Stroke Risk Factors Unique to Women

Data on the relationship of endogenous sex hormones and risk of stroke in women are relatively limited. Estrogen levels fluctuate dramatically in women with the menstrual cycle and then drop dramatically in the menopausal transition and in post-menopause. In data from the Copenhagen City Study, neither high nor low estradiol levels were associated with increased risk of ischemic stroke.¹ In premenopausal women, those in the lowest 10th percentile of estradiol had a >2-fold increased risk of ischemic stroke, but this was based on small case numbers. There was no relationship observed for postmenopausal estradiol levels and risk of ischemic stroke. Similarly, the authors of a study of French women over the age of 65 years found no association between estradiol levels and risk of ischemic stroke.² In the Study of Osteoporotic Fractures, women in the highest category of free estrogen index had a higher age-adjusted risk of ischemic stroke, but this was not independent of standard stroke risk factors, including hypertension, diabetes mellitus, and adiposity.³ Subsequently, a meta-analysis of the 3 available studies found no association, further supporting the lack of a relationship between estradiol levels and risk of ischemic stroke.¹

Testosterone levels are more stable than estrogen levels across the lifespan in women, with relatively constant levels from ages 30 to 70 years.¹ Although low testosterone levels have been associated with increased stroke risk in men, no clear relationship has been seen for testosterone levels and risk of stroke in women.¹ The investigators of the aforementioned study of French women over the age of 65 years found no association between high or low testosterone levels and risk of stroke.²

Dehydroepiandrosterone, an adrenal hormone which can also be used for the synthesis of estrogen and testosterone, has also been investigated. Low dehydroepiandrosterone levels have been associated with increased risk of ischemic stroke, with women in the lowest quartile having a relative risk (RR) of 1.41 (95% confidence interval [CI], 1.03–1.92) for ischemic stroke after adjustment for other risk factors.⁴ Dehydroepiandrosterone levels at presentation of acute stroke were also inversely associated with stroke severity in a hospital-based study of stroke in postmenopausal women.⁵ Another study of women undergoing coronary angiography provided evidence that lower dehydroepiandrosterone levels were associated with increased cardiovascular mortality, including death from stroke.⁶

Additional prospective studies of endogenous sex hormones and risk of stroke in women are needed, particularly with more sensitive measures of hormones, and in high-risk groups including black and Hispanic women.

Earlier age at menarche has been associated with greater cardiovascular disease (CVD) morbidity and mortality in some,^7–9 but not all studies,^10–12 and data specific for stroke are limited. In the Million Women Study from the United Kingdom, a U-shaped relationship between age at menarche and cerebrovascular disease was observed.⁹ Women who experienced menarche at age ≤10 years were at higher risk of developing stroke in later life compared with those with age at menarche at 13 years (RR, 1.16 [95% CI, 1.09–1.23]); however, women who experienced menarche at age ≥17 years were also at higher risk of developing stroke compared with those with age at menarche at 13 years (RR, 1.13 [95% CI, 1.03–1.24]).⁹ Women with extremely early age at menarche may experience hormonal disturbances, such as higher exposure to estradiol, potentially mediated through childhood obesity.¹³ The timing of menarche is associated with type 2 diabetes mellitus risk,^14,15 an association which may be influenced by childhood adiposity and endocrinopathies.^13,16 Although the Million Women Study attempted to control for potential confounding factors, such as body mass index, through statistical adjustment,⁹ obesity may have been present before the onset of menarche, complicating inferences about cause and effect.

Women of reproductive age are at a lower risk of CVD compared with men of similar age and lifestyle, but women who experience early menopause have increased cardiovascular risk.¹⁷ In a recent meta-analysis, investigators reported that early age at natural menopause (menopause onset before 45 years) was associated with a slightly higher risk of total CVD mortality (RR, 1.12 [95% CI, 1.03–1.21]) than onset at age 45 years or later; however, this association was not observed for stroke mortality risk independently.¹⁸ Surgical menopause, bilateral oophorectomy with or without hysterectomy, has also been associated with higher risk of CVD.^19,20 In the Nurses’ Health Study, bilateral oophorectomy before age 50 years was associated with increased CVD mortality in women and especially in women who did not use hormone therapy.²¹ When a sensitivity analysis of stroke mortality was conducted, the CI of this association widened potentially because of low numbers although the risk estimate remained elevated (RR, 1.15 [95% CI, 0.85–1.56]).²¹ Therefore, further investigations are warranted to examine these potential associations for early menopause and stroke.

Specific mechanisms responsible for the association between the timing of age at menopause and CVD are unclear. However, CVD incidence rising sharply after menopause suggests protective benefits of ovarian hormones.²² Estrogen inhibits hepatic lipase,²³ thus decline in endogenous estrogens in the menopausal transition may adversely affect lipid levels and subsequently cardiovascular risk.²⁴ The menopausal transition is associated with declines in high-density lipoprotein cholesterol and increases in low-density lipoprotein cholesterol,²⁴ as well as changes in high-density lipoprotein composition, with higher number of small high-density lipoprotein particles, which confer less cardiovascular protection than large high-density lipoprotein particles.²⁵ Hence, decreased estrogen concentrations over the menopause transition and effects on lipoprotein profiles may subsequently contribute to atherosclerosis. In a cross-sectional, population-based study, longer duration of reproductive lifespan and years from menarche to menopause, were associated with a lower 10-year CVD risk assessed by the Framingham Risk Score in postmenopausal women.²⁶ In the prospective cohort Nurses’ Health Study, a shorter duration of reproductive lifespan was associated with a higher risk of stroke, as well as CVD, which was likely driven by earlier age at menopause (either naturally or surgically).²⁷

Hormonal contraceptives, including oral, transdermal, and vaginal formulations, are effective and are used worldwide by >100 million women (World Health Organization 2014). There are various formulations containing either combined estrogen and progestogen or progestogen alone, administered as pills, patches, and rings. Combined oral contraceptives (COC), comprised both estrogen and progestogen, are thrombogenic²⁸ and, historically, have been associated with increased risk of CVD.^29,30 Oral estrogens have a dose–response association with risk, and doses have declined since their introduction in the 1960s. Most COCs now contain <50 μg and some contain as low as 15 μg of estrogen. Authors who evaluated the risk of second- and third-generation estrogen-containing oral contraceptives continued to find a 60% to 80% increased odds (95% CI, 1.2–2.8) of the combined end point of myocardial infarction or ischemic stroke among COC users compared with nonusers.^30–33 In a separate study, second-generation COCs were associated with an odds ratio=2.54 (95% CI, 1.96–3.28) and third-generation oral contraceptives with an odds ratio=2.03 (95% CI, 1.15–3.57) of stroke.³⁴ Progestogen-only hormonal contraceptives have not been associated with increased risk of ischemic stroke although data are limited.^30,35 Nonoral methods of delivering combined hormonal contraceptives, including the vaginal ring and contraceptive patches, seem to have the same risk as oral contraceptives.³⁶

Risk of stroke with COC use rises in the presence of other cardiovascular risk factors (ie, smoking, age [>35 years], and history of migraine with aura). Migraine with aura is a common condition in younger women, and the risk of stroke in patients with migraine with aura is increased ≈2-fold.³⁷ Women with migraine who also use COCs have a further increased risk of ischemic stroke (7.02 [95% CI, 1.51–32.68]) where women with migraine with aura, COC use, and who are active smokers have a dramatically elevated risk for stroke (RR, 10 [95% CI, 1.4–73.7]).³⁷ Guidelines from the International Headache Society Task Force on COC prescribing recommendations have been published previously.³⁸ Women who have migraine with aura should be advised to control all modifiable risk factors, including tobacco use and hypertension, and birth control methods other than COCs should be considered.³¹

Hormonal contraceptives are used by millions of women, and for most low-risk women, the risk of stroke associated with COC is lower than the risk of stroke during pregnancy. However, there is a clear association between hormone-containing birth control methods and ischemic stroke. This is magnified by stroke risk factors. Although a COC pill containing 30 μg of estrogen is considered safe and effective hormonal contraception,³⁰ careful attention to stroke risk should be made before prescribing. Nonhormonal and progestogen-only methods of contraception should also be considered in high-risk patients. Further research to evaluate the risk of progestogen-only methods (depot injection, pills, implants, and intrauterine devices) is needed.

Prospective observational studies and randomized trials consistently demonstrate an increased risk of stroke, particularly ischemic stroke, with oral postmenopausal hormone therapy.

In prospective cohort studies, data suggest that postmenopausal users of oral estrogens with or without progestin have a 27% to 39% increased risk of stroke compared with nonusers.³⁹ In the Women’s Health Initiative, women randomized to combined estrogen plus progestin had a hazard ratio of 1.31 (95% CI, 1.02–1.68) for total stroke and 1.44 (95% CI, 1.09–1.90) for ischemic stroke.⁴⁰ In the Women’s Health Initiative trial of unopposed estrogen, women randomized to active therapy had a hazard ratio of 1.37 (95% CI, 1.09–1.73) for total stroke and 1.55 (95% CI, 1.19–2.01) for ischemic stroke.⁴¹

Although some data suggest an association between timing of hormone therapy and coronary heart disease, time since menopause is not associated with differences in stroke incidence in either observational studies³⁹ or clinical trials.⁴² The incidence of stroke is relatively low in younger women (age, 50–59 years), with ≈2 additional cases of stroke per 10 000 women per year taking postmenopausal hormones.⁴² In addition, there is a dose–response relationship between dose of oral conjugated estrogen and stroke, with RRs of 0.93 for a dose of 0.3 mg, 1.54 at 0.625 mg, and 1.62 at 1.25 mg (P for trend, <0.001).³⁹

Similar results have been found in secondary cardiovascular prevention. Both the HERS (Heart and Estrogen/Progestin Replacement Study) in women with prior coronary heart disease⁴³ and the WEST (Women’s Estrogen for Stroke Trial) in women with recent mild ischemic stroke or transient ischemic attack⁴⁴ found no significant effect of treatment with oral estrogen or combined oral estrogen and progestin on risk of stroke, with a trend toward harm.

Limited data are available for transdermal estrogens, which have been associated with lower risk of venous thromboembolism. In a population-based nested case–control study, current use of transdermal hormone therapy was not associated with an increased risk of stroke (hazard ratio, 0.95 [0.75–1.20]).⁴⁵ However, when the dose was examined, low-dose transdermal estrogen (≤50 μg/d estradiol) was not associated with risk while high-dose transdermal estrogen (>50 μg/d) was associated with increased stroke risk.⁴⁵

Transgender individuals are people whose sex identity differs from their sex assigned at birth. The prevalence of self-identified transgender adults in the United States is estimated to be ≈0.5% of the population.⁴⁶ Some transgender people pursue hormonal therapy or sex-affirming surgery to assume secondary sex characteristics consistent with their sex identity. The use of certain hormonal therapies has implications for the incidence of cerebrovascular disease in these individuals.

Transwomen are people with an assigned male sex and a female sex identity. Transwomen may undergo medical treatment with estrogens, antiandrogens, or a combination of both.⁴⁷ Those who have undergone orchiectomy may pursue only estrogen therapy.

Antiandrogen therapies do not seem to increase stroke risk in transwomen. Spironolactone is the antiandrogen most commonly prescribed to transwomen in the United States.⁴⁷ Spironolactone, a potassium-sparing diuretic, may lower blood pressure but does not increase thrombotic risk. Similarly, finasteride, a less commonly used antiandrogen, does not seem to increase thrombotic risk.

Direct data on the effect of exogenous estrogens in transwomen are scant. Much of our knowledge about the effects of exogenous estrogen is derived from studies of the increased risk of thrombotic complications, including stroke among postmenopausal women using postmenopausal hormone therapy.^48,49 Prospective trials of thrombotic risk in transwomen receiving estrogen therapy are lacking.⁵⁰ A 1997 Dutch single-center retrospective descriptive study of 816 transwomen treated for a mean 9.5 patient-years with ethinyl estradiol and the antiandrogen cyproterone acetate found that 45 (5.5%) developed deep vein thrombosis or pulmonary embolism, 5 (0.6%) experienced a transient ischemic attack, and none experienced ischemic stroke.⁵¹ A 2013 Belgian single-center case–control study evaluated 214 transwomen who were maintained on estrogen therapy for a median of 6 years.⁵² Eleven of the 214 transwomen (5.1%) developed deep vein thrombosis or pulmonary embolism during hormonal treatment. Five of the 214 transwomen (2.3%) were diagnosed with transient ischemic attack or cerebrovascular disease during treatment, a higher prevalence than in the age-matched control men. In a 2011 Dutch retrospective single-clinic cohort mortality study of 966 transwomen on estrogen with or without antiandrogen therapy with a mean follow-up of 19.4 years, no difference was found in the incidence of fatal stroke in transwomen compared with the incidence in the general population.⁵³

As we await prospective studies of estrogen therapy in transwomen, we recommend that medical providers maintain a high index of suspicion for deep vein thrombosis/pulmonary embolism and cerebral venous thrombosis in transwomen receiving estrogen therapy. Cardiovascular risk should be evaluated, and transwomen who smoke should be encouraged to quit smoking and provided with appropriate pharmacological and psychosocial supports.

Transmen are individuals with an assigned female sex and male sex identity. Transmen may undergo treatment with testosterone to promote development of male secondary sex characteristics. Testosterone is available via transdermal and intramuscular routes. Unlike estrogen, testosterone does not seem to be associated with an increased risk of thromboembolic complications. The majority of existing studies of transmen do not suggest an increased risk of cardiovascular morbidity with exogenous testosterone therapy.^51–54

In general, providers should be aware that transgender people may be less likely to seek medical attention than their cisgender peers because of previous negative interactions with the medical community, poor psychosocial wellbeing, and fear of stigma.^55,56 This has direct implications for delay of appropriate stroke care. Health systems and medical providers can improve the medical care of transgender people by asking about sex identity and preferred pronouns on intake forms⁵⁷; promoting an explicitly supportive and inclusive clinic or unit culture for transgender patients and their families; and pursuing research into the unique health needs of transmen and transwomen.