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Endocrine abnormalities and outcome of ischaemic stroke
Biomed Pharmacother 2001 ; 55 : 458-65 © 2001 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S0753332201000865/REV
Review
Endocrine abnormalities and outcome of ischaemic stroke R. Franceschini*, G.L. Tenconi, F. Zoppoli, T. Barreca Cattedra di Medicina Interna II, Department of Internal Medicine, University of Genoa, Genoa, Italy (Received 21 May 2001; accepted 6 June 2001)
Summary – Multiple endocrine abnormalities have been reported in stroke patients. In the past few years, it has been claimed that some of these abnormalities may play a role in worsening the neurological deficit and the outcome of stroke. Several mechanisms have been hypothesised, including a direct effect on the development of neuronal cell death, vasospasm, and development of brain edema. In this brief review, we discuss the current knowledge concerning the role of endothelin-1, arginine vasopressin, and cortisol in the pathogenesis of stroke. Finally, we discuss the possibility that leptin, the OB gene product, may be the link of some of these endocrine abnormalities, and that its abnormal secretion during stroke may contribute to the eating disorders and poor nutritional status often seen in these patients. © 2001 Éditions scientifiques et médicales Elsevier SAS arginine vasopressin / cortisol / endothelin-1 / ischemic stroke / leptin
Among the world’s rising elderly population few diseases are more dreaded than stroke. With an increasing incidence and a mortality rate of 30%, stroke can be considered one of the most important causes of death or long-term disability and suffering. Elevated blood arterial pressure, type II diabetes mellitus, hypercholesterolaemia, and obesity are well-known risk factor for stroke, which may also worsen the neurological deficit and outcome [1]. In recent years, several endocrine disorders, mainly regarding the hypothalamo-pituitary axis, have also been reported in stroke patients, namely: absence of a sleep-related increase of growth hormone plasma levels [2], elevated prolactin nocturnal release [3] and blunted serotonin-mediated prolactin release [4], low basal thyroid-stimulating hormone levels and impaired
*Correspondence and reprints: Dipartimento di Medicina Interna, Viale Benedetto XV, n 6, Genova 16132, Italy. E-mail address: [email protected] (R. Franceschini).
thyrotropin-releasing hormone-stimulated secretion of thyroid-stimulating hormone [5], and increase of beta-endorphin cerebrospinal fluid levels [6] have been reported in these patients. Abnormalities of the pituitary-gonadal axis, in particular high LH serum levels and low serum testosterone levels, have also been reported [7]. Furthermore, disruption of some biological rhythms, namely of beta-endorphin [8] and melatonin [9], have been described. In the past few years, attention has also been devoted to the clinical significance of these endocrine abnormalities, particularly with regard to the possibility that they may worsen the extension of the ischaemic area and outcome of stroke. In this brief review, we will analyse current evidence suggesting that some endocrine abnormalities can play a role in the pathogenesis of stroke. We will discuss the pathophysiological mechanisms which may be responsible for such abnormalities, and the possible influence of these on outcome of stroke.
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ENDOTHELINS Endothelins (ETs) are 21 amino-acid peptides produced in many different tissues. Discovered as products of the vascular endothelium [10], these peptides have now been shown to be produced in blood vessels by smooth muscle cells [11] and elsewhere by others cells in different tissues. Genes have been cloned for 3 ETs, ET-1, -2, -3 [12], and for 2 ET receptor subtypes, ETA [13] and ETB [14]. ETS, mainly ET-1, are potent and long-lasting vasoconstrictors, and it is generally accepted that increased production of ET-1 may contribute to the pathogenesis of a number of cardiovascular diseases [15]. In the cerebral vasculature ET-1 is thought to be involved in several pathological conditions, including vasospasm following subarachnoidal hemorrhage [16] and migraine [17]. Experimental animal studies have demonstrated that ET-1 produces a concentration-dependent contraction of large cerebral arteries, pial arteries, and parenchymal arteries from a wide variety of species, including humans [18-23]. Furthermore, the intraventricular administration of ET-1 has been reported to reduce cerebral blood flow and to lead to the development of brain infarction [24]. Theoretically, an increased secretion of ET-1 from damaged endothelial cells might occur in acute cerebral ischemia. The severe and long-lasting vasoconstrictor action of the peptide might play a role in the pathogenesis and outcome of stroke. Several recent clinical studies measured plasma levels of ET-1 during the acute phase of stroke. Data are conflicting. Some studies [25-27] show that in acute stroke plasma ET-1 levels markedly increase and tend to correlate with the severity of neurological deficit. However, the mechanisms for this increase in circulating ET-1 remain unknown. Plasma ET-1 may result from the excessive local production of ET-1 induced by the ischaemic insult and arising from injured endothelial cells of the involved cerebral microvessels. Hypoxia is known to stimulate ET-1 synthesis [28]. Moreover, elevated thrombin concentrations within the ischaemic area may contribute to the release of ET-1 [29]. On the other hand, the increase in ET-1 levels may represent a nonspecific enhancement of ET-1 production by systemic vascular endothelium in response to stress associated with the acute cerebral infarction or with the patient’s hypoxic condition. Indeed, the ET-1 gene contains a
consensus sequence for acute phase reactant elements [30]. Moreover, the finding of an increase in ET-1 during haemodynamic stress, cold pressure test and surgical stress would support the hypothesis that the peptide is involved in the pathophysiology of biological response to varying stressful conditions [31-33]. The increase of ET-1, either locally produced or derived from the systemic circulation, is putatively deleterious to the already damaged cerebral tissue, as it further reduces regional blood flow. This might contribute to increasing the severity or the size of the infarcted tissue, and therefore to a worsening of the neurologic outcome. There are, however, several mechanisms which may limit the effects of ET-1. First, the preproendothelin-1 mRNA is short-lived and this may counteract overproduction. Moreover, in vitro studies suggest that activation of ETB receptors on vascular endothelin by ETS mediates the release of nitric oxide, thus counterbalancing the vasoconstrictor effect of activation of ETA receptors by ET-1 [34-35]. Data on increased plasma levels of ET-1 in stroke patients have not been confirmed by other studies, in which ET-1 plasma levels were reported to be normal [36-37]. Recently, in a large population of stroke patients ET-1 plasma levels were normal, and no correlation was found between ET-1 levels and neurological score, cause of stroke or risk factors for stroke [38]. These conflicting results may be due to a different timing of sampling in the various studies. ET-1 levels may be increased in the early stage of stroke (within 24 hours after the onset of symptoms), but are reported normal if the sampling is performed after 24 hours. However, it should be borne in mind that ET-1 is released to the abluminal side of the vasculature [39-40]; thus, measurement from the cerebrospinal fluid (CSF) might yield more accurate results. However, the few data available on ET-1 CSF levels are few and also controversial, being reported as both normal [41] and increased [27]. Furthermore, such an approach raises ethical questions and would not be practical in clinical practice. ARGININE VASOPRESSIN Experimental evidence indicates that arginine vasopressin (AVP), produced in the hypothalamic
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paraventricular and supraoptic nuclei, in addition to its primary physiological action as a water-retaining hormone, plays an important role in regulating brain volume and electrolyte homeostasis and microvascular resistance in ischaemic cerebral tissue [42-43]. These findings suggest that an alteration of hypothalamic AVP secretion in stroke patients may affect the severity and outcome of the cerebral injury. At present, very few studies on AVP secretion in stroke patients have been carried out. In the first study reported in the literature, simultaneous AVP and serum osmolality values were determined in a population of stroke patients, and compared to those recorded in patients with subarachnoid hemorrhage and in controls [44]. Increased levels of AVP were found in the absence of variation of serum osmolality and/or hyponatremia. By contrast, these findings were not confirmed by other authors [45], who measured AVP in the CSF and plasma of patients with different neurological and psychiatric disorders. In the group of stroke patients, normal serum AVP levels were reported, whereas increased CSF AVP values were found only in patients with raised intracranial pressure. Recently, we reported the secretory pattern of plasma AVP over a 24-hour period in a group of 24 patients with unprecedented ischaemic cerebral infarction [46]. In these patients, mean 24-hour plasma AVP levels were higher than in control subjects, and correlated with the severity score of the neurological deficit (assessed by the Scandinavian Stroke Scale) and with the mean size of the lesion. The increase occurred independently of osmotic and/or baroreceptorial mechanisms, which are known to be the major stimuli for AVP secretion. In fact, in our patients no variations in plasma osmolality or mean arterial pressure were found during the study day. Various mechanisms may account for increased AVP secretion during stroke. It has been speculated that high AVP levels may depend on damage to the anterior hypothalamus [44]; this hypothesis was proposed for those cases of subarachnoid hemorrhage secondary to aneurysm rupture, and conjectured that such damage directly involved the magnocellular nuclei (supraoptic and paraventricular) where AVP is produced [47]. However, this theory does not explain the increased release of AVP in most cerebral infarctions, and in our study no correlation was found between AVP levels and vascular territory of the ischaemic lesion. Another possible mechanism
could involve heightened intracranial pressure, which may contort the pituitary stalk and interfere with the regulation of AVP release from the posterior pituitary. Alternatively, a release of neuromodulators from the peri-infarct lesion into the third ventricle and affecting the cells within the magnocellular nuclei may be suggested. Non-osmotic control of AVP release undergoes neurotransmitter regulation mediated by serotonin and dopamine, which act as stimulating and inhibiting factors, respectively [48-49]. It has been demonstrated that cerebral ischaemia in humans is followed by a significant drop in CSF homovanillic acid content, while CSF 5-hydroxyindolacetic acid content does not decrease [50]. Thus, it may be possible that in the course of cerebral ischaemia an increased serotoninergic and/or a decreased dopaminergic tone may induce an enhanced AVP release from the hypothalamus. At present, explanations of the meaning and the effects of increased plasma AVP levels in ischaemic stroke are merely speculative. In an animal model, AVP was recently reported to play a role in the pathophysiological process of delayed neuronal damage following cerebral ischaemia and reperfusion [51]. Thus, in ischaemic stroke, the possibility that AVP may be directly involved in the development of neuronal cell death can be suggested. Arginine vasopressin is a potent vasoconstrictor peptide [52]. Although there is no direct evidence that AVP can alter the vasotonicity of cerebral vessels in humans, in vitro studies have shown that vasopressin fibers mediate cerebral microvascular vasospasm, which is blocked by a specific pressor receptor antagonist of AVP [43]. Furthermore, V1 receptors for AVP have been identified on brain capillary endothelium [53]. Thus, it may also be hypothesised that, in ischaemic stroke, high levels of AVP may cause further constriction of the cerebral vessels involved in the ischaemic area and/or of collateral vessels, thus contributing to a further reduction in regional blood flow. Moreover, attenuated development of ischaemic brain edema in vasopressin-deficient rats has recently been reported [42]. These results support the hypothesis that AVP is a regulator of brain volume and electrolyte homeostasis in the ischaemic brain. Thus, it cannot be ruled out that increased plasma AVP levels may contribute to the development of brain edema after ischaemic stroke.
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HYPOTHALAMUS-PITUITARY ADRENOCORTICAL AXIS Increased activity of the hypothalamic-pituitaryadrenal axis (HPAA), as well as of the sympathoadrenal system, is commonly seen in various forms of acute stress, including stroke [54-55]. Hypercortisolism per se has potentially serious side effects on many organ systems [54], and a higher mortality rate has been described in stroke patients with a higher stress response, as measured by plasma cortisol levels and cathecolamine excretion [55]. Furthermore, cognitive disturbances have been associated to hypercortisolism. In patients with Alzheimer’s disease, increased levels of plasma cortisol and decreased ability of dexamethasone to suppress cortisol secretion have been reported [56-57]. Major depression has also been associated to heightened activity of the HPAA [58-59]. Soon after stroke, abnormalities at various levels of the HPAA have been documented in several studies, demonstrating an increased cortisol production rate, both in urine [60] and in plasma [61-65]. In 1994, we described a blunted circadian rhythm of plasma cortisol in 15 stroke patients in the acute phase of the ischaemic injury [8]. In the same patients, the 24-hour mean values of plasma cortisol and the circadian rhythm returned to the normal range 10 days after hospitalisation admission for the ischaemic stroke. The HPAA shows abnormalities also at a central level. A reduced suppressibility of serum cortisol levels by dexamethasone has been reported [66-67], particularly in patients with cognitive disturbances [68-69]. The mechanisms by which this hypercortisolism occurs may be several. Repeated stresses, such as various cardiovascular complications, infections and emotional reactions, are commonplace in stroke patients. These repeated stresses may increase the adrenal sensitivity to ACTH [54] and therefore prolong the hypercortisolism. Furthermore, it has been shown in patients undergoing major abdominal surgery that high levels of plasma cortisol in the first 2 days after surgery are associated with increased levels of ACTH and corticotropin-releasing hormone (CRH), indicating an increased central drive [70]. An increased secretion of beta-endorphin has also been reported in stroke patients during the acute phase of the ischaemic injury [8]. It is known that ACTH, betaendorphin and related peptides derive from the common precursor pro-opiomelanocortin, are released by
the pituitary gland and fluctuate concomitantly during the day [71]. Stimulating effects of cytokines on the HPAA and direct effects of a rise in intracranial pressure may also influence cortisol levels. Recently, it has been reported that plasma interleukin-6 levels are increased following stroke, and correlate to plasma cortisol [72-73]. Finally, it has been demonstrated that a significant increase in extracellular serotonin release ensues after cerebral ischaemia [74]. Serotonin is known to play a stimulatory role on HPAA function [75], and a cerebral ischaemia-related stimulation of HPAA, mediated by serotoninergic pathway activation, may be also hypothesised. Disregulation of HPAA activity may play a role in the motor, cognitive and behavioural function following ischaemic stroke. A similar pattern of cortisol and beta-endorphin diurnal secretion has been observed in stroke as well as Alzheimer’s disease patients [56], and there also seems to be an association between hypercortisolism and major depression late after stroke [68-69]. Glucocorticoid receptors are present in the human brain [76], and high glucocorticoid levels, endogenous and/or exogenous, have been suggested to be toxic to neuronal cells, especially in the hippocampus [77-78]. Furthermore, the hippocampus seems to be very sensitive to ischaemic damage, with experimental lesions of this area causing impairment of learning and memory in animals [79]. Thus, hypercortisolism might reinforce the ischemic damage to hippocampal neurons and thereby contribute to cognitive disturbances after stroke. Furthermore, hypercortisolism per se may induce various negative effects on body functions, e.g., carbohydrate metabolism and the immune system, possibly rendering stroke patients more susceptible to a number of complications. LEPTIN Leptin, a recently identified circulating hormone secreted by the adipocytes as a product of the obese (OB) gene, seems to play a crucial role in the regulation of body weight in mammals [80]. In humans, leptin is thought to act as a satiety hormone [81] in a feedback loop linking food ingestion, the hypothalamus, and adipocyte tissue mass [82]. Although serum leptin levels vary considerably amongst individuals [83], several findings indicate that leptin secretion is mainly correlated with body fat content, being higher in obese than in lean subjects [84]. Furthermore, lep
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tin has been suggested to have adverse effects in an ‘overflow’ situation, including effects on blood pressure regulation. Thus, leptin may constitute an important link between obesity, insulin resistance and increased risk for vascular diseases. Recently, it has been reported that raised serum leptin levels are associated with an increased risk of myocardial infarction [85]. Little is known at present about a possible association between leptin secretion and stroke. In a recent study in a large population of stroke patients, both ischaemic and haemorrhagic, circulating leptin levels were found to be a powerful marker for the future risk of haemorrhagic, but not ischaemic stroke [86]. These results conflict to some extent with those reported in acute myocardial infarction. The authors attribute this discrepancy to the different pathophysiological mechanisms, including atherothrombotic, lacunar, and cardioembolic infarction, which characterise subgroups of ischaemic stroke. Hyperleptinemia has been suggested to be part of the insulin resistance syndrome [87], which in turn has been associated with cardiovascular disease, namely with atherothrombotic stroke, but not with lacunar or cardioembolic strokes. Indeed, in a very recent study, high plasma levels and a blunted diurnal rhythm of leptin were reported in a group of stroke patients with a concomitant abnormal diurnal rhythmicity of cortisol [73]. In the same patients, a negative correlation was also found between leptin serum levels and tumour necrosis factor-alpha (TNF-alpha). It has been suggested that leptin release is influenced by cytokines, notably TNF-alpha, and glucocorticoids [88-89]. However, in other pathological conditions, e.g., liver cirrhosis, plasma TNF-alpha, albeit increased, correlates poorly with serum leptin levels [90]. Nevertheless, this finding is very interesting. Though in part contradictory, there is increasing evidence that leptin plays an important role in neuroendocrine balance, including HPAA regulation [91-94]. Leptin may thus be a key factor not only for the development of ischaemic stroke, but also of the multiple endocrine abnormalities observed after stroke. Furthermore, human studies have revealed a negative correlation between serum leptin levels and the amount of food intake [95], and alluded to the fact that leptin may partially affect the resting energy expenditure [96]. Exposure to a supraphysiological circulating leptin level may have clinical consequences, possibly contributing to the maintenance of
negative energy balance and poor nutritional status often seen in stroke patients, when, due to neurological deficit, a total enteral and/or parenteral nutrition is necessary. CONCLUSIONS Endocrine abnormalities are common and often profound after stroke. The possibility that increased levels of some hormones, namely ET-1, AVP and cortisol, play an important role in aggravating the neurological deficit and outcome of stroke, deserves further investigation. The pathophysiological mechanisms involved may be several, including a direct effect on the development of neuronal cell death, constriction of collateral vessels with further reduction in regional blood flow, and development of brain edema. Finally, the recent finding on abnormal leptin secretion during stroke has to be underlined. Leptin may well be the major link of some endocrine abnormalities observed during stroke and, on the other hand, the cause of the eating disorders and the poor nutritional status that often lead to problems in the clinical management of these patients.
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Review
Endocrine abnormalities and outcome of ischaemic stroke R. Franceschini*, G.L. Tenconi, F. Zoppoli, T. Barreca Cattedra di Medicina Interna II, Department of Internal Medicine, University of Genoa, Genoa, Italy (Received 21 May 2001; accepted 6 June 2001)
Summary – Multiple endocrine abnormalities have been reported in stroke patients. In the past few years, it has been claimed that some of these abnormalities may play a role in worsening the neurological deficit and the outcome of stroke. Several mechanisms have been hypothesised, including a direct effect on the development of neuronal cell death, vasospasm, and development of brain edema. In this brief review, we discuss the current knowledge concerning the role of endothelin-1, arginine vasopressin, and cortisol in the pathogenesis of stroke. Finally, we discuss the possibility that leptin, the OB gene product, may be the link of some of these endocrine abnormalities, and that its abnormal secretion during stroke may contribute to the eating disorders and poor nutritional status often seen in these patients. © 2001 Éditions scientifiques et médicales Elsevier SAS arginine vasopressin / cortisol / endothelin-1 / ischemic stroke / leptin
Among the world’s rising elderly population few diseases are more dreaded than stroke. With an increasing incidence and a mortality rate of 30%, stroke can be considered one of the most important causes of death or long-term disability and suffering. Elevated blood arterial pressure, type II diabetes mellitus, hypercholesterolaemia, and obesity are well-known risk factor for stroke, which may also worsen the neurological deficit and outcome [1]. In recent years, several endocrine disorders, mainly regarding the hypothalamo-pituitary axis, have also been reported in stroke patients, namely: absence of a sleep-related increase of growth hormone plasma levels [2], elevated prolactin nocturnal release [3] and blunted serotonin-mediated prolactin release [4], low basal thyroid-stimulating hormone levels and impaired
*Correspondence and reprints: Dipartimento di Medicina Interna, Viale Benedetto XV, n 6, Genova 16132, Italy. E-mail address: [email protected] (R. Franceschini).
thyrotropin-releasing hormone-stimulated secretion of thyroid-stimulating hormone [5], and increase of beta-endorphin cerebrospinal fluid levels [6] have been reported in these patients. Abnormalities of the pituitary-gonadal axis, in particular high LH serum levels and low serum testosterone levels, have also been reported [7]. Furthermore, disruption of some biological rhythms, namely of beta-endorphin [8] and melatonin [9], have been described. In the past few years, attention has also been devoted to the clinical significance of these endocrine abnormalities, particularly with regard to the possibility that they may worsen the extension of the ischaemic area and outcome of stroke. In this brief review, we will analyse current evidence suggesting that some endocrine abnormalities can play a role in the pathogenesis of stroke. We will discuss the pathophysiological mechanisms which may be responsible for such abnormalities, and the possible influence of these on outcome of stroke.
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ENDOTHELINS Endothelins (ETs) are 21 amino-acid peptides produced in many different tissues. Discovered as products of the vascular endothelium [10], these peptides have now been shown to be produced in blood vessels by smooth muscle cells [11] and elsewhere by others cells in different tissues. Genes have been cloned for 3 ETs, ET-1, -2, -3 [12], and for 2 ET receptor subtypes, ETA [13] and ETB [14]. ETS, mainly ET-1, are potent and long-lasting vasoconstrictors, and it is generally accepted that increased production of ET-1 may contribute to the pathogenesis of a number of cardiovascular diseases [15]. In the cerebral vasculature ET-1 is thought to be involved in several pathological conditions, including vasospasm following subarachnoidal hemorrhage [16] and migraine [17]. Experimental animal studies have demonstrated that ET-1 produces a concentration-dependent contraction of large cerebral arteries, pial arteries, and parenchymal arteries from a wide variety of species, including humans [18-23]. Furthermore, the intraventricular administration of ET-1 has been reported to reduce cerebral blood flow and to lead to the development of brain infarction [24]. Theoretically, an increased secretion of ET-1 from damaged endothelial cells might occur in acute cerebral ischemia. The severe and long-lasting vasoconstrictor action of the peptide might play a role in the pathogenesis and outcome of stroke. Several recent clinical studies measured plasma levels of ET-1 during the acute phase of stroke. Data are conflicting. Some studies [25-27] show that in acute stroke plasma ET-1 levels markedly increase and tend to correlate with the severity of neurological deficit. However, the mechanisms for this increase in circulating ET-1 remain unknown. Plasma ET-1 may result from the excessive local production of ET-1 induced by the ischaemic insult and arising from injured endothelial cells of the involved cerebral microvessels. Hypoxia is known to stimulate ET-1 synthesis [28]. Moreover, elevated thrombin concentrations within the ischaemic area may contribute to the release of ET-1 [29]. On the other hand, the increase in ET-1 levels may represent a nonspecific enhancement of ET-1 production by systemic vascular endothelium in response to stress associated with the acute cerebral infarction or with the patient’s hypoxic condition. Indeed, the ET-1 gene contains a
consensus sequence for acute phase reactant elements [30]. Moreover, the finding of an increase in ET-1 during haemodynamic stress, cold pressure test and surgical stress would support the hypothesis that the peptide is involved in the pathophysiology of biological response to varying stressful conditions [31-33]. The increase of ET-1, either locally produced or derived from the systemic circulation, is putatively deleterious to the already damaged cerebral tissue, as it further reduces regional blood flow. This might contribute to increasing the severity or the size of the infarcted tissue, and therefore to a worsening of the neurologic outcome. There are, however, several mechanisms which may limit the effects of ET-1. First, the preproendothelin-1 mRNA is short-lived and this may counteract overproduction. Moreover, in vitro studies suggest that activation of ETB receptors on vascular endothelin by ETS mediates the release of nitric oxide, thus counterbalancing the vasoconstrictor effect of activation of ETA receptors by ET-1 [34-35]. Data on increased plasma levels of ET-1 in stroke patients have not been confirmed by other studies, in which ET-1 plasma levels were reported to be normal [36-37]. Recently, in a large population of stroke patients ET-1 plasma levels were normal, and no correlation was found between ET-1 levels and neurological score, cause of stroke or risk factors for stroke [38]. These conflicting results may be due to a different timing of sampling in the various studies. ET-1 levels may be increased in the early stage of stroke (within 24 hours after the onset of symptoms), but are reported normal if the sampling is performed after 24 hours. However, it should be borne in mind that ET-1 is released to the abluminal side of the vasculature [39-40]; thus, measurement from the cerebrospinal fluid (CSF) might yield more accurate results. However, the few data available on ET-1 CSF levels are few and also controversial, being reported as both normal [41] and increased [27]. Furthermore, such an approach raises ethical questions and would not be practical in clinical practice. ARGININE VASOPRESSIN Experimental evidence indicates that arginine vasopressin (AVP), produced in the hypothalamic
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paraventricular and supraoptic nuclei, in addition to its primary physiological action as a water-retaining hormone, plays an important role in regulating brain volume and electrolyte homeostasis and microvascular resistance in ischaemic cerebral tissue [42-43]. These findings suggest that an alteration of hypothalamic AVP secretion in stroke patients may affect the severity and outcome of the cerebral injury. At present, very few studies on AVP secretion in stroke patients have been carried out. In the first study reported in the literature, simultaneous AVP and serum osmolality values were determined in a population of stroke patients, and compared to those recorded in patients with subarachnoid hemorrhage and in controls [44]. Increased levels of AVP were found in the absence of variation of serum osmolality and/or hyponatremia. By contrast, these findings were not confirmed by other authors [45], who measured AVP in the CSF and plasma of patients with different neurological and psychiatric disorders. In the group of stroke patients, normal serum AVP levels were reported, whereas increased CSF AVP values were found only in patients with raised intracranial pressure. Recently, we reported the secretory pattern of plasma AVP over a 24-hour period in a group of 24 patients with unprecedented ischaemic cerebral infarction [46]. In these patients, mean 24-hour plasma AVP levels were higher than in control subjects, and correlated with the severity score of the neurological deficit (assessed by the Scandinavian Stroke Scale) and with the mean size of the lesion. The increase occurred independently of osmotic and/or baroreceptorial mechanisms, which are known to be the major stimuli for AVP secretion. In fact, in our patients no variations in plasma osmolality or mean arterial pressure were found during the study day. Various mechanisms may account for increased AVP secretion during stroke. It has been speculated that high AVP levels may depend on damage to the anterior hypothalamus [44]; this hypothesis was proposed for those cases of subarachnoid hemorrhage secondary to aneurysm rupture, and conjectured that such damage directly involved the magnocellular nuclei (supraoptic and paraventricular) where AVP is produced [47]. However, this theory does not explain the increased release of AVP in most cerebral infarctions, and in our study no correlation was found between AVP levels and vascular territory of the ischaemic lesion. Another possible mechanism
could involve heightened intracranial pressure, which may contort the pituitary stalk and interfere with the regulation of AVP release from the posterior pituitary. Alternatively, a release of neuromodulators from the peri-infarct lesion into the third ventricle and affecting the cells within the magnocellular nuclei may be suggested. Non-osmotic control of AVP release undergoes neurotransmitter regulation mediated by serotonin and dopamine, which act as stimulating and inhibiting factors, respectively [48-49]. It has been demonstrated that cerebral ischaemia in humans is followed by a significant drop in CSF homovanillic acid content, while CSF 5-hydroxyindolacetic acid content does not decrease [50]. Thus, it may be possible that in the course of cerebral ischaemia an increased serotoninergic and/or a decreased dopaminergic tone may induce an enhanced AVP release from the hypothalamus. At present, explanations of the meaning and the effects of increased plasma AVP levels in ischaemic stroke are merely speculative. In an animal model, AVP was recently reported to play a role in the pathophysiological process of delayed neuronal damage following cerebral ischaemia and reperfusion [51]. Thus, in ischaemic stroke, the possibility that AVP may be directly involved in the development of neuronal cell death can be suggested. Arginine vasopressin is a potent vasoconstrictor peptide [52]. Although there is no direct evidence that AVP can alter the vasotonicity of cerebral vessels in humans, in vitro studies have shown that vasopressin fibers mediate cerebral microvascular vasospasm, which is blocked by a specific pressor receptor antagonist of AVP [43]. Furthermore, V1 receptors for AVP have been identified on brain capillary endothelium [53]. Thus, it may also be hypothesised that, in ischaemic stroke, high levels of AVP may cause further constriction of the cerebral vessels involved in the ischaemic area and/or of collateral vessels, thus contributing to a further reduction in regional blood flow. Moreover, attenuated development of ischaemic brain edema in vasopressin-deficient rats has recently been reported [42]. These results support the hypothesis that AVP is a regulator of brain volume and electrolyte homeostasis in the ischaemic brain. Thus, it cannot be ruled out that increased plasma AVP levels may contribute to the development of brain edema after ischaemic stroke.
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HYPOTHALAMUS-PITUITARY ADRENOCORTICAL AXIS Increased activity of the hypothalamic-pituitaryadrenal axis (HPAA), as well as of the sympathoadrenal system, is commonly seen in various forms of acute stress, including stroke [54-55]. Hypercortisolism per se has potentially serious side effects on many organ systems [54], and a higher mortality rate has been described in stroke patients with a higher stress response, as measured by plasma cortisol levels and cathecolamine excretion [55]. Furthermore, cognitive disturbances have been associated to hypercortisolism. In patients with Alzheimer’s disease, increased levels of plasma cortisol and decreased ability of dexamethasone to suppress cortisol secretion have been reported [56-57]. Major depression has also been associated to heightened activity of the HPAA [58-59]. Soon after stroke, abnormalities at various levels of the HPAA have been documented in several studies, demonstrating an increased cortisol production rate, both in urine [60] and in plasma [61-65]. In 1994, we described a blunted circadian rhythm of plasma cortisol in 15 stroke patients in the acute phase of the ischaemic injury [8]. In the same patients, the 24-hour mean values of plasma cortisol and the circadian rhythm returned to the normal range 10 days after hospitalisation admission for the ischaemic stroke. The HPAA shows abnormalities also at a central level. A reduced suppressibility of serum cortisol levels by dexamethasone has been reported [66-67], particularly in patients with cognitive disturbances [68-69]. The mechanisms by which this hypercortisolism occurs may be several. Repeated stresses, such as various cardiovascular complications, infections and emotional reactions, are commonplace in stroke patients. These repeated stresses may increase the adrenal sensitivity to ACTH [54] and therefore prolong the hypercortisolism. Furthermore, it has been shown in patients undergoing major abdominal surgery that high levels of plasma cortisol in the first 2 days after surgery are associated with increased levels of ACTH and corticotropin-releasing hormone (CRH), indicating an increased central drive [70]. An increased secretion of beta-endorphin has also been reported in stroke patients during the acute phase of the ischaemic injury [8]. It is known that ACTH, betaendorphin and related peptides derive from the common precursor pro-opiomelanocortin, are released by
the pituitary gland and fluctuate concomitantly during the day [71]. Stimulating effects of cytokines on the HPAA and direct effects of a rise in intracranial pressure may also influence cortisol levels. Recently, it has been reported that plasma interleukin-6 levels are increased following stroke, and correlate to plasma cortisol [72-73]. Finally, it has been demonstrated that a significant increase in extracellular serotonin release ensues after cerebral ischaemia [74]. Serotonin is known to play a stimulatory role on HPAA function [75], and a cerebral ischaemia-related stimulation of HPAA, mediated by serotoninergic pathway activation, may be also hypothesised. Disregulation of HPAA activity may play a role in the motor, cognitive and behavioural function following ischaemic stroke. A similar pattern of cortisol and beta-endorphin diurnal secretion has been observed in stroke as well as Alzheimer’s disease patients [56], and there also seems to be an association between hypercortisolism and major depression late after stroke [68-69]. Glucocorticoid receptors are present in the human brain [76], and high glucocorticoid levels, endogenous and/or exogenous, have been suggested to be toxic to neuronal cells, especially in the hippocampus [77-78]. Furthermore, the hippocampus seems to be very sensitive to ischaemic damage, with experimental lesions of this area causing impairment of learning and memory in animals [79]. Thus, hypercortisolism might reinforce the ischemic damage to hippocampal neurons and thereby contribute to cognitive disturbances after stroke. Furthermore, hypercortisolism per se may induce various negative effects on body functions, e.g., carbohydrate metabolism and the immune system, possibly rendering stroke patients more susceptible to a number of complications. LEPTIN Leptin, a recently identified circulating hormone secreted by the adipocytes as a product of the obese (OB) gene, seems to play a crucial role in the regulation of body weight in mammals [80]. In humans, leptin is thought to act as a satiety hormone [81] in a feedback loop linking food ingestion, the hypothalamus, and adipocyte tissue mass [82]. Although serum leptin levels vary considerably amongst individuals [83], several findings indicate that leptin secretion is mainly correlated with body fat content, being higher in obese than in lean subjects [84]. Furthermore, lep
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tin has been suggested to have adverse effects in an ‘overflow’ situation, including effects on blood pressure regulation. Thus, leptin may constitute an important link between obesity, insulin resistance and increased risk for vascular diseases. Recently, it has been reported that raised serum leptin levels are associated with an increased risk of myocardial infarction [85]. Little is known at present about a possible association between leptin secretion and stroke. In a recent study in a large population of stroke patients, both ischaemic and haemorrhagic, circulating leptin levels were found to be a powerful marker for the future risk of haemorrhagic, but not ischaemic stroke [86]. These results conflict to some extent with those reported in acute myocardial infarction. The authors attribute this discrepancy to the different pathophysiological mechanisms, including atherothrombotic, lacunar, and cardioembolic infarction, which characterise subgroups of ischaemic stroke. Hyperleptinemia has been suggested to be part of the insulin resistance syndrome [87], which in turn has been associated with cardiovascular disease, namely with atherothrombotic stroke, but not with lacunar or cardioembolic strokes. Indeed, in a very recent study, high plasma levels and a blunted diurnal rhythm of leptin were reported in a group of stroke patients with a concomitant abnormal diurnal rhythmicity of cortisol [73]. In the same patients, a negative correlation was also found between leptin serum levels and tumour necrosis factor-alpha (TNF-alpha). It has been suggested that leptin release is influenced by cytokines, notably TNF-alpha, and glucocorticoids [88-89]. However, in other pathological conditions, e.g., liver cirrhosis, plasma TNF-alpha, albeit increased, correlates poorly with serum leptin levels [90]. Nevertheless, this finding is very interesting. Though in part contradictory, there is increasing evidence that leptin plays an important role in neuroendocrine balance, including HPAA regulation [91-94]. Leptin may thus be a key factor not only for the development of ischaemic stroke, but also of the multiple endocrine abnormalities observed after stroke. Furthermore, human studies have revealed a negative correlation between serum leptin levels and the amount of food intake [95], and alluded to the fact that leptin may partially affect the resting energy expenditure [96]. Exposure to a supraphysiological circulating leptin level may have clinical consequences, possibly contributing to the maintenance of
negative energy balance and poor nutritional status often seen in stroke patients, when, due to neurological deficit, a total enteral and/or parenteral nutrition is necessary. CONCLUSIONS Endocrine abnormalities are common and often profound after stroke. The possibility that increased levels of some hormones, namely ET-1, AVP and cortisol, play an important role in aggravating the neurological deficit and outcome of stroke, deserves further investigation. The pathophysiological mechanisms involved may be several, including a direct effect on the development of neuronal cell death, constriction of collateral vessels with further reduction in regional blood flow, and development of brain edema. Finally, the recent finding on abnormal leptin secretion during stroke has to be underlined. Leptin may well be the major link of some endocrine abnormalities observed during stroke and, on the other hand, the cause of the eating disorders and the poor nutritional status that often lead to problems in the clinical management of these patients.
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