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Weekly UpdatesABSTRACT
Stroke is one of the leading causes of death and disability annually, and one of the larger populations for which neuroscience nurses care. Differences in gender have been identified as a risk factor for stroke repeatedly throughout the literature. The purpose of this evidence-based literature review is to provide information to healthcare professionals regarding stroke and its relationship with estrogen, the major female sex hormone. Background information on the three types of stroke is outlined, and information on estrogen compounds and hormone replacement therapy is detailed. A review of articles relating estrogen and/or hormone replacement therapy with stroke was performed. Fifty-seven articles met the criteria for inclusion in the review, 19 articles support the use of estrogen and/or an estrogen-related compound in the prevention or treatment of stroke, 6 articles claim estrogen and/or estrogen-related compounds are risk factors for stroke, and 11 articles remain inconclusive with regard to an estrogen and stroke relationship.
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Stroke (both ischemic [87%] and hemorrhagic [10%]) is one of the leading causes of death in the U.S. population, affecting approximately 780,000 Americans each year (Rosamond et al., 2008). Of these, approximately 157,000 people die of the event annually, and as many as 30% become permanently disabled (Thorn et al., 2006). Research on the incidence and outcome of stroke has repeatedly identified sex differences, although the causative factor(s) behind the effect of sex on stroke has not been established. Data show that recently postmenopausal women have a higher incidence of subarachnoid hemorrhage (SAH) and that women in general tend to have poorer outcomes after any stroke type than do men (Harrod, Batjer, & Bendok, 2006). One theory behind the difference in both the incidence and outcome of stroke based on sex is that hormonal factors, particularly estrogen (Bushnell et al., 2006), may play a role in these neurological insults. Conversely, estrogens have also been identified as providing neuroprotective effects in ischemic brain injury and continue to be studied in a variety of settings (Yang, Liu, Wu, & Simpkins, 2003). The purpose of this article is to present a literature review regarding the hormonal influences of estrogen, estradiol, and hormone replacement therapy (HRT) relative to the incidence and outcome of stroke.
Types of Stroke
Ischemic strokes occur when a blood vessel or vessels that supply the brain are occluded by either a thrombus or an emboli (American Stroke Association, 2006), causing decreased or absence of blood flow to brain tissue and leading to inadequate oxygenation and nutrient delivery. Risk factors for ischemic stroke include hypertension, atherosclerosis, heart valve defects, diabetes, atrial fibrillation, excessive blood-clotting factors (i.e., fibrinogen), elevated homocysteine, elevated low-density lipoprotein cholesterol, and increased age (American Stroke Association, 2006). The stroke incidence rates of women are higher than those of men at older ages (Rosamond et al., 2008). The male-to-female incidence ratio is 0.76 in those 85 years of age or older (Rosamond et al., 2008).
Intracerebral hemorrhage (ICH), or intraparenchymal hemorrhage, occurs when there is bleeding into the brain, typically as a result of a hypertensive episode. ICH is the least treatable, most disabling, and deadliest type of stroke (Ribo & Grotta, 2006). It causes cell death by direct tissue destruction, neurotoxicity, inflammation, edema, impairments in blood flow, and apoptosis (Auriat, Plahta, McGie, Yan, & Colbourne, 2005). Both hematoma formation and cerebral edema increase the deleterious effects of ICH. Fortunately, many risk factors are modifiable and include hypertension, diabetes, tobacco use, and alcohol abuse. Nonmodifiable risk factors include advanced age, race, and sex, with African Americans and men more likely to experience ICH (American Stroke Association, 2006).
SAH, the least common type of stroke, occurs when blood spills into the subarachnoid space. The majority (75%-90%) of all SAH occur as a result of either a ruptured intracranial aneurysm or trauma (Lin et al., 2006). Less common causes of SAH are arteriovenous malformations and mycotic aneurysms; however, approximately 10% to 20% of SAH do not have an identifiable source (Tatter, Crowell, & Ogilvy, 1995). Factors that pose a risk of SAH are the use of anticoagulant therapy, hemophilia and thrombocytopenic purpura, arterial dissection, and cocaine use (Weibers, 2001). Women typically experience SAH more frequently than do men, usually just after menopause. Also, women who have recently given birth are 28 times more likely to have a hemorrhagic stroke than the average person (Weibers, 2001). Consequently, the role of estrogen in the pathogenesis of SAH has been questioned repeatedly in connection with etiology of this stroke type.
Estrogen Compounds and HRT
Estrogens are steroid compounds that function as the primary sex hormone in females; progesterone also plays a major role. The three naturally occurring estrogens are estrone, estriol, and estradiol. From menarche to menopause, the primary form of estrogen in women is 17 [beta]-estradiol, which acts as a growth hormone for female reproductive organs. Estradiol is produced in the granulosa cells of the ovaries during puberty, through the process of aromatization of testosterone from the theca cells. Aromatase, the enzyme that converts testosterone to estrogen, is also produced by glial cells and neurons in the brain and by the cells of arterial blood vessels. Estradiol has been found to have an antioxidant neuroprotective function. Estrone is an estrogenic hormone secreted by the ovary and is the least prevalent of the three hormones. Estrone is relevant to health and disease because of its conversion to estrone sulfate, a precursor that can be converted to estradiol as needed. Estriol is more prevalent during pregnancy as it is produced by the placenta. Figure 1 shows a partial list of hormone metabolites.
[FIGURE 1 OMITTED]
Estrogens readily diffuse across cell membranes into the cell. Within the cell, they interact with estrogen receptors (ERs) on the nuclear membrane. 17 [beta]-Estradiol binds equally well to both ER [alpha] and ER [beta]. Estrone binds preferentially to ER [alpha], whereas estriol binds to ER [beta]. The binding of estrone, estriol, or estradiol to intracellular receptors forms a complex that binds to the hormone response element (a sequence of DNA occurring before a gene). These compounds influence gene transcription and thereby protein production (see Figure 2). Estrogen also influences gene transcription and protein production through its interactions with other proteins such as activator protein 1, Sp-1, and PELP-1. Figure 3 shows the movement and binding sites of estrogen.
Estrogens are also used in oral contraceptives and HRT; however, these are synthetic equine estrogens (conjugated equine estrogens [CEE]) and may have differences from endogenous human estrogen. The U.S. Preventive Services Task Force recommends against combination estrogen-progestin therapy (CEE and medroxyprogesterone acetate) on the basis of an overall balance of harm versus benefit (Abramson, 2004). Questions are repeatedly raised regarding the benefits and risks of HRT to menopausal women (Ahramson, 2004).
Materials and Methods
Search Strategy and Selection Criteria
Articles published between 1993 and 2008 in English-language journals indexed by Ovid, PubMed, CINAHL, and the Cochrane Database of Systematic Reviews were searched for original research articles that reported the potential association between estrogen or HRT and stroke. Key words used for the search were "estrogen," "estradiol," "hormone replacement therapy (HRT)," "stroke," "intracerebral hemorrhage," "ischemia," "subarachnoid hemorrhage," and "neuroprotection." In addition, bibliographies of articles that were generated from this search were reviewed to identify other potential articles. To be included in the literature review, the articles must have presented data regarding estrogen, HRT, the various types of stroke pathology previously reviewed, neuroprotection or risks associated with estrogen, or any combination of aforementioned topics.
[FIGURE 2 OMITTED]
Data Extraction and Synthesis
Each article was reviewed by the lead author. Because the information gathered is heterogeneous in nature, a literature review was written to provide the reader with a clear concept of the evidence available. In this literature review, we classified levels of evidence of human studies based the American Association of Neuroscience Nursing Clinical Practice Guidelines. This ranking is similar to the U.S. Preventative Services Task Force classification for evidence based practice as well (see Table 1).
Background information on stroke and estrogen is provided, and then details regarding current literature exploring the relationship between estrogen and stroke are outlined.
Results
From a total of 562 articles generated by the search, 57 met the criteria for inclusion in this review. Of these articles, 19 support estrogens as having a beneficial impact on cerebral health, either as a neuroprotective agent or a factor related to the reduction of stroke risk, 11 articles describe the neuroprotective effect of estrogen and estrogen-related compounds as inconclusive, and 6 depict estrogen and estrogen-related compounds as significant risk factors in the development of different types of stroke. The remaining articles were used to gather additional information for the readers.
[FIGURE 3 OMITTED]
Positive Effects of Estrogens
Of the articles reviewed, 19 support the use of estrogen and estrogen-related compounds for a variety of reasons. Based on various experimental approaches, estrogen has been shown to affect hemorrhage volume, tissue survival, cerebral blood flow, and the immune response, all of which may affect the response to stroke and improve outcomes. Falkeborn and associates (1993) found that women taking HRT (either potent estrogen or CEE) had a reduced risk of stroke (all types, 30%-40%) (Class 2).
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