Menstruation: An Important Indicator for Assessing Stroke Risk and Its Outcomes

Hormonal changes after stroke have not been well-studied. One study showed that postmenopausal women with stroke in the caudate nucleus had low serum follicle stimulating hormone and low serum luteinizing hormone. 117 This could be true in premenopausal women which could then affect the menstrual cycle, but to our knowledge this has not been studied. Various secondary stroke prevention strategies significantly affect menstruation. 118 Anticoagulants, both vitamin K antagonists and novel oral anticoagulants, and clopidogrel are associated with increased uterine bleeding whereas low dose aspirin is associated with fewer abnormal bleeding reports. 118 , 119 Many menstruating women on antithrombotics will need treatment to reduce bleeding as heavy menstrual bleeding contributes both to poor quality of life 118 and possibly to stroke risk. 25 Once uterine pathology has been excluded, appropriate treatments may include levonorgestrel-releasing intrauterine devices and endometrial ablation. While estrogen-containing contraceptives are contraindicated in women with history of stroke, progesterone-only methods are reasonable. 118 Less commonly, treatment for stroke-causing autoimmune diseases such as antiphospholipid syndrome can affect menstruation. Patients with severe antiphospholipid syndrome and/or lupus are sometimes treated with immunomodulatory agents including mycophenolate mofetil, cyclophosphamide, and azathioprine. 120 Cyclophosphamide may be associated with menstrual abnormalities including amenorrhea, oligomenorrhea, and menorrhagia, 121 though as discussed above, this is confounded by menstrual abnormalities related to disease activity in lupus. 61

Patient factors that influence both menstruation and stroke risk include coagulopathies, ovulatory dysfunction, endometriosis, migraine, menopause, and other systemic disorders. Coagulopathies that impact stroke risk and cause irregular menstruation include platelet disorders, sickle cell anemia, and iron deficiency anemia. Immune thrombocytopenia is associated with heavy menstrual bleeding, and, to a lesser extent, both ischemic and hemorrhagic stroke, especially in young patients. 38 Patients with sickle cell disease, a well-recognized stroke risk factor, suffer from heavy menstrual bleeding, dysmenorrhea, and menstruation-associated pain crises. 39 , 40 Irregular menstruation is often a patient’s presenting symptom of coagulopathy and therefore may be a stroke risk indicator. Polycystic ovarian syndrome is the most common cause of anovulatory infertility, affecting 6–10% of reproductive-aged women. It is characterized by menstrual irregularity, hyperandrogenism, and polycystic ovaries, but its etiology is poorly understood. 41 Of patients with polycystic ovarian syndrome, 50–80% have obesity, 30–35% have impaired glucose tolerance, and 8–10% have type 2 diabetes. They tend to have higher low-density lipoprotein and triglycerides and lower high-density lipoprotein cholesterol levels. 41 Premenopausal patients with polycystic ovarian syndrome have an increase in subclinical atherosclerosis, 42 but there is significant heterogeneity in studies of associations between polycystic ovarian syndrome and cardiovascular disease including stroke. 43 The conflicting results may reflect heterogeneity in diagnostic criteria for polycystic ovarian syndrome, in addition to the uncertainty of whether any association found is due to shared cardiovascular risk factors or an increased risk specific to polycystic ovarian syndrome—it is unclear if polycystic ovarian syndrome mediates or indicates stroke risk. Nonetheless, irregular menstruation (often used as a proxy for polycystic ovarian syndrome) was found to be associated with an increase in cardiovascular disease, with a nonsignificant increase in stroke risk, in the Nurses’ Health Study. 44 Guidelines for management of patients with polycystic ovarian syndrome state that patients should be monitored regularly for obesity, cigarette smoking, dyslipidemia, hypertension, impaired glucose tolerance, and lack of physical activity. 45 This monitoring should include measurements of weight, body mass index, waist circumference, fasting lipid profile for overweight and obese patients, and blood pressure. Depending on individual risk factors, management strategies include statins, metformin, and lifestyle modifications such as regular exercise. 42 , 44 No evidence to date shows an increase in cardiovascular events in patients with polycystic ovarian syndrome with low-dose oral contraceptives, and thus they are recommended to treat ovulatory dysfunction. 42 Recent evidence indicates an improvement in dyslipidemia with ultra-low-dose combined oral contraceptives compared to low-dose pills in nonobese patients with polycystic ovarian syndrome. 46 The effect of treatment of ovulatory dysfunction on metabolic abnormalities and therefore cardiovascular disease risk is a promising area of research ( Table 1 ). Besides polycystic ovarian syndrome, other major causes of ovulatory dysfunction and amenorrhea (not from pregnancy, lactation, or menopause) include hypothalamic amenorrhea, hyperprolactinemia, and ovarian failure. 9 , 42 Of these etiologies, premature ovarian failure may be linked to increased cardiovascular disease risk (covered below). Of special importance in adolescents, amenorrhea may indicate an underlying eating disorder. 9 Severe malnutrition from eating disorders can cause arteriosclerosis and hypoperfusion leading to ischemic stroke. 47 Endometriosis is an inflammatory chronic condition in which endometrium-like tissue grows outside of the uterus causing painful menses. 48 It is estimated to affect 10% of reproductive aged women, though the actual prevalence is unknown because many women do not undergo laparoscopic biopsy. 49 Previous research has indicated that endometriosis confers greater risk of hypertension, 50 coronary heart disease, 51 , 52 and stroke, 51 – 53 particularly at younger ages. Endometriosis is thought to be a stroke mediator due to alterations in the endogenous inflammatory, immunologic, and hormonal milieu of individuals with the disorder. 54 Additionally, some endometriosis treatments may increase risk of cardiovascular disease, 53 , 55 though some data indicate that treatment lowers risk 56 or find no difference. 57 Recent data from us show that aspirin is unlikely to lower cardiovascular disease risk in endometriosis. 52 Alternative approaches are needed ( Table 1 ). Several other systemic disorders are thought to be stroke mediators. Kidney disease, a well-recognized stroke risk factor, is associated with irregular menses and amenorrhea, possibly due to abnormal hypothalamic-pituitary-ovarian axis function, increased levels of prolactin, or gonadotoxic medications. 58 Amenorrhea and infertility is associated with liver disease, with possible recovery after transplant. 59 , 60 Lupus is associated with menstrual abnormalities and stroke risk (even in the absence of antiphospholipid antibodies), and higher risk of both correlate with higher disease activity. 61 , 62 Certain lupus treatments may impact cardiovascular disease risk (covered below). Migraine attacks related to the fall in estradiol immediately prior to normal menstruation are common in women who suffer from migraine. 63 Some women suffer from migraine only in the setting of pre-menstruation, termed “pure menstrual migraine,” whereas others have menstruation-related exacerbations. Either may be treated with oral contraceptives or with short-term transdermal estradiol. 64 Despite ample evidence linking stroke with estrogen-containing oral contraceptives in women with migraine with aura, 65 there is little evidence to link stroke with estrogen-containing treatments specifically used to control menstruation-related migraine. It is possible that controlling the fluctuations in estradiol and therefore decreasing aura frequency may reduce stroke risk, but this is unknown. 65 Non-estrogen-containing options to control the menstrual cycle include progesterone-only methods such as levonorgestrel-containing intrauterine devices, which are not associated with risk of stroke. 66 – 68 While migraine exacerbations are often related to normal menstruation, women with migraine may also be more likely to suffer from menstrual abnormalities including endometriosis and heavy menses, for unclear reasons ( Table 1 ). 69 Menopause is defined as 12 consecutive months of amenorrhea. Menopause is a normal transition in midlife, but it merits attention here because cardiovascular disease risk doubles during the first decade after menopause, contributing substantially to sex differences in stroke. 70 More strokes occur in women than men due to women’s longer life expectancy and high stroke rates in elderly women. 70 This also leads to worse functional outcomes in women than men after stroke. Stroke risk is thought to worsen after menopause due to hormonal changes. During menopause, estradiol levels decrease by around 60%, while circulating androgen levels decrease more slowly, resulting in a relative androgen excess. 70 Endogenous estrogen is likely protective for stroke risk. So, this relative androgen excess is thought to contribute to the worsening of stroke risk factors associated with the menopause transition, namely increase in abdominal obesity, triglycerides, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, and blood pressure, leading to an increase in subclinical vascular disease. 70 Use of exogenous estrogen, hormone replacement therapy, remains controversial. The Women’s Health Initiative found an increased risk of stroke with exogenous estrogen (with or without progesterone) especially at older ages. 71 , 72 However, there was a trend towards lower mortality with estradiol use within 10 years of menopause, 72 and more recent research has shown less progression of subclinical atherosclerosis with estradiol initiated within six years or menopause but not after 10 years. 73 Overall, findings suggested harm with hormone therapy in older women and inconclusive results in younger women. 72 Hormone replacement therapy is indicated to treat vasomotor symptoms in women under age 60, within 10 years of menopause, and without cardiovascular risk factors, liver disease, or breast cancer. 74 In sum, menstrual abnormalities may indicate underlying stroke risk factors including coagulopathies, ovulatory dysfunction, endometriosis, menopause, and other systemic disorders. Additionally, normal menstruation may impact migraine which is associated with stroke.

Assessing menstruation is an important part of determining stroke risk in women. Some abnormalities of menstruation like heavy menstrual bleeding may mediate stroke risk. Other abnormalities of menstruation such as irregular cycles as in polycystic ovarian syndrome, painful menstruation as in endometriosis, or premature cessation of menstruation in the case of early menopause, are important indicators of underlying stroke risk in women. Treatments of menstrual abnormalities, like contraceptives and hysterectomy, can change underlying stroke risk and merit discussion of risks and benefits. Finally, stroke treatment can affect menstruation requiring ongoing attention and care. We recommend that clinicians treating patients with prior stroke or at risk for stroke screen patients for menstrual abnormalities, consider etiologies of menstrual abnormalities in workup, and work closely with gynecologists to optimize stroke prevention strategies.

Iatrogenic and environmental factors that influence both menstruation and stroke risk include estrogen-containing contraceptives, oophorectomy and hysterectomy, xenoestrogens, phytoestrogens, and tobacco. Close to 90% of women in the United States use some form of contraception at some point in time, 75 and around one fifth of those women use oral contraceptive pills. 76 Oral contraceptives are commonly used to control menstrual cycles in addition to family planning purposes. Estrogen-containing transdermal patches, vaginal rings, and oral contraception with any generation progestin are associated with increased risk of ischemic stroke, especially in women with migraine, smoking, hypertension, or age over 35. 77 Oral contraception with any estrogen dose is associated with an increased risk of ischemic stroke, 77 with higher risk at estrogen doses above 50μg 78 or 30μg 79 and during the first year of use. 80 Injectable, subdermal, and oral progesterone-only methods of contraception in addition to levonorgestrel intrauterine devices are not associated with increased stroke risk and can also be used to control menstruation. 67 , 81 Chronic contraceptive use to suppress menstruation in women with conditions like menstrual migraine or heavy menstrual bleeding has an unknown impact on stroke risk and other health outcomes ( Table 1 ). Women may undergo hysterectomy for many reasons including leiomyomas, adenomyosis, malignancy, and uterine prolapse, and oophorectomy to treat ovarian pathology, reduce risk of ovarian cancer in high-risk individuals, or as definitive treatment for endometriosis. Oophorectomy before natural menopause results in surgical menopause. Hysterectomy theoretically leaves ovaries intact, but may impact ovarian function regardless. 82 A 2016 metanalysis found an increased stroke risk in women who had oophorectomy, but not for hysterectomy. 83 More recent data has indicated that risk of ischemic stroke may be increased by both oophorectomy and hysterectomy without oophorectomy 84 whereas other data has indicated increased risk of heart disease with hysterectomy alone but not stroke. 85 As in primary ovarian insufficiency, many clinicians favor hormone replacement therapy to reduce cardiovascular risk and cognitive decline in young, premenopausal women who undergo surgical menopause due to early oophorectomy, but data is lacking ( Table 1 ). 86 , 87 Xenoestrogens are synthetic chemicals with high lipid solubility that mimic endogenous estrogens and can bind to estrogen receptors. They are found in a variety of products and environments, including (1) plastics: chemicals like bisphenol A found in plastic containers, water bottles, and food packaging; (2) pesticides: certain pesticides, such as dichlorodiphenyltrichloroethane, also known as DDT, and atrazine, have xenoestrogenic effects; (3) personal care products: parabens and phthalates used in cosmetics, lotions, and shampoos; (4) household products: detergents, cleaning agents, and some air fresheners; (5) industrial compounds: polychlorinated biphenyls used in electrical equipment and other industrial products; (6) food products: hormones used in meat and dairy production, as well as phytoestrogens found in soy products. These compounds enter the body through ingestion, inhalation, or skin absorption, and may disrupt normal hormonal functions. 88 Because of their high lipid solubility, xenoestrogens accumulate in the brain. The most potent endogenous estrogen, 17β-estradiol, is neuroprotective in the setting of acute or chronic brain injury in adults, including stroke. 88 Xenoestrogens can suppress the effect of 17β-estradiol in animal models by binding to estrogen receptors, which has a variety of possible downstream effects on both the brain and endocrine systems. 88 Xenoestrogens may effect onset and regularity of menstruation. Some, but not all, studies have found an association between pre- and post-natal exposure to xenoestrogens like dichlorodiphenyltrichloroethane, which can behave as estrogen agonist and/or an androgen antagonist, and either early or delayed menarche. 89 , 90 Dichlorodiphenyltrichloroethane, while banned in the United States and western Europe, is still used in many developing countries. In animal models, exposure to bisphenol A or the pesticide lindane was associated with menstrual cycle irregularity. 90 Xenoestrogens may also affect onset and effect of menopause. In humans, exposure to bisphenol A was associated with ovarian aging 91 and with markers of inflammation 92 in postmenopausal women. Similarly, xenoestrogens may affect stroke risk via several mechanisms. Xenoestrogens can alter hypothalamic control of energy balance potentially leading to metabolic diseases, leading to increase in risk of stroke. 93 Urine bisphenol A concentration has been associated with stroke and other cardiovascular disease incidence. 94 It is also plausible that xenoestrogens could exacerbate stroke risk by contributing to earlier menopause, which is associated with stroke risk. 95 Xenoestrogens may also exacerbate brain injury in the setting of stroke in premenopausal women by reducing the protective effect of 17β-estradiol. 88 In sum, exposure to xenoestrogens may increase cardiovascular disease risk and exacerbate the deleterious effects of stroke in addition to causing menstrual cycle irregularly and altering the onset of menstruation and menopause ( Table 1 ). Phytoestrogens are also estrogen-mimicking chemicals, but of plant origin. They are routinely consumed in traditional Asian diets mainly in soy. 96 Phytoestrogens may have an effect on onset of menstruation, but the effect differs depending on the specific phytoestrogen. 97 Phytoestrogen consumption has been hypothesized to be the reason women in Asian compared to Western countries experience fewer perimenopausal vasomotor symptoms. 96 Asian countries also have a lower incidence of coronary heart disease than Western countries. 98 (The opposite pattern is observed for stroke, possibly due to hypertension and smoking. 98 ) The reduction in coronary heart disease might be due to an improved lipid profile with phytoestrogen consumption, which is stronger in females than males in animal models. 99 Certain phytoestrogens appear to exert a similar neuroprotective effect in animal models as endogenous estrogen. 100 , 101 These possible protective effects of phytoestrogens combined with the lower incidence of perimenopausal vasomotor symptoms in Asia compared to Western countries has led to interest in phytoestrogens to treat perimenopausal vasomotor symptoms, in addition to other estrogen-mediated conditions such as menstrual migraine. 102 Unfortunately, evidence for reduction in vasomotor symptoms with phytoestrogen supplementation is inconsistent thus far. 103 , 104 With respect to cardiovascular indications, phytoestrogen supplementation may modestly improve lipid profiles in postmenopausal women, but may adversely affect carotid intima-media thickness. 105 Smoking cigarettes is a well-established stroke risk factor. 106 Nicotine from cigarettes has exceptionally deleterious effects on stroke risk in women, in addition to deleterious effects on menstruation. 107 Nicotine has been associated with shorter and more variable menstrual cycles 108 and early menopause, 109 possibly due to reduction in circulating estrogen. 110 , 111 As reviewed above, smoking greatly increases stroke risk in women taking oral contraceptives. 81 , 112 Nicotine also likely worsens outcomes in women with stroke. In animal models, nicotine inhibits protective estrogen signaling in post-ischemic cerebral tissue. 113 Newly marketed battery-powered nicotine delivery (also known as electronic cigarette) exposure exacerbates ischemic infraction and cognition in female rats. 114 Nicotine combined with oral contraceptives exacerbates post-ischemic damage 113 via loss of estrogen receptor β signaling in rats. 115 , 116 In sum, nicotine disrupts normal menstruation, is associated with early menopause, is associated with increased stroke risk, and exacerbates ischemic cerebral injury especially in combination with oral contraceptives.

Menstruation is an indicator of overall health. In cisgendered, premenopausal women, regular menstrual cycles signal that ovulation and hormone regulation are functioning properly, while irregularities can be early signs of underlying health issues, including polycystic ovary syndrome, coagulopathies, or even cardiovascular problems. Menstruation offers valuable insights into stroke risk in young and mid-life women, especially when stroke rates in young and mid-life women have reportedly increased. 1 , 2 In a sample of insured American patients from 2001–2014, the index stroke rate per 100,000 people for ages 25–34 was 16.9 in women versus 11.9 in men, and for ages 35–44 was 39.9 in women versus 34.9 in men. 1 European studies have also found higher stroke rates in young women than young men, despite lower rates of traditional vascular risk factors in young women, 3 – 5 which suggests the relevance of sex-mediated stroke risk factors. Menstruation is the shedding of the endometrium (the uterine lining) at the beginning of each menstrual cycle. Around day five of the menstrual cycle, estrogen levels increase, causing the endometrium to thicken. Around day 14, one of the ovaries releases an oocyte. At this point, estrogen levels start to decrease and progesterone levels increase. Around day 28, if the oocyte is not fertilized, the endometrium is shed, and both estrogen and progesterone levels drop. 6 Hormonal changes during normal menstruation may be beneficial for neurovascular health. Naturally circulating endogenous estrogens have potent effects on arterial endothelium that promote vasodilation and blood flow as well as protective effects by promoting cell survival, increasing mitochondrial efficiency, and stimulating angiogenesis. 7 A longer lifetime exposure to ovarian estrogens is protective against non-cardioembolic ischemic stroke. 8 Although hormonal changes associated with normal menstruation may be beneficial, our understanding of how abnormal menstruation correlates with stroke outcomes remains elusive. Menstrual abnormalities range from amenorrhea (absence of menstruation) to heavy, painful, and/or unpredictable periods. 9 Focusing on cisgendered women who are not pregnant or lactating, we will review (1) the impact on stroke risk of heavy menstrual bleeding from local uterine causes, (2) patient factors that influence both menstruation and stroke risk, (3) iatrogenic and environmental factors that influence both menstruation and stroke risk, (4) the impact of stroke on menstruation. Some menstrual abnormalities are likely stroke mediators (contributing directly to stroke risk) while some are stroke risk indicators (clues about underlying patient factors that increase stroke risk).