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Department of Neurosurgery (I.K.-A., S.N., S.P., V.R., J.M.G.), Endocrine Outpatient Clinic (C.H., S.N., S.M.), Department of Internal Medicine III, Department of Medical Psychology and Sociology (B.O.H.), Institute for Clinical Chemistry and Pathobiochemistry (A.G.), University Hospital Aachen, D-52074 Aachen, Germany; and Pfizer GmbH (B.S.), D-76032 Karlsruhe, Germany
Address all correspondence and requests for reprints to: Dr. Ilonka Kreitschmann-Andermahr, University Hospital Aachen, Department of Neurosurgery, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail: ilonka.kreitschmann{at}post.rwth-aachen.de.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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When comparing the bodily, cognitive, and psychosocial sequelae of aneurysmal SAH to those of untreated partial or complete pituitary insufficiency, astonishing similarities are encountered. Corticotropin and TSH deficiency may present with symptoms such as fatigue, weakness, headache, altered mental activity, or impaired memory, whereas symptoms attributable to GH deficiency (GHD) include lack of vigor, decreased exercise tolerance, and decreased social functioning (11). Wallymahmed et al. (12) found significantly more depression and mental fatigue and significantly less self-esteem and life fulfillment in adult patients with GHD compared with patients with diabetes mellitus and healthy controls, whereas other investigators reported evidence of cognitive disturbances in this patient group (13). Because of these similarities, the authors hypothesized that aneurysmal SAH itself or perhaps in combination with disease-related clinical variables may cause pituitary insufficiency.
Pituitary function assessment has so far not been a consideration in the management of patients after aneurysmal SAH. Indeed, apart from an investigation of posttraumatic hypopituitarism that included two patients after aneurysmal SAH (14), the long-term effects of aneurysmal SAH on pituitary function have not been reported. It was the aim of the present investigation to elucidate the incidence and severity of persisting pituitary insufficiency in patients with previous aneurysmal SAH. To address this question, patients in the chronic phase after aneurysmal SAH, i.e. more than 1 yr after the acute event, underwent two different tests of dynamic pituitary function: the insulin tolerance test (ITT) and a combined THRH-LHRH-arginine (ARG) test. Preliminary results of this investigation with a smaller number of patients (n = 21) have recently been published as a short report (15). This paper reports the detailed endocrinological findings in relation to disease- and treatment-related variables of the entire patient group.
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Patients and Methods |
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A consecutive series of 303 patients was admitted to the Department of Neurosurgery, University Hospital Aachen, between March 1997 and February 2002 with aneurysmal SAH. Twenty-nine patients had died during their hospital stay (9.5%) either before or after aneurysm treatment (microneurosurgical clipping or coiling). For the present study, medical records were screened of a consecutive series of 274 patients who had survived aneurysmal subarachnoid hemorrhage in the above mentioned time window and were operated on in the Department of Neurosurgery, University Hospital Aachen (n = 252), or treated by means of coil embolization in the Department of Neuroradiology, University Hospital Aachen (n = 22). Diagnosis of SAH was proven by computed tomography (CT) scanning or lumbar puncture, and diagnosis of aneurysm location was made by four-vessel angiography. Inclusion criteria for the present study included a time window of SAH of more than 12 months but less than 6 yr before pituitary function testing, age between 18 and 60 yr at the time of testing, and no history of convulsions or adequate anticonvulsive treatment followed by a 6-month convulsion-free period. Patients were excluded from participation if they exhibited severe liver disease, coronary heart disease, kidney disease, or diabetes mellitus as well as severe depression defined as a score more than 21 in the Beck Depression Inventory (BDI) (16). Severe depression was defined as an exclusion criterion for the present investigation because of the potentially altered cortisol metabolism in severely depressed patients. Furthermore, patients who were discharged from hospital in a vegetative or severely confusional state were also excluded because of the presumed inability to give informed consent. On the basis of the 274 records screened, 106 patients were excluded because of their age, 28 had a poor neurological result and were considered unable to give informed consent, 50 were excluded for medical reasons, and two patients had died. An additional 21 patients considered eligible for the study on the basis of their medical records had moved with address unknown and could not be contacted by mail or telephone. Of the remaining 67 patients invited to take part in the study, 17 did not want to participate for personal reasons. Of the 50 patients who initially consented to take part in the investigation and came to a first study visit, eight withdrew their consent before pituitary testing (n = 7) or did not complete both tests (n = 1). Two additional patients had to be excluded after visit one because of severe depression in the BDI. The reported results are therefore based on the 40 patients (14 male, 26 female) who completed dynamic pituitary testing. The study was conducted in accordance with the principles set out in the Declaration of Helsinki and was formally approved by the Ethical Review Committee of the University Hospital. Written informed consent was obtained from all patients.
Patient demographics
Mean age at the time of pituitary function testing war 43.8 yr, with a SD of 7.6 and a range of 26–59 yr. Patients were tested on average 27.3 months after the SAH (SD, 15.0 months; range, 12–66 months).
Their clinical grades on admission to the hospital, according to the grading system of Hunt and Hess (17), the distribution of the severity grades of the bleeding according to the grading system of Fisher et al. (18), and the neurological outcome of the patients at the time of the testing according to the GOS are listed in Tables 1–3
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). Patients had gained on average 5.7 kg weight since the bleeding (range, –10 to 20 kg; SD, 6.5 kg) and exhibited a mean body mass index (BMI) of 26.4 kg/m2 (range, 16.5–38.4 kg/m2; SD, 5.0 kg/m2). Self-rated depression as assessed by means of the BDI ranged from 0–21 points with a mean of 8.3 (SD 5.8). Patients with a BDI score greater than 21, indicating severe depression, were excluded from the present study.
Endocrine function testing
After prior routine laboratory testing and physical examination, the patients underwent endocrine function testing for pituitary dysfunction. The following were measured in all patients between 0800 and 0900 h: TSH, free (f)T4, fT3, LH, FSH, total testosterone (in males), estradiol (in females), prolactin, serum cortisol, plasma ACTH, and IGF-I. In addition, a combined TRH-LHRH-ARG test and an ITT were performed on two separate days with a minimum of 48 h between both tests. All tests were done after an overnight fast and started between 0800 and 0900 h. In cases of current treatment with thyroid hormones or estrogens, treatment was discontinued before pituitary function testing (4 wk in the case of substitution with thyroid hormones if given for goiter treatment and not for substitution of previously established hypothyroidism and 6 wk in the case of estrogen treatment).
For the TRH-LHRH-ARG test, 200 µg of TRH (Relefact TRH 200, Aventis Pharma, Frankfurt, Germany) and 100 µg of LHRH (Relefact LH-RH, Aventis Pharma) were given as an iv bolus injection, followed by a 30-min iv infusion of 30 g arginine hydrochloride (Fresenius Kabi, Bad Homburg, Germany). Measurements of TSH were done at 0 and 30 min, measurements of LH and FSH at 0, 30, and 60 min, and measurements of GH at 0, 15, 30, 45, 60, 90, and 120 min.
For the ITT, 0.1 IU/kg of regular insulin (Actrapid, Novo Nordisk, Mainz, Germany) was given iv at 0 min. The insulin dose was adjusted to up to 0.2 IU/kg if the patient was considered to be insulin resistant. Samples for measurements of serum glucose, serum cortisol, plasma ACTH, and GH were drawn at –30, 0, 15, 30, 45, 60, 90, and 120 min. In addition, monitoring of bedside blood glucose levels and clinical symptoms of hypoglycemia were done regularly throughout the test. Adequate hypoglycemia less than 40 mg/dl (2.2 mmol/liter) with or without overt clinical symptoms of hypoglycemia was achieved in all patients. No adverse events occurred during the functional dynamic tests.
Statistical analysis
Statistical analysis was performed using the statistical software package SPSS version 11.0 (SPSS Inc., Chicago, IL). Mann-Whitney U tests were calculated for rank-ordered variables, 
2 tests for categorical variables, and t tests for variables counted on an interval scale. Bivariate correlations were calculated by means of Pearson correlation coefficients.
Assays
TSH (reference range, 0.35–4.5 U/ml), fT4 (reference range, 0.8–1.7 ng/dl = 10.3–21.9 pmol/liter), fT3 (reference range, 2.0–4.2 pg/ml = 3.1–6.5 pmol/liter), LH, FSH, total testosterone (reference range for males, 2.4–6.9 ng/ml = 8.2–24.0 nmol/liter), estradiol, prolactin (reference range, 2.8–29.2 ng/ml = 59–619 mU/liter), serum cortisol (reference range, 43.1–224.0 µg/liter = 119–618 nmol/liter), and plasma ACTH (reference range, 9.1–50.0 ng/liter = 2–11 pmol/liter) were measured using the Centaur automatic chemiluminescence system (Bayer Diagnostics, Fernwald, Germany). GH and IGF-I levels were measured by the Nichols Advantage automatic chemiluminescence system (Bad Nauheim, Germany). IGF-I levels were evaluated according to age-related reference ranges, which have been published recently (19).
ACTH deficiency was diagnosed if peak serum cortisol levels during ITT were less than 181.25 µg/liter (500 nmol/liter). Diagnosis of gonadotropin deficiency was based on basal and stimulated LH and FSH levels, levels of testosterone in men, and levels of estradiol as well as on the presence of menstrual disturbances in women. TSH deficiency was defined as a decreased fT4 level in the presence of inadequately low basal and stimulated TSH levels. Posterior pituitary deficiency was considered in case of reported polydipsia and polyuria in combination with electrolyte disturbances.
Severe GHD was defined as a peak GH response of less than 3 µg/liter in the ITT, partial GHD by a peak GH response of greater than or equal to 3 and less than or equal to 5 µg/liter in the ITT (20).
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Results |
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Figure 1 gives an overview of the prevalence of pituitary dysfunction in our patient group. A total of 22 patients (55%), 18 of whom were women, presented with some degree of hypopituitarism after aneurysmal SAH. Disturbances of gonadotropin secretion or diabetes insipidus were not observed in the study group. Mild hyperprolactinemia without clinical symptoms of prolactin excess were seen in four patients (29.9, 33.7, 34.6, 54.8 ng/ml; 634, 715, 743, 1160 mU/liter, respectively).
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A total of 16 patients (15 females and one male) presented with stimulated serum cortisol levels of less than 181.25 µg/liter (500 nmol/liter) in the ITT and were, therefore, classified as corticotroph deficient. Of these, stimulated serum cortisol was less than 72.5 µg/liter (200 nmol/liter) in one (6.25%), between 72.5 and 108.8 µg/liter (201–300 nmol/liter) in two (12.5%), between 108.9 and 145 µg/liter (301 and 400 nmol/liter) in four (25%), and between 109 and 180.9 µg /liter (401 and 499 nmol/liter) in nine (56.25%) patients. In 13 patients (12 females and one male), corticotroph deficiency was not combined with any other deficient hormone axis. The remaining three patients (females) presented additionally with severe GHD. In the patients with an insufficient cortisol response, basal cortisol levels ranged between 67.4 and 155.9 µg/liter (186 and 430 nmol/liter; mean, 105.7 µg/liter = 291.6 nmol/liter; SD, 27.8 µg/liter = 76.7 nmol/liter), whereas basal cortisol levels in patients with a normal cortisol response lay between 59.8 and 217.1 µg/liter (165 and 599 nmol/liter; mean, 138.5 µg/liter = 382 nmol/liter; SD, 42.6 µg/liter = 117.4 nmol/liter). Basal and stimulated cortisol levels were significantly correlated (r = 0.55; P < 0.0001).
The mean ACTH response in the ITT was 35.6 ng/liter (7.85 pmol/liter; range, 15.0–83.1 ng/liter = 3.3–18.3 pmol/liter; SD, 19.3 ng/liter = 4.25 pmol/liter) in patients with a cortisol response less than 181.25 µg/liter (500 nmol/liter) and 106.3 ng/liter (23.40 pmol/liter; range, 4.5–296.0 ng/liter = 1.0–65.2 pmol/liter; SD, 64.9 = 14.3 pmol/liter) in patients with a normal cortisol response. ACTH and cortisol response were also significantly correlated (r = 0.50; P = 0.001). This result implies that a low cortisol response was generally associated with a low ACTH response (see Fig. 2).
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The patient (male) with thyrotroph deficiency underwent partial thyroidectomy because of nodular goiter several years ago and, therefore, had been treated with levothyroxine 100 µg/d. After a 4-wk discontinuation of thyroid medication, his basal TSH was 0.46 U/ml, stimulated 1.6 U/ml, in the presence of a low fT4 level (9.4 ng/ml) and a low normal fT3 (3.2 ng/ml) indicating secondary hypothyroidism.
Somatotrophic axis
In eight patients (five females and three males), severe GHD with a peak GH response in the ITT of less than 3 µg/liter was diagnosed. In three of these patients, stimulated GH levels were less than or equal to 1 µg/liter and ranged between 2.1 and 2.7 µg/liter in the remaining five. GHD was an isolated deficit in five patients (two females and three males) and was combined with corticotroph deficiency in three (all females). In addition, partial GHD with a peak GH greater than or equal to 3 and less than or equal to 5 µg/liter was seen in nine patients (seven females and two males).
One of the eight patients with severe GHD had an IGF-I value of less than –2 SD of the age-related normal range, and four had levels between –1 and –2 SD of the age-related reference range (Fig. 3). In three cases, IGF-I levels were above the age-related mean. In these patients, the peak GH levels in the ITT were 2.1, 2.6, and 2.7 µg/liter, whereas their peak GH levels in the ARG test amounted to 1.8, 8.6, and 14.3 µg/liter, respectively. The BMIs of these patients were 24.5, 26.0, and 29.0 kg/m2. Interestingly, all three had a remarkable weight gain of 10, 20, and 17 kg since the SAH.
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gives the comparison between GH responses in the ITT and ARG test. Overall, peak GH levels in both tests showed no substantial portion of shared variance (r = 0.28; not significant). Peak GH levels of less than 3 µg/liter in both tests were observed in five patients, whereas discordant results between the tests were seen in 13 patients. Three had a peak GH of less than 3 µg/liter in the ITT in the presence of a response in the ARG test of greater than 3 µg/liter, and 10 had a peak GH of less than 3 µg/liter in the ARG test in the presence of a response of greater than 3 µg/liter in the ITT.
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The following clinical variables were analyzed with respect to corticotroph deficiency, severe GHD, and partial pituitary deficiency within the 40 patients in the study group: clinical grade on admission (Hunt and Hess grade), severity of the bleeding on CT scans (Fisher grade), neurological outcome at discharge from the hospital, neurological grade at the time of testing, elapsed time between SAH and pituitary function testing, patient age, gender, early vs. late surgery, location of the symptomatic aneurysm, ACoA aneurysm location vs. all other aneurysm locations, intraventricular hemorrhage, duration of surgery in minutes, total time of temporary clipping, premature aneurysm rupture, presence of vasospasm, duration of vasospasm in days, presence of shunted hydrocephalus, self-reported weight gain, BMI, and depression.
Statistically significant findings
There was a significant effect of gender on the presence of corticotroph deficiency (2 test P = 0.002). Furthermore, six of the seven patients in whom premature aneurysm rupture (intraoperative rupture of aneurysm before neck is secured by clips) occurred had a stimulated serum cortisol of less than 181.25 µg/liter (500 nmol/liter) in the ITT (Fisher’s exact test P = 0.028). The statistical results did not change when comparing patients with corticotroph deficiency with patients without any hormone disturbances after aneurysmal SAH.
Vasospasm was significantly less frequent in patients with severe GHD compared with all other patients (Fisher’s exact test P = 0.042). Patients with severe GHD had gained significantly more weight since their SAH (mean, 10.00 kg; SD,6.84 kg) than all other patients (mean, 4.62 kg; SD,6.00 kg; t test P < 0.0001) and exhibited a significantly higher BMI (mean of 32.00 kg/m2 and SD of 4.95 kg/m2 vs. mean of 24.95 kg/m2 and SD of 3.92 kg/m2; t test P = 0.033).
Patients with partial pituitary deficiency in general could not be differentiated from the other investigated patients by any of the above mentioned clinical variables except for sex (2 test P = 0.004).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We saw a high incidence of isolated mild to severe corticotroph deficiency as the only manifestation of neuroendocrine dysfunction after aneurysmal SAH. This result and the missing evidence for lasting gonadotroph insufficiency after the hemorrhage point to a hypothalamic rather than pituitary origin of hormonal malfunction. The high percentage of isolated corticotroph dysfunction seen in the present study has so far not been reported in patients after traumatic head injury. Kelly et al. (14) described only one patient with borderline corticotroph function with a maximum cortisol of 10.3 µg/dl in the ITT. Liebermann et al. (21), however, found below normal basal cortisol levels in 45.7% of 70 adult patients after traumatic brain injury, whereas stimulated cortisol levels in a short ACTH stimulation test were insufficient (peak < 500 nmol/liter) in only 7.1%. This disparity in our results may be caused by the use of different dynamic tests of the hypothalamic-pituitary-adrenal axis. The ACTH stimulation test used in the study by Liebermann et al. may have a lower sensitivity to detect impairments of cortisol secretion caused by subtle hypothalamic dysfunctions than the ITT.
In addition, Dhillo et al. (22) recently have provided evidence that cortisol-binding protein (CBP) is important in the interpretation of dynamic tests of the hypothalamicpituitary-adrenal axis. Because, in the present study, the assessment of adrenal function has relied on total cortisol response in the ITT and CBP concentrations have not been measured, it cannot be ruled out that CBP variations have affected the interpretation of corticotroph function. Nevertheless, this seems unlikely for two reasons. First, all patients were in a stable situation without evidence for acute illness at the time of endocrine function testing, and none of the patients received sex steroid replacement, making significant variations in CBP concentrations unlikely. Second, peak cortisol levels were significantly correlated with peak ACTH levels in the ITT, and a low cortisol response was generally associated with a low ACTH response.
The reasons for the high incidence of disruption of the cortisol axis are uncertain from the scope of the study. In our series, corticotroph disturbances were seen not only in patients with prematurely ruptured ACoA aneurysms (n = 2) but likewise in patients with prematurely ruptured MCA (n = 2), ICA (n = 2), and vertebral artery (n = 1) aneurysms. Corticotroph dysfunction caused by the premature rupture of an aneurysm other than the ACoA aneurysm, where the bleeding or the subsequent surgical manipulation could damage hypothalamic structures, is barely explainable, which indicates that premature rupture cannot be considered an independent factor of hypothalamic damage.
One surgical step, commonly used in aneurysm surgery, is fenestration of the lamina terminalis to relax the brain, facilitate the exposure of the aneurysm, and reduce the rate of shunt-dependent hydrocephalus after aneurysmal SAH (23). In view of the unexpectedly high incidence of isolated abnormal stimulated cortisol levels in our mostly surgically treated SAH patients, one can speculate that intraoperative opening of the lamina terminalis may disrupt neuroendocrine pathways involved with corticotropin releasing factor expression (24). However, the number of patients who underwent endovascular therapy (in which the lamina terminalis is left untouched) was too low to decide whether indeed lamina terminalis opening during surgery is one of the causes of endocrine disturbance after aneurysmal SAH.
Based on the results from the ITT, eight patients had a peak GH response of less than 3 µg/liter, indicating severe GHD. It is well known that obesity might influence the results from GH stimulation tests, even from the ITT, and may cause an overestimation of the prevalence of GHD in an overweight population (20, 25). Indeed, our patients with GHD had significantly higher BMIs compared with those with a normal GH response in ITT and also had a significantly higher weight gain since the SAH. When analyzing IGF-I levels in these patients, five had levels of less than –1 SD of a well established age-related reference range, further supporting the diagnosis of true GHD. However, because IGF-I was above the age-related mean in the other three patients, it could not be excluded that in these cases the low GH response in the ITT could be caused by other factors than true GHD.
Another potential cause of misinterpretation of our GH stimulation tests is the use of an automated chemiluminescence immunoassay for GH measurement instead of a polyclonal RIA (20). Freda et al. (26) have recently provided evidence that for modern two-site immunoassays, lower cutoff values could be appropriate. In this respect, it is interesting to note that all of the above mentioned three patients with high IGF-I levels had peak GH levels in ITT between 2 and 3 µg/liter, whereas all three patients with a GH response of less than 1 µg/liter had IGF-I levels below –1 SD of the age-related normal range.
In conclusion, the results of our investigation indicate that neuroendocrine dysfunction seems to be a more common long-term sequel of aneurysmal SAH than has so far been recognized, with a high incidence of corticotroph dysfunction seen in the present study. Although the pattern of hormonal dysfunction suggests a hypothalamic rather than pituitary origin, the underlying pathophysiological mechanisms remain to be elucidated. Additional studies are called for to define the risk factors of disturbances of the hypothalamo-pituitary system in the wake of aneurysmal SAH and to determine the benefits of hormone replacement in these patients. At present, pituitary function testing is probably warranted in patients after aneurysmal SAH who have not recovered fully from the bleeding, including those with a good neurological outcome.
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Footnotes |
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Abbreviations: ACoA, Anterior communicating artery; ARG, arginine; BMI, body mass index; BDI, Beck Depression Inventory; CBP, cortisol-binding protein; CT, computed tomography; fT4, free T4; GHD, GH deficiency; GOS, Glasgow Outcome Scale; ICA, internal carotid artery; ITT, insulin tolerance test; MCA, middle cerebral artery; PCoA, posterior communicating artery; SAH, subarachnoid hemorrhage.
Received January 28, 2004.
Accepted July 8, 2004.
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