatment, particularly the increased risk of stroke. The impact of HRT on stroke risk has been the subject of extensive research, and evidence suggests that the type of hormones used and the timing of HRT initiation play a crucial role.

The Link Between HRT and Stroke

Several studies have found a link between HRT and an increased risk of stroke in postmenopausal women. The Women's Health Initiative (WHI) clinical trials, which included a large cohort of postmenopausal women, found that estrogen, alone or in combination with a progestogen, increased the risk of stroke by about a third. This risk was primarily associated with ischemic stroke, and the absolute risk was higher for older women. Other studies, such as the Nurses' Health Study, have supported these findings, showing a similar increase in stroke risk with HRT use.

The Role of Hormone Type

The type of hormones used in HRT may influence stroke risk. Evidence suggests that standard-dose hormone therapy, particularly oral estrogen, increases stroke risk. On the other hand, lower doses of transdermal estradiol (≤50μg/d) may not alter stroke risk. Oral estrogen has been associated with a prothrombotic effect, increasing the risk of blood clots. In contrast, transdermal estrogen, which is applied to the skin, has been linked to a lower risk of venous thrombosis compared to oral estrogen.

Timing of HRT Initiation

The timing of HRT initiation in relation to menopause may also impact stroke risk. Some studies have suggested that initiating HRT closer to menopause may reduce the risk of cardiovascular disease. However, research specifically focusing on stroke risk has found no significant difference in stroke risk based on the timing of HRT initiation. The Nurses' Health Study, for example, showed no evidence that stroke risk was modified by age or the timing of HRT use.

Patient Care Implications

Due to the potential risks associated with HRT, it is essential to carefully assess each patient's situation before initiating treatment. The 2017 Hormone Therapy Position Statement of The North American Menopause Society (NAMS) recommends a patient-specific and tailored approach to HRT decision-making. For women with bothersome vasomotor symptoms, low-dose, non-systemic estrogen therapy is often recommended before trying systemic therapy to maintain a lower stroke risk. Additionally, doctors advise limiting HRT to the lowest effective dose and using it for the shortest duration necessary.

HRT and stroke: the influence of route of administration

Hormone replacement therapy (HRT) is used to relieve perimenopausal symptoms and is the most effective treatment for menopausal symptoms. However, HRT is associated with an increased risk of stroke, and neurologists are often asked to consult with prescribing physicians to assess stroke risk. The risk of stroke events in postmenopausal women with or without HRT is not clear. Efforts have been made to assess the risks and benefits of HRT after menopause.

Route of administration

A study by Løkkegaard et al. examined stroke and stroke sub-type incidence based on the route of administration of hormone therapy. Using five 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 a decreased risk of stroke with vaginal estrogen use.

Timing of initiation

The time since menopause and the initiation of HRT have been shown to have an 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. Initiation of HRT more than 5 years after menopause increased the risk of ischemic and hemorrhagic stroke.

Dose

The effect of dose is not clear, but some evidence points to lower stroke risks with lower doses of oral estrogens. In the Nurses' Health Study, low-dose conjugated estrogens (0.3 mg/d) were unassociated with stroke risk. In the General Practice Research Database, however, "low-dose" conjugated estrogens (defined as ≤0.625 mg) were still linked to increased risk. Use of transdermal estrogen is also addressed in the General Practice Research Database, where lower doses of transdermal estrogen (≤50μg/d estradiol) were not significantly associated with stroke.

Other compounds

Other drugs with the ability to interact with estrogen receptors have the potential to affect stroke risk. These include raloxifene, tamoxifen, and tibolone.

HRT and stroke risk: the effect of dose

Hormone replacement therapy (HRT) is used to alleviate symptoms of menopause, such as hot flashes and night sweats. However, it has been linked to an increased risk of stroke, which has been observed to vary depending on the dosage and route of administration.

Evidence from Clinical Trials and Observational Research

Clinical trials and observational research indicate that standard-dose HRT increases the risk of stroke in postmenopausal women by about a third. This risk is not influenced by age, the timing of initiation, or the use of estrogen alone or in combination with progestogen.

Dose and Route of Administration

Evidence suggests that lower doses of transdermal estradiol (≤50μg/d) may not increase stroke risk. In contrast, oral HRT, particularly at higher doses, has been associated with an elevated risk of stroke.

Initiation of HRT and Stroke Risk

The time since menopause does not seem to influence stroke risk. However, initiating HRT more than 5 years after menopause has been linked to an increased risk of ischemic stroke.

Absolute Risk

It is important to note that the absolute risk of stroke from standard-dose HRT is relatively rare, with about 2 additional strokes per 10,000 person-years of use for women under 60. The risk is significantly higher for older women.

Other Factors Influencing Stroke Risk

Other factors that may influence stroke risk in women using HRT include a history of stroke or blood clots, certain medications, severe migraines, complicated diabetes, and heart abnormalities or disease.

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