Hrt After A Stroke: Is It Safe?

Hormone replacement therapy (HRT) is a treatment option for women to alleviate menopausal symptoms such as hot flushes. However, the use of HRT has been linked to an increased risk of stroke, with studies showing that HRT increases the relative risk of stroke by about a third. This risk is not modified by the age of hormone initiation or use, or by the temporal proximity to menopause.

The mechanism by which HRT increases the risk of stroke is not fully understood. One hypothesis, the timing hypothesis, suggests that estrogen is protective against cardiovascular disease when women are younger and their vessels are healthy. However, after menopause or in the presence of early-onset atherosclerosis, estrogen may accelerate atherosclerosis and increase the risk of thrombosis, thereby increasing the risk of stroke.

Another hypothesis, the unified hypothesis, proposes that combination HRT increases the risk of plaque erosion and rupture when initiated early but may reduce plaque formation and antagonise the vasculoprotective effects of estrogens when used long-term.

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

Given the potential risks, it is recommended that HRT be limited to the lowest effective dose and used for the shortest duration necessary.

Oral contraceptives and stroke risk

Oral contraceptives (OCs) are a type of hormonal birth control that can increase the risk of stroke, with studies showing a 1.6 times higher risk of stroke and heart attack. The risk is higher for oral contraceptives containing estrogen, with a 20% increased risk of ischemic stroke and total stroke with every 10 micrograms (μg) of estrogen or with each 5-year use of oral contraceptives. The risk of stroke is also higher for people with other risk factors such as smoking or high blood pressure.

The risk of stroke associated with oral contraceptives is dependent on the dose and duration of use. Higher doses of estrogen are associated with a higher stroke risk, with oral contraceptives containing 50 μg or higher doses of estrogen increasing the risk of ischemic stroke. The risk of stroke also increases with longer durations of oral contraceptive use, with a 20% increased risk of ischemic stroke and total stroke for every 5-year increment in duration of use.

The risk of stroke associated with oral contraceptives may be higher in certain populations. For example, a study of Chinese women found that the risk of stroke was higher for women using oral contraceptives with higher levels of estrogen. Additionally, the risk of stroke may be influenced by genetic factors, with a study finding that women carrying specific genetic variants had a higher risk of stroke when using oral contraceptives.

The risk of stroke associated with oral contraceptives may also depend on other factors such as age and the presence of other health conditions. For example, the risk of stroke may be higher for older women or women with conditions such as hypertension, diabetes, or obesity.

It is important to note that the risk of stroke associated with oral contraceptives is generally low, and oral contraceptives are considered a safe and effective method of contraception for most people. However, it is recommended that people with multiple stroke risk factors use non-hormonal or non-estrogen forms of contraception. People can work with their healthcare providers to determine the best form of contraception for them, taking into account their individual risk factors and health history.

Hormone therapy and stroke prevention

Hormone therapy (HT) is not recommended for stroke prevention, and it appears to cause harm. The Women's Health Initiative (WHI) clinical trials found that hormone therapy, whether estrogen alone or with a progestogen, increases a woman's risk of stroke. The findings suggest that standard-dose hormone therapy increases stroke risk for postmenopausal women by about a third. The absolute risk of stroke from standard-dose hormone therapy is about two 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 reason for the increased stroke risk is not well understood, but some suggest that the initiation of HT closest to the time of menopausal transition should decrease the risk. However, research shows that the risk of stroke is not modified by a woman's age or the timing of hormone use.

Stroke risk in postmenopausal women

Stroke is the fourth leading cause of death and a major cause of disability. Women have a lower risk of stroke during middle age than men, but their risk doubles in the decade after menopause. This is due to the menopausal transition, during which women develop cardiovascular risk factors. Endogenous oestrogen levels decline by 60% during this transition, leading to a relative androgen excess, which could contribute to the increased risk.

The age at which menopause occurs may influence stroke risk, but the data are unclear. Some studies suggest that women who experience menopause before the age of 42 have twice the risk of ischemic stroke compared to those who experience it after 42. However, other studies have found no association between age at menopause and stroke mortality.

Hormone therapy and stroke

Hormone therapy (HT) is the most effective treatment for menopausal symptoms, but it has been linked to an increased risk of stroke in postmenopausal women. Randomised trials have shown that HT increases the risk of stroke, whether it is estrogen alone or estrogen combined with progestin. The Women's Health Initiative (WHI), a primary prevention study, found that HT increased the risk of stroke by 40%. As a result, HT is not recommended for stroke prevention.

The mechanism by which HT increases stroke risk is not well 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. However, after menopause or in the presence of early-onset atherosclerosis, estrogen may accelerate atherosclerosis and increase the risk of thrombosis. Another hypothesis is the unified hypothesis, which proposes that combination HT increases the risk of plaque erosion and rupture when initiated early but may reduce plaque formation and antagonise the vasculoprotective effects of estrogens when initiated later.

The Kronos Early Estrogen Prevention Study (KEEPS) and the Early Versus Late Intervention Trial with Estradiol (ELITE) are two ongoing studies that may shed light on the association between HT and stroke. These trials aim to determine the effects of HT on the progression of subclinical atherosclerosis in perimenopausal and early postmenopausal women.

Route, dose, and type of hormone therapy

The route of administration may also play a role in stroke risk. Transdermal estrogen may be safer than oral estrogen because it does not undergo first-pass liver metabolism, which can increase clotting factors and inflammatory markers. Observational data suggest that transdermal HT is associated with a lower risk of stroke than oral HT.

Dose may also be a factor. Some studies have found a dose-response relationship between oral conjugated equine estrogen (CEE) and stroke risk, with higher doses increasing risk. However, the Nurses' Health Study found that low-dose CEE (0.3 mg/d) was not associated with an increased risk of stroke.

The type of HT may also be a factor. Observational studies have found no difference in stroke risk between users of mono and dual therapy. However, clinical trials have shown that both estrogen alone and estrogen plus progestin increase stroke risk.

The timing of hormone therapy initiation

The timing of HT initiation may also affect stroke risk. The WHI found that women who were 10 years or less since menopause had a non-significant benefit from HT, while those who were 20 years or more since menopause had an increased risk. However, there was no difference in stroke risk based on age or timing of initiation. This was also shown in the Nurses' Health Study.

While HT is effective for treating menopausal symptoms, it is not recommended for stroke prevention due to the increased risk. More research is needed to understand which women are at greatest stroke risk during midlife and to determine the safest formulation, dose, and duration of HT that will treat symptoms without increasing stroke risk. The ongoing KEEPS and ELITE trials may provide valuable insights in this regard.

Stroke risk and menopause

Stroke is the fourth leading cause of death and a major cause of disability. Women have a lower risk of stroke during middle age, but their risk roughly doubles in the decade after menopause. This is thought to be due to the decline in oestrogen levels during the menopausal transition, which can lead to a relative androgen excess and an increase in cardiovascular risk factors.

Risk factors

During the menopausal transition, women experience an increase in abdominal obesity, triglycerides, total cholesterol and LDL cholesterol, fasting glucose and other measures of insulin resistance, BMI, and blood pressure. Low levels of sex hormone-binding globulin (SHBG) and the free androgen index (FAI) have also been associated with increased cardiovascular risk factors during this time.

Age at menopause and stroke risk

There is some evidence to suggest that women who experience menopause before the age of 40 have a higher risk of stroke than those who experience it between the ages of 50 and 54. However, the data on this is not clear, and other studies have found no association between age at menopause and stroke mortality.

Hormone therapy and stroke risk

Randomised clinical trial data indicates that the use of oestrogen plus progestogen, as well as oestrogen alone, taken orally increases stroke risk in healthy postmenopausal women. However, it is hypothesised that transdermal estrogen may be safer than oral estrogen due to the lack of exposure to first-pass liver metabolism and the associated increase in clotting factors and inflammatory markers.

More research is needed to understand which women are at greatest stroke risk during midlife and to determine the safest formulation, dose, and duration of hormone therapy that will treat vasomotor symptoms without increasing the risk for stroke.

Stroke risk and hormone replacement therapy

Hormone replacement therapy (HRT) is a treatment that involves taking hormones to replace the ones the body no longer produces after menopause. HRT is used to relieve menopausal symptoms such as hot flushes, night sweats, and vaginal dryness. It can also help prevent bone loss and reduce the risk of bone fractures in postmenopausal women. However, HRT is not without risks and has been associated with an increased risk of certain health conditions, including stroke.

Hormone Replacement Therapy and Stroke Risk

Several studies have found a link between HRT use and an increased risk of stroke, particularly ischemic stroke. The Women's Health Initiative (WHI) clinical trials, for instance, showed that estrogen alone or in combination with progestogen increased a woman's risk of stroke by about a third. This means that for every 10,000 women taking HRT for a year, there would be about two to nine additional strokes. The risk appears to be higher for older women and is not affected by the age of hormone initiation or the time since menopause.

The mechanism behind the increased stroke risk with HRT is not yet fully understood. Some researchers have suggested that the timing of HRT initiation may play a role, with earlier initiation potentially reducing the risk. However, studies like the WHI and the Nurses' Health Study have found no association between the timing of HRT and stroke risk. Other factors, such as dose and type of estrogen or progestogen, may also influence stroke risk, but more research is needed to confirm these findings.

Types of Hormone Replacement Therapy and Stroke Risk

Different types and formulations of HRT may have varying effects on stroke risk. Oral HRT, for example, has been consistently linked to an increased risk of stroke, particularly during the first year of use. Transdermal estrogen, on the other hand, has been associated with a lower risk of venous thrombosis compared to oral HRT. Additionally, lower doses of transdermal estrogen may not increase stroke risk at all. More research is needed to confirm these findings and determine the optimal dose and formulation of HRT to minimize stroke risk.

Alternative Treatments and Stroke Risk

Other compounds that interact with estrogen receptors, such as selective estrogen receptor modulators (SERMs) like raloxifene and tamoxifen, have also been studied for their effects on stroke risk. These drugs are used for the treatment and prevention of osteoporosis and breast cancer. While raloxifene has not been shown to significantly increase stroke risk, tamoxifen has been associated with an increased risk of ischemic stroke in women with breast cancer. Tibolone, a progestogenic steroid used in many countries for the treatment of menopausal symptoms and osteoporosis, has been found to increase the risk of stroke in older postmenopausal women.

Physical Activity and Hormone Replacement Therapy

Physical activity may play a role in mitigating the increased stroke risk associated with HRT use. A study in the California Teachers Study cohort found that meeting the American Heart Association's recommendations for leisure-time physical activity (LTPA) may help reduce short-term stroke risk in women using HRT. In this study, current HRT users who met the LTPA recommendations had a similar stroke risk to never users, while those who did not meet the recommendations had an increased risk. These findings suggest that physical activity may be a valuable tool for managing stroke risk in women using HRT.

In conclusion, while HRT can be an effective treatment for menopausal symptoms, it is important to consider the potential risks, including an increased risk of stroke. More research is needed to fully understand the mechanisms behind this increased risk and to identify ways to minimize it. Physical activity may be one strategy to reduce stroke risk in women using HRT.

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