http://stroke.ahajournals.org/content/49/3/518?etoc=
Stroke
is the third leading cause of death in women in the United States and
is a leading cause of disability. Each year 55 000 more women than men
have a stroke, a discrepancy largely driven by longer life expectancy in
women (www.stroke.org). Although
the majority of stroke incidence can be attributed to traditional
vascular risk factors that occur in both men and women, including
hypertension, hyperlipidemia, diabetes mellitus, smoking, and atrial
fibrillation, there are several stroke risk factors that are specific to
women. Specifically, differences in sex hormones, exogenous estrogens,
and pregnancy exposures are factors exclusively experienced by women. In
this review, we will summarize the current state of the literature with
regards to women-specific factors, such as endogenous hormone levels,
exogenous hormone therapy, pregnancy, parity, timing of age at menarche,
and menopause in relation to stroke risk.
Methods
The
following terms were searched with women and stroke in PubMed and
Google Scholar, mainly for original articles and
meta-analysis/systematic reviews: estrogens, estradiol, testosterone,
DHEAS, menarche, menopause, oophorectomy, postmenopausal hormone
therapy, oral contraception, transgender, transmen, transwomen,
pregnancy, peripartum, postpartum, and parity The following search was
also performed: therapy OR treatment OR secondary prevention AND
pregnancy AND stroke. The resultant literature was reviewed by the
authors, and the data covering the topics outlined below were reviewed
in this manuscript.
Endogenous Estrogen State
Endogenous Hormone Levels
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.
Age at Menarche
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.
Age at Natural Menopause and Surgical Menopause
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
Exogenous Estrogens and Stroke Risk
Hormone-Containing Birth Control and Stroke
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.
Postmenopausal Hormone Therapy and Stroke Risk
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 Medicine
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.
Issues of Pregnancy, Parity, and Stroke
Pregnancy
and the peripartum are associated with increased risk of stroke. The
peripartum period from 2 days before to 1 day after delivery and, to a
lesser extent, up to 6 weeks postpartum is associated with an increased
risk of ischemic stroke and intracerebral hemorrhage.58–60
In a large population-based study of women in England (age, 15–49
years), authors found that the baseline incidence of stroke was
25.0/100 000 person-years in women when they were not pregnant. The
incidence rate dropped during early pregnancy but was 9-fold higher in
the peripartum period (161.1/100 000 person-years) and 3-fold higher in
the early postpartum period (47.1/100 000 person-years; 95% CI,
31.3–70.9).61 For subarachnoid hemorrhage, only the peripartum period confers increased risk60,61;
nonaneurysmal subarachnoid hemorrhage is likely a major contributor to
this risk. The risk of any thrombotic event that includes ischemic
stroke remains increased to a lesser extent until 12 weeks postpartum,62 but it is not established that the risk of stroke remains increased beyond 6 weeks postpartum.61
Eclampsia and preeclampsia are the strongest risk factors for both
ischemic stroke and intracerebral hemorrhage accounting for 24% to 48%
of all pregnancy-associated strokes58,59;
this risk is potentiated by preexisting genitourinary tract infection,
chronic hypertension, prothrombotic states, and coagulopathies.63
Complications
of pregnancy, specifically pregnancy-inducted hypertension, gestational
diabetes mellitus, and preeclampsia are also associated with long-term
risk of stroke.64
There is evidence that women with pregnancy outcomes of preterm birth
and small for gestational age infants have higher rates of
cerebrovascular events even after adjusting for other pregnancy
complications.65
For
women with prior stroke, the risk of recurrent stroke is increased in
the peripartum and postpartum periods. Limited data from case series66–68
suggest an absolute risk of recurrent arterial ischemic stroke
associated with pregnancy of 0.7%, similar to the <1% yearly risk of
recurrent stroke among young adults who have no vascular risk factors69;
however, the 95% CI is wide, 0.04% to 4.4%, indicating the need for
further study. In addition, the absolute risk depends on clinical
circumstances, with the presence of vascular risk factors or a definite
cause of stroke, including thrombophilic disorders, conferring an
increased risk. Similarly, there is a paucity of information on the
excess risk of pregnancy complications to mother and child among women
with prior ischemic stroke.70
The
role of pregnancy on risk of intracranial hemorrhage from preexisting
arteriovenous malformations is uncertain. The 2 largest case-crossover
studies of arteriovenous malformations, single-center studies from China71 and Baltimore,72
yielded conflicting results. The preponderance of available evidence
suggests that pregnancy and delivery does not increase the risk of
aneurysm rupture.73,74
Conclusions
It
is important to be aware of stroke risk factors specific to women. The
Table summarizes the associations for stroke risk factors unique to
women. Specific considerations that include endogenous hormone levels,
exogenous hormone therapy, pregnancy and the peripartum period, and
pregnancy-related complications change the risk of stroke for women as
well as the optimal stroke prevention strategies. Special attention and
further research are also needed in the area of transgender individuals.
Further research to determine whether risk prediction models should
include risk factors specific to women, including hormonal and
reproductive exposures, is needed.
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