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Section of Endocrinology (M.B., M.R.A., A.O., M.C.Z., E.C.d.U.), Department of Biomedical Sciences and Advanced Therapies, University of Ferrara; and Department of Rehabilitation Medicine (A.B., S.L., N.B.), Arcispedale S. Anna, 44100 Ferrara, Italy; and Eli Lilly & Co. (D.V.), 50019 Florence, Italy
Address all correspondence and requests for reprints to: Ettore C. degli Uberti, Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, via Savonarola 9, 44100 Ferrara, Italy. E-mail: ti8{at}unife.it.
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Abstract |
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Objective: The objective of the study was to evaluate pituitary function, in particular GH-IGF-I axis, in adult patients receiving rehabilitation after an ischemic stroke.
Subjects and Methods: We studied 42 patients (12 females; age range, 50–88 yr) during rehabilitation after stroke, evaluating the relationship between the GH-IGF-I axis and the severity (National Institutes of Health stroke scale) and outcome [Rancho Los Amigos Scale of Cognitive Functioning (LCFS); Functional Independence Measure (FIM); modified Ranking Scale] from stroke.
Results: GH deficiency was demonstrated in five patients (11.9%). Peak GH after GHRH + arginine test and IGF-I levels did not correlate with severity of stroke. IGF-I was positively correlated with LCFS (r = 0.305, P < 0.05) and the difference between FIM on admission and at discharge from rehabilitation (
FIM; r = 0.361, P < 0.02). Outcome indexes (LCFS, FIM at discharge, FIM) and occurrence of favorable outcome (modified Ranking Scale 0–1) were significantly (P < 0.05) higher in patients with IGF-I levels 161.8 µg/dl or greater (50th percentile of the patient distribution). LH-FSH deficiency (three cases), ACTH deficiency (one case), and hyperprolactinemia (two cases) were detected. One patient had primary hypogonadism, and six males had low testosterone with normal LH and FSH levels. By multivariate analysis, IGF-I level was the main significant predictor of FIM and LCFS.
Conclusions: Ischemic stroke may be associated with pituitary dysfunction, particularly GH and gonadotropin deficiencies. The higher IGF-I levels observed in patients with better outcome suggest a possible neuroprotective role of IGF-I. Circulating IGF-I may predict functional performance during rehabilitation and ischemic stroke outcome.
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Introduction |
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The GH-IGF-I system has been implicated in the development of atherosclerosis and vascular disease (2, 3). Indeed, it is well known that GH deficiency (GHD) in adults may lead to a high cardiovascular risk and an increased mortality from cardio- and cerebrovascular disease (4, 5). Epidemiological studies in the general population demonstrate that IGF-I levels in the low normal range may be associated with increased morbidity and mortality from ischemic heart disease and stroke (6, 7, 8, 9). In fact, in patients with a lower IGF-I level, death after ischemic or hemorrhagic stroke was increased by 1.5- and 5.2-fold, respectively (10).
IGF-I is involved in the maintenance of endothelial function and may contribute to the balance between apoptosis and survival in the atherosclerotic process, resulting in both protecting and promoting effects. IGF-I accumulation has been found at the site of ischemic injury, and in experimental models, IGF-I treatment enhances and normalizes vascular muscle cell proliferation, suggesting an important role for IGF-I in arterial response to injury (2, 3, 11).
IGF-I expression is also increased after hypoxic injury in brain regions with neuronal loss, and IGF-I administration in animals reduces infarct volume and improves neurological function after ischemia (12, 13). In elderly subjects, low IGF-I levels have been associated with a poor outcome after ischemic stroke, suggesting that circulating IGF-I may influence the outcome (14). However, the role of the GH-IGF-I system in ischemic stroke in humans remains to be clarified.
The purpose of the present study was to evaluate pituitary function and, in particular, GH-IGF-I axis in a cohort of adult patients receiving rehabilitation for an ischemic stroke after discharge from an acute care hospital. The relationships among GH-IGF-I axis function, clinical characteristics of the patients, and severity of the acute event, as well as outcome from stroke, were evaluated.
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Subjects and Methods |
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We examined 42 patients [30 males, 12 females; mean age 66.6 ± 1.7 yr, median 67 yr, range 50–88 yr; body mass index (BMI) 25.3 ± 0.4 kg/m2], admitted from January 1, 2005, to December 31, 2005, to the rehabilitation department of St. Anna’s Hospital of Ferrara after an ischemic stroke. The study protocol was approved by the Ethical Committee of the University of Ferrara, and informed consent was obtained from subjects or next of kin.
Patients were studied from 19 to 209 d (mean 61.7 ± 8.4 d; median 40.5 d) after the acute event, during hospitalization for an intensive rehabilitation program that was specially designed for patients who are transferred from acute hospital care and who are medically stable and able to tolerate a minimum of 3 h of therapeutic intervention per day, 5 d/wk.
Criteria for patient exclusion were as follows: age younger than 50 yr; hemorrhagic stroke and/or previous traumatic brain injury; history of preexisting endocrine, neurological, cardiac, or pulmonary diseases; diabetes mellitus requiring insulin therapy; liver or renal failure; infectious diseases; treatment with barbiturates, glucocorticoids, or medications that could affect the GH-IGF-I axis. Moreover, none of the patients was receiving enteral or parenteral nutrition.
According to the criteria established by the National Survey of Stroke (15), ischemic stroke was defined as a focal neurological deficit of presumably vascular origin lasting 24 h or longer, excluding primary hemorrhage on initial cerebral imaging.
The severity of initial neurological deficit was assessed by the National Institutes of Health Stroke Scale (NIHSS) (16) at baseline, dividing the patients into three groups according to their NIHSS (low, <8; moderate, 8–14; high, >14).
At admission and/or discharge from the in-patient rehabilitation, clinical outcome was evaluated by using the Rancho Los Amigos Scale of Cognitive Functioning (LCFS), which provides for eight levels, assessing the patient’s cognitive level (17), and the Functional Independence Measure (FIM) (18), an 18-item, 7-level functional assessment scale evaluating the amount of assistance a subject with a disability requires to perform basic daily activities safely and effectively. Each of the 18 items has a minimum score of 1 (complete dependence) and a maximum score of 7 (independence); total scores can range from 18 to 126. The difference between FIM at the beginning and end of the rehabilitation period (FIM) was also calculated.
The modified Rankin Scale (mRS) score was used to classify clinical outcome as favorable (score 0–1) or unfavorable (score 2–5). The mRS is a global outcome rating scale ranging from 0 (no impairment) to 5 (bedridden, incontinent, requiring constant nursing care and attention) and 6 (fatal outcome) (1).
Experimental procedures
In all subjects, after an overnight fast, baseline venous blood samples were drawn at 0800 h for determinations of IGF-I, TSH, free T4, ACTH, cortisol, LH, FSH, and testosterone (T) or estradiol concentrations. Two baseline blood samples were drawn for prolactin (PRL) determination. Posterior pituitary function was assessed by measurement of serum sodium, creatinine, and osmolality as well as urine osmolality and specific gravity.
The cutoff basal cortisol value for diagnosis of adrenal insufficiency was 3.5 µg/dl or less (98 nmol/liter). Patients with basal serum cortisol greater than 3.5 µg/dl (98 nmol/liter) and less than 11 µg/dl (285 nmol/liter) underwent a low-dose (1.0 µg) ACTH test. A peak response 21 µg/dl or greater (600 nmol/liter) was considered normal (19).
In all subjects, GH reserve was assessed by GHRH (1 µg/kg bolus) plus arginine (ARG; 30 g in 60 ml saline, infused over a 30-min period) testing. A GH response peak less than 11 µg/liter in patients with BMI less than 25 kg/m2, less than 8 µg/liter in patients with BMI between 25 and 30 kg/m2, and less than 4.2 µg/liter in those with BMI 30 kg/m2 or greater was considered diagnostic for GHD (20).
Blood pressure was measured with a mercury sphygmomanometer in the right arm, with the subject in a relaxed sitting position and with the arm supported at heart level, considering the average of six measurements (two measurements on 3 different days).
Normal nutritional status was demonstrated by: serum albumin greater than 3.5 g/dl, prealbumin greater than 25 mg/dl, transferrin greater than 200 mg/dl, total lymphocyte count greater than 1.800/mm3, and no significant weight loss (>5%, >7.5%, and >10% after 1, 3, and 6 months, respectively) during hospitalization (21, 22). Serum electrolytes, glucose, total cholesterol, blood urea nitrogen, iron, magnesium, calcium, and phosphate were also determined.
Analytical procedures
GH was measured by a two-site chemiluminescence immunoassay (Immulite 2000; Diagnostic Products Corp., Los Angeles, CA). The limit of detection was 0.01 µg/liter, with intra- and interassay variation coefficients of 4.2 and 7.2%, respectively, at a concentration of 1.4 µg/liter and 2.8 and 4.6% at a concentration of 12.2 µg/liter.
Serum IGF-I was determined by a two-site chemiluminescence immunoassay (Nichols Advantage; Nichols Institute Diagnostic, San Juan Capistrano, CA) after acid-ethanol extraction. The sensitivity of the method was 6 µg/liter. The intra- and interassay coefficients of variation were 4.8 and 7.1%, respectively, in the concentration range of 65–825 µg/liter.
The other hormonal determinations were performed by commercially available automated chemiluminescence immunoassay systems. The intra- and interassay coefficients of variation for all methods were less than 5.8% and less than 7.8%, respectively.
The age- and sex-specific normal ranges for IGF-I were: 61–285 µg/liter (50–54 yr), 56–271 µg/liter (55–59 yr), 50–255 µg/liter (60–64 yr), 44–238 µg/liter (65–69 yr), 38–223 µg/liter (70–74 yr), 35–213 µg/liter (
75 yr) for males; and 49–292 µg/liter (50–54 yr), 42–272 µg/liter (55–59 yr), 35–248 µg/liter (60–64 yr), 27–223 µg/liter (65–69 yr), 22–204 µg/liter (70–74 yr), and 21–199 µg/liter (75 yr) for females (23).
The normal ranges for the other assays were: ACTH, 1.5–11.5 pmol/liter; TSH, 0.4–4.2 mIU/liter; free T4, 10.3–19.4 pmol/liter; PRL, 4–24 µg/liter in women and 2–16 µg/liter in men; estradiol, less than 180 pmol/liter (menopausal women); T, 10.1–34.7 nmol/liter; LH, 40–104 U/liter in menopausal women and 1–10 U/liter in men; and FSH, 34–96 U/liter in menopausal women and 1–7 U/liter in men.
Serum sodium and osmolality, urinary osmolality and specific gravity, serum albumin, prealbumin, transferrin, electrolytes, glucose, total cholesterol, blood urea nitrogen, iron, magnesium, calcium, phosphate, and lymphocyte count were determined by standard methods.
Statistical analysis
All results are expressed as the mean ± SEM. Baseline GH and PRL levels were obtained from the mean (± SEM) of two values determined at times –30 and 0 min. Comparison between groups of continuous variables was performed by using Student’s t test or one-way ANOVA and the post hoc analysis of Student-Newman-Keuls for multiple variables. Percentage comparison was made with Fisher’s exact test. Data were also compared between two subsets with different IGF-I concentrations, either equal to or greater than or less than the 50th percentile of distribution of the patient population. Correlations between hormonal values and clinical measures of stroke severity and outcome or patient characteristics were performed by linear regression analysis. The effects of independent variables (NIHSS, age, BMI, peak GH, and IGF-I levels) on outcome measures (dependent variable FIM or LCFS) were also calculated by multiple regression analysis. Values were considered statistically significant when P < 0.05. Analyses were performed by using InStat3 and Prism (GraphPad Software, Inc., San Diego, CA).
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Results |
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The mean baseline NIHSS was 11.02 ± 0.87, with values less than 8 in 14 patients (mild stroke), 8–14 in 19 patients (moderate stroke), and greater than 14 in nine patients (severe stroke).
At the time of the study, all patients showed biochemical values that were indicative of good nutritional status and no significant weight loss during hospitalization.
Outcome measures
As shown in Table 1
, the mean FIM values were 63.1 ± 3.2 on admission (FIMa) and 89.4 ± 3.5 at discharge (FIMd) from the rehabilitation department, with an increasing trend in relation to a milder stroke degree. The mean LCFS value was 6.95 ± 0.14 and was slightly, but not significantly, higher in patients with mild (7.29 ± 0.19) or moderate (7.0 ± 0.22) stroke, compared with severe stroke (6.33 ± 0.33). mRS scores indicated a favorable outcome in 14 (four females) and unfavorable in 28 patients (eight females), resulting favorable in seven of 14 patients with mild, seven of 19 with moderate, and none of nine with severe stroke (P < 0.05). Prevalence of cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia, and cigarette smoking) was similar in the three groups of patients.
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FIM (r = 0.313, P < 0.05). Moreover, FIMd (r = –0.346) and FIM (r = –0.316) were negatively associated with patient age (P < 0.05).
On the contrary, BMI and blood pressure levels did not correlate with either NIHSS or outcome measures (FIM, LCFS, mRS). Similarly, the length of stay in the rehabilitation department or the time elapsed from the acute event did not significantly correlate with FIM, LCFS, or mRS.
GH-IGF-I axis function
A GHRH plus ARG test demonstrated a normal GH response in 37 patients (88.1%), whereas it was diagnostic for GHD in five patients (11.9%). No significant difference in the occurrence of GHD was observed between women and men.
No significant differences were observed in occurrence of GHD and/or mean (± SEM) peak GH responses to GHRH plus ARG among patients who had suffered severe (GHD: none of nine; GH peak 25.7 ± 1.8 µg/liter), moderate (GHD: two of 19; GH peak 22.5 ± 4.2 µg/liter), and mild (GHD: three of 14; peak 22.8 ± 3.1 µg/liter) disease according to the NIHSS (Fig. 1).
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) in patients with a favorable outcome was similar to that observed in patients with an unfavorable outcome (two of 14 vs. three of 28, NS).
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Other hormonal parameters
Three of 30 male patients (10%) had low blood T concentrations associated with low LH and FSH levels, indicative of central hypogonadism. Six patients (20%) had low T (ranging from 188 to 267 ng/dl) with normal LH and FSH levels. One patient (3%) had low T with elevated FSH levels, indicative of primary hypogonadism. All females had gonadotropin levels in the menopausal range.
None of the patients had basal cortisol values 3.5 µg/dl or less. An ACTH test, performed in four patients with basal cortisol 11 µg/dl or less and normal ACTH levels, was indicative of central adrenal insufficiency in one case. None of the patients had central hypothyroidism. One patient with central hypogonadism also had subclinical primary hypothyroidism, which was replaced with L-thyroxine before performing the GHRH plus ARG test. Prolactin concentration was moderately elevated in two patients. No clinical or biochemical signs of diabetes insipidus were detected.
In summary (Fig. 3), anterior hypopituitarism was detected in eight of 42 patients with stroke (19.0%) and multiple deficiencies in only one patient (GH and ACTH deficiency). By adding hyperprolactinemia, 23.8% of stroke patients had some degree of pituitary dysfunction.
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No significant correlation was found between NIHSS values and IGF-I levels or GH peak values after GHRH plus ARG. No correlation was detected between either IGF-I levels or GH peak and the time elapsed from the acute event or the length of stay in the rehabilitation department.
The age of patients negatively correlated with GH peak after GHRH plus ARG (r = –0.320, P < 0.05) but not with IGF-I levels (r = –0.070, NS).
IGF-I positively correlated with LCFS (r = 0.328, P < 0.05) and FIM (r = 0.361, P < 0.02) (Fig. 4).
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).
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Moreover, outcome indexes (LCFS, FIMd, and FIM) were significantly (P < 0.05) higher in patients with IGF-I levels of 161.8 µg/dl or greater. Occurrence of favorable outcome was significantly (P < 0.05) higher in patients with IGF-I levels of 161.8 µg/dl or greater, compared with patients with IGF-I less than 161.8 µg/dl.
At the multiple regression analysis, FIM was significantly related to IGF-I (P < 0.02), whereas LCFS was related to both NIHSS and IGF-I (P < 0.005 and P < 0.02, respectively).
Relationships among pituitary function, clinical characteristics, and outcome of the patients
No significant differences in the severity of stroke (NIHSS) were observed in patients with pituitary dysfunction as compared with normal pituitary function.
Pituitary dysfunction was observed in three of six patients (50%) with previous cerebrovascular event and eight of 36 patients (22.2%) with no previous event.
No significant differences in outcome indexes (LCFS, FIM, mRS), length of the in-patient rehabilitation period, time elapsed from acute event, and age were observed in patients with pituitary dysfunction as compared with those with normal pituitary function.
No significant correlation was found between gonadal, thyroid, and adrenal function parameters and outcome measures. In males, T levels did not correlate with NIHSS, LCFS, FIM, or mRS.
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Discussion |
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Recent evidence indicates that several endocrine abnormalities may be observed in critically ill patients with stroke during the early hospitalization period. In particular, patients with acute space occupying ischemic stroke showed impairment in the central regulation of adrenal and thyroid function as well as in PRL release (24). Moreover, pituitary axis function impairment was documented in 25 of 33 (79%) mechanically ventilated patients with hemorrhagic or ischemic stroke (25). The relevance of these findings is underlined by the fact that a functional or organic hypopituitarism may compromise the clinical outcome and influence therapeutical management. However, the changes in pituitary hormone profile detected in acute stroke might be temporary and part of the acute adaptive response to the injury and/or related to drugs used to treat critical illness (26, 27).
To understand whether the outcome from stroke could be influenced by an altered pituitary hormone profile, we assessed GH-IGF-I axis and pituitary function in middle advanced-age patients who have survived ischemic stroke after discharge from the acute care hospital, when they were medically stable and able to perform rehabilitation. Our findings confirm the possibility that ischemic stroke is associated with pituitary dysfunction in 23.8% of cases, without any relationship between hormone levels and time elapsed from stroke. Therefore, a timely assessment of hormonal status in these patients allows early identification and correction of endocrine abnormalities. In particular, when GHD is demonstrated, replacement therapy with GH or IGF-I could promote neuromuscular and cognitive recovery from ischemic brain injury (10, 28).
The cause-effect relationship between pituitary dysfunction and stroke still remains to be clarified. In fact, only large prospective studies in the general population could elucidate whether pituitary dysfunction may increase the risk of stroke or may take place after stroke.
The major finding of the present study is the positive association between serum IGF-I concentrations and the outcome indexes. FIM is a widely used functional performance measure developed specifically for inpatient rehabilitation, recommended as a measure of activities of daily living after stroke (18, 29). FIM assesses various aspects of motor and cognitive function and has well-established reliability and validity in patients with stroke, being able to detect minimal changes in physical functioning (29). As already previously reported by other authors (30), in our patients, severity of stroke was associated with lower FIMa but not with the improvement in functioning and ability (FIM), which was, on the contrary, associated with higher IGF-I circulating levels. Moreover, we assessed cognitive functioning by LCFS, which is more specifically used to evaluate the extent of recovery in rehabilitation programs after traumatic brain injury (17). Our data suggest that LCFS score can also be useful in stroke patients because it displayed a positive correlation with both FIM and IGF-I levels. We evaluated the global outcome by mRS, which is a sensitive measure for assessing disability after stroke and a good tool to differentiate among the various effects of treatment (1). In our study, mRS was favorable in patients with a milder stroke score, as previously reported (31), and in those with IGF-I levels over the 50th percentile of distribution.
In animal models, expression of IGF-I and its receptors increases after hypoxic ischemic injury (13), suggesting that IGF-I may play a role in the endogenous protective mechanism aimed to limit injury. IGF-I promotes survival and myelinization of neuronal cells as well as stimulating brain angiogenesis in response to hypoxic stimuli due to ischemia or trauma (32, 33). It has been demonstrated that IGF-I can cross the blood-brain barrier, with an enhanced movement of IGF-I from periphery to the central nervous system after hypoxic injury (13). Therefore, higher serum IGF-I levels could promote an increased delivery of IGF-I from periphery to brain damaged sites, contributing to a better recovery of neuromuscular and cognitive functions in stroke patients. In line with this hypothesis, it has been demonstrated that, in humans, low IGF-I levels during the acute phase of stroke are associated with a poor outcome or death (14).
It is well known that, in healthy adults, genetic factors substantially contribute to circulating IGF-I (34). A recent study on IGF-I promoter polymorphisms demonstrated an increased risk of death for stroke in the noncarriers of the 192-bp allele with lower IGF-I concentrations, compared with the carriers (10). All these data indicate that IGF-I status assessment may have a useful predictive value of clinical outcome from stroke and, moreover, suggest the potential use of IGF-I in the treatment of stroke patients. Indeed, animal studies have demonstrated that peripheral IGF-I administration markedly reduces brain infarct volume and improves neurological function after cerebral ischemia (12, 13, 33). Moreover, IGF-I stimulates protein synthesis, and its anabolic action may be helpful during rehabilitation (35).
Epidemiological evidence suggests a protective role for IGF-I on the vascular system. IGF-I concentrations in the low normal range have been reported to be associated with increased risk of carotid atherosclerosis (36), ischemic heart disease (6), and stroke (8, 9). In particular, a case-control study including 57,053 participants showed a 2-fold increased risk of ischemic stroke in subjects in the bottom quartile of IGF-I, when compared with those in the top quartile during a 5-yr follow-up (8). The role of IGF-I in the vascular system is confirmed by studies of adult GHD patients showing a high-risk cardiovascular profile that improves after GH replacement (28, 37). The biological mechanisms underlying this association still remain to be clarified. Indeed, it should not be forgotten that circulating IGF-I levels in the high normal range may be associated with increased risk of cancer (38).
We did not find any association between GHD and severity or outcome from stroke, most likely because the number of GHD patients was too small and did not allow definite conclusions on this issue. Moreover, we did not find any relationship between IGF-I levels and the presence of cardiovascular risk factors or stroke severity. On the other hand, IGF-I levels were measured during rehabilitation, and they could not reflect IGF-I status before stroke.
We found a close relationship between increasing age and unfavorable outcome from stroke in patients of middle or advanced age. Elderly subjects may be more susceptible to vascular insults as a result of brain senescence, per se characterized by a reduction in cortical vascular density and angiogenesis, impaired cell repair, and increased neuronal death (32, 39). All these processes may, at least in part, depend on the decline in plasma IGF-I levels (32, 39).
Low T levels were frequently recorded in our male patients because 10% had central hypogonadism, 3% primary hypogonadism, and 20% low T with normal gonadotropin levels. The latter finding is consistent with aging hypogonadism, which is present in 20–30% of men 60–70 yr of age (40). Little is known about the impact of sex steroids on brain recovery from ischemic brain injury. Animal studies have indicated that T may increase, whereas estrogen attenuates ischemic damage and cerebrovascular inflammation after stroke (41), suggesting that these effects may contribute to the sex differences in stroke risk and mortality (42). According to this hypothesis, in our stroke population, there were more males than females, but we did not find significant correlations between T levels and severity or outcome from stroke.
In conclusion, the present work demonstrates that ischemic stroke may be associated with pituitary dysfunction, in particular with GH and gonadotropin deficiency. Higher IGF-I levels were observed in patients with better outcome, suggesting a possible neuroprotective role of IGF-I and its potential use to improve motor and cognitive recovery during rehabilitation after stroke. Multivariate analysis identified IGF-I as an independent predictor of functional performance during rehabilitation. By contrast, T levels do not seem to modify outcome from stroke. These data suggest that a careful monitoring of serum IGF-I level in ischemic stroke may be useful as an important predictor of outcome during rehabilitation.
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Footnotes |
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M.B., M.R.A., A.O., A.B., S.L., M.C.Z., N.B., and E.C.d.U. have nothing to declare. D.V. is employed by Eli Lilly Italy.
First Published Online August 1, 2006
Abbreviations: ARG, Arginine; BMI, body mass index; FIM, Functional Independence Measure; FIM, difference between FIM at the beginning and end of the rehabilitation period; FIMa, FIM values on admission; FIMd, FIM values at discharge; GHD, GH deficiency; LCFS, Rancho Los Amigos Scale of Cognitive Functioning; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; PRL, prolactin; T, testosterone.
Received May 15, 2006.
Accepted July 26, 2006.
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