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Erciyes University Medical School, Departments of Endocrinology (F.T., K.U., F.K.) and Neurosurgery (H.S., A.S.), Kayseri, Turkey; and Department of Medicine, School of Medicine, and Complejo Hospitalario Universitario de Santiago, Santiago de Compostela University (F.F.C.), Santiago de Compostela, Spain
Address all correspondence and requests for reprints to: Dr. Fahrettin Kelestimur, Department of Endocrinology, Erciyes University Medical School, 38039 Kayseri, Turkey. E-mail: fktimur{at}erciyes.edu.tr.
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Abstract |
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Objectives: The aim of this study was to determine 1) the prevalence of anterior pituitary hormone deficiencies in the acute phase of TBI and after 12 months, 2) whether severity of trauma correlated with basal hormone levels, and 3) whether initial hormone deficiencies predicted medium-term hormonal status.
Design and Patients: Fifty-two TBI patients (43 men and nine women) were included in the prospective study. Pituitary function was evaluated within 24 h of admission and after 1 yr.
Results: Some 5.8% of the patients had TSH deficiency, 41.6% had gonadotropin deficiency, 9.8% had ACTH deficiency, and 20.4% had GH deficiency (GHD). Twelve months after TBI, 5.8% had TSH deficiency, 7.7% had gonadotropin deficiency, 19.2% had ACTH deficiency, and 37.7% had GHD. Twenty-six patients (50.9%) had at least one anterior pituitary hormone deficiency, 21 patients (41.2%) had isolated hormone deficiencies, and five patients (9.7%) had combined hormone deficiencies. Overall, the pituitary hormone deficiencies recovered in 30 (57.7%) patients after 1 yr, and new pituitary hormone deficiencies were present in 27 (51.9%) patients after 1 yr.
Conclusions: GHD is the most common pituitary deficit 12 months after TBI, and 50.9% of the patients had at least one anterior pituitary hormone deficiency. Pituitary function may improve or worsen in a considerable number of patients over 12 months.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Hypopituitarism due to TBI may be partial or complete, and 25–50% of patients have some degree of pituitary dysfunction (3, 5, 6, 7, 8). However, all of the above-mentioned studies are retrospective, and various degrees of pituitary hormone deficiencies have been reported.
To the best of our knowledge, no research has been conducted in which the pituitary function of the same patients has been investigated immediately after trauma and 1 yr later. Therefore, we planned a prospective study to investigate pituitary function in patients who suffered from mild, moderate, or severe TBI in the acute phase and 12 months after trauma. The aim was to determine the prevalence of anterior pituitary hormone deficiencies in the acute phase and 12 months after TBI, whether the severity of the trauma correlated with the basal hormone levels, whether dysfunction detected at an early phase was stress related or pituitary dysfunction, and whether initial hormone deficiencies predict the medium-term hormonal status.
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Patients and Methods |
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Fifty-two TBI patients (43 men and nine women; age, 35.9 ± 13.8 yr; range, 17–65 yr) who were admitted to the neurosurgery intensive care unit (NICU) were included in the study. The study was approved by the local committee on ethics.
The level of consciousness of the patients was evaluated by the Glasgow Coma Scale (GCS) as soon as the patient was admitted to the NICU. A score of 13–15 is considered mild, 9–12 moderate, and 8 or less severe TBI (9). Thirty-one (59.6%) patients had mild, eight (15.4%) had moderate, and 13 (25%) had severe TBI. The cause of TBI was traffic accidents in 31 patients, falls in 14 patients, and other reasons in seven patients.
Basal hormonal evaluation in the acute phase
All patients underwent a basal hormonal evaluation within 24 h of admission to the NICU. Blood samples were taken between 0800 and 0900 h. Basal hormone levels including free T3 (fT3), fT4, TSH, prolactin (PRL), cortisol, ACTH, FSH, LH, IGF-I, GH, and total and free testosterone in males or estradiol in females were measured. Menstrual history was also obtained in female patients.
In males, gonadotropin deficiency was defined by basal total and free testosterone levels below the normal range (total testosterone, <134 ng/dl; free testosterone, <11.5 pg/ml) in the presence of normal or low gonadotropin levels. In premenopausal females, gonadotropin deficiency was defined by serum estradiol level less than 11 pg/ml, with an inappropriately low serum gonadotropin concentration. In postmenopausal women, gonadotropin levels in the premenopausal range were used to diagnose the deficiency (10, 11). TSH deficiency was defined by a low serum fT4 level (<8 pg/ml) without appropriate elevation in serum TSH (10, 11). ACTH deficiency was suggested when basal cortisol was less than 7 µg/dl (6). GH deficiency (GHD) was suggested in patients who had IGF-I levels below 84 ng/ml (12).
Hyperprolactinemia was defined as a basal level greater than the normal reference range (Table 1
). The gonadotropin levels were not available in four patients (n = 48), cortisol level was not available in one patient (n = 51), and IGF-I levels were not available in three patients (n = 49).
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Fifty-two patients evaluated in the acute phase were reevaluated 12 months after TBI. None of the patients was receiving hormone replacement therapy. Gonadotropin and TSH deficiencies were defined by the same criteria used during the acute phase. ACTH deficiency was suggested when the basal cortisol level was less than 7 µg/dl and was confirmed by low-dose ACTH stimulation test using 1 µg tetracosartin (Synacthten, Novartis, Lyon, France) as previously described. A peak cortisol level lower than 20 µg/dl was accepted as ACTH deficiency (13).
GHD was investigated by the combined test [GHRH and GH-releasing peptide (GHRP-6)] in all patients. For the combined test, a peak value of 10 µg/liter or less was accepted as GH deficiency, and a peak higher than 20 µg/liter was considered a normal response. GH peak values between 11 and 19 µg/liter were considered uncertain. The combined test [1 µg/kg GHRH (Geref Serono, Madrid, Spain) and 1 µg/kg GHRP-6 (Clinalfa, Laufelfinger, Switzerland)] was performed as previously described (14).
Analytical methods
Serum GH levels were measured using an immunoradiometric assay (IRMA) with a commercial kit (Diagnostic Systems Laboratories, Webster, TX), and the IGF-I level was measured by IRMA after formic acid-ethanol extraction (Diagnostic Systems Laboratories).
Other serum hormones, except TSH (IRMA), ACTH (IRMA), and estradiol (chemiluminescent assay), were measured by RIA with commercial kits.
Statistical analysis
All data are presented as the mean ± SD (SPSS 10.0 program, SPSS, Inc., Chicago, IL). Normally distributed values between two variables were compared by unpaired t test. More than two variables (not normally distributed) were compared by the Kruskal-Wallis test, and the Dunn test was performed for post hoc analysis. The percentages were compared using the 
2 test. P < 0.05 was considered significant. In addition, we used Pearson’s correlation analysis to determine whether significant correlations existed between chosen variables.
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Results |
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There was no significant difference in mean age, fT3, fT4, TSH, PRL, cortisol, ACTH, FSH, LH, IGF-I, GH, and free testosterone levels among the subjects with mild, moderate, and severe TBI. However, the total testosterone level was significantly lower in the patients with severe TBI compared with those with mild and moderate TBI (Table 1
).
Six (five men and one woman) of 50 subjects (12%) had hyperprolactinemia. Twenty-seven of 52 patients (51.9%) had low T3 syndrome (normal fT4, normal TSH, and low fT3 levels). A significant positive correlation was noted between total testosterone levels and GCS, PRL levels were negatively correlated with GCS (Fig. 1), and cortisol levels were positively correlated with ACTH levels (r = 0.32; P = 0.03; data not shown).
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. The mean acute phase GH level of 10 patients with IGF-I levels less than 84 ng/ml was 0.56 ± 1.12 µg/liter, and this was significantly lower than the mean acute phase GH level (5.17 ± 7.18 µg/liter) of the patients with IGF-I levels higher than 84 ng/ml (P < 0.05). When we compared acute phase GH levels of the patients with IGF-I levels less than 84 ng/ml and GH levels 12 months after TBI, there was a nonsignificant difference.
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). In 46 patients, all pituitary axes were available. When individually analyzed, 26 patients (56.5%) had at least one anterior pituitary hormone deficiency. Seventeen patients (36.9%) had isolated hormone deficiencies, nine patients (19.6%) had combined hormone deficiencies, and none of the patients had panhypopituitarism.
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We reevaluated all patients who were initially seen, and none of these patients were receiving any hormonal therapy. Mild hyperprolactinemia was present in four men of the 51 patients (7.8%), and three of 52 patients (5.7%) had low T3 syndrome (normal fT4, normal TSH, and low fT3 levels). All of the significant correlations seen in the acute phase were no longer present (data not shown).
GH and IGF-I axis.
Of the 52 patients who were dynamically tested for GHD with the GHRH and GHRP-6 test, 26 patients (50%) had peak GH higher than 20 µg/liter and were considered as having normal GH secretion. Seventeen patients (32.7%) showed a GH peak of 10 µg/liter or less and were accepted as GHD (Fig. 2). According to the diagnostic criteria, GH peaks between 11 and 19 µg/liter (17.3%) are considered uncertain.
IGF-I determinations at 12 months were available for 47 patients. Four of 47 patients had IGF-I levels lower than 84 ng/ml. Two of these patients had normal GH secretion, one had GHD, and one had an uncertain GH secretion according to the GHRH and GHRP-6 test.
When we performed correlation analyses, there were no significant correlations between the following parameters: GCS vs. after 1 yr IGF-I, GCS vs. peak GH response to GHRH and GHRP-6 test, initial IGF-I vs. IGF-I levels at 12 months, initial IGF-I levels vs. peak GH response to GHRH and GHRP-6 test, and IGF-I levels at 12 months vs. peak GH response to GHRH and GHRP-6 test.
Comparisons between GHD and GH-sufficient patients are shown in Table 3. There were no significant differences between the mean basal hormone levels in GHD and GH-sufficient patients (data not shown).
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Hypothalamo-pituitary-adrenal axis.
ACTH deficiency was suggested in 13 of 52 (25%) patients who had a basal cortisol level lower than 7 µg/dl, and a low dose ACTH stimulation test was performed in 12 of them. Ten patients (19.2% of all patients) showed a cortisol peak of 20 µg/dl or less and were accepted as ACTH deficient (Fig. 2).
Ten ACTH-deficient patients were individually analyzed; six patients had isolated ACTH deficiency, and four patients had at least one hormone deficiency other than ACTH (while calculating the percentages, we assumed the uncertain group as normal for GHD). In nine of 10 patients, basal cortisol levels in the acute phase were higher than 7 µg/dl. Additionally, two of 10 ACTH-deficient patients (20.0%) had no any pituitary hormone deficits during the acute phase evaluation.
Other hormonal abnormalities.
Four of 52 (7.7%) patients (three men and one woman) had gonadotropin deficiency, which was associated with mild hyperprolactinemia in two male patients. One of four patients had isolated FSH/LH deficiency, and the others had at least one hormone deficiency other than low gonadotropin levels (Fig. 2).
In one of the patients, baseline thyroid hormone levels and TRH stimulation test were compatible with primary hypothyroidism (peak TSH response was 158.3 mIU/ml at 30 min). Three of 52 (5.8%) patients had TSH deficiency, and one of them had isolated TSH deficiency (Fig. 2).
Overall results and individual evaluation from acute to 12 months after TBI
The percentages of the pituitary hormone deficiencies in the acute phase and 12 months after TBI are summarized in Fig. 2. During the 1-yr follow-up, there was a significant decrease in FSH/LH deficiency (P < 0.0001) and a nonsignificant increase in ACTH (P = 0.175) and GH (P = 0.163) deficiencies.
After individual evaluation of pituitary hormone deficiencies from the acute phase to 12 months after TBI, the numbers of patients who recovered and developed new-onset hormone deficiencies were determined (summarized in Table 4). Overall, pituitary hormone deficiencies recovered in 30 (57.7%) patients after 1 yr, and new-onset pituitary hormone deficiencies were present in 27 (51.9%) patients after 1 yr (Table 4).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The pituitary gland responds to acute traumatic events, and several changes in hormone levels become apparent during the first hours or days after injury (16). In the acute phase of TBI, high or low basal GH levels associated with low IGF-I levels have been demonstrated (17, 18, 19). Peripheral resistance to GH action, manifested by high basal GH concentrations with low IGF-I concentrations, has been reported in patients with critical illness (20). In this study, the mean basal GH level in the acute phase was significantly higher than the GH level at 12 months, whereas the IGF-I level in the acute phase was significantly lower than the IGF-I level at 12 months, compatible with peripheral GH resistance. When we performed subgroup analysis of acute phase GH levels in 10 patients with IGF-I levels less than 84 ng/ml, the mean GH level was significantly lower than the mean acute phase GH level of the patients with IGF-I levels greater than 84 ng/ml. Also, there was no significant difference between the acute phase GH levels and GH levels at 12 months in patients with IGF-I levels less than 84 ng/ml, implying that instead of peripheral resistance, decreased GH secretion may be responsible in patients with IGF-I levels lower than 84 ng/ml. Additionally, GH and IGF-I levels were not correlated with the severity of the trauma.
Elevated serum cortisol levels associated with increased ACTH release during the initial phase of trauma have been previously reported, and there was a positive correlation between the severity of the injury and cortisol levels in patients with mild or moderate TBI, but not in those with severe injury (21, 22). In contrast, primary or secondary adrenal failure has been shown 7–60 d after TBI in 15% of patients with moderate to severe injury (23). We found that the mean cortisol level was significantly higher in the acute phase compared with the level 12 months after TBI, and cortisol levels were positively correlated with ACTH levels, implying a centrally activated hypothalamo-pituitary-adrenal axis. However, we did not find any correlation between cortisol levels and the severity of the injury, although others have demonstrated a correlation between GCS and initial cortisol levels and between cortisol levels and outcome (21, 22, 23). We did not perform any stimulation tests for diagnosis of GH and cortisol deficiencies during the acute phase, because it was difficult to perform these tests under intensive care unit conditions, and the diagnosis was challenging in acute severe illness due to the difficulties in selecting a reliable stimulation test (7, 24).
Acute illness or trauma induces several changes in thyroid hormone levels, and rapid decreases in T4 as well as T3 levels have been demonstrated (24). The presence of the low T3 syndrome and recovery over weeks have been demonstrated in few studies (25, 26). We demonstrated that the percentages of low T3 syndrome in the acute phase and 12 months after TBI were 51.9 and 5.7%, respectively.
The percentages of TSH, ACTH, GH, and gonadotropin deficiencies were 5.8, 9.8, 20.4, and 41.6%, respectively. Overall, 56.5% of the patients had anterior pituitary dysfunction in the acute phase. In a recent study, Agha et al. (27) evaluated 50 consecutive patients in the acute phase (median, 12 d) of TBI. Pituitary hormone deficiencies were TSH (2%), cortisol (16%), GH (18%), and gonadotropin (80%). Recent studies have shown that various inflammatory mediators, including cytokines and free radicals, may affect a variety of acute phase changes in endocrine function after TBI (28, 29). However, it is not clear whether the reported hormone deficiencies are secondary to structural hypothalamic-pituitary injury and are permanent or if they reflect adaptive mechanism to acute illness.
Consistent with some (3, 5, 15, 30, 31), but not with other (2, 6, 32) reports, this study clearly demonstrated that GHD was the most common (32.7%) abnormality 1 yr after TBI. We used a combined test for the diagnosis of GHD, which is a stringent and a reliable test (14). To avoid the overestimation of GHD, we accepted the strict criteria and did not include the uncertain GH secretion group in the analysis (14). Similar to the previous studies, GHD was not correlated to the severity of the brain injury (5, 7, 32). Additionally, we could not demonstrate any significant difference in IGF-I levels between GHD and GH-sufficient patients. Using the GHRH and arginine test, Bondanelli et al. (30) reported the prevalence of GHD as 28% in 50 patients 1–5 yr after TBI. Although Leal-Cerro et al. (6) used the combined test, GHD was less frequent than in the present study. However, Leal-Cerro et al. (6) applied dynamic tests for GHD only in subjects with IGF-I levels lower than 200 ng/ml or who had a pituitary hormone deficiency other than GH, but in most GHD patients, IGF-I levels were higher than 200 ng/ml in our patient group, and 13 of 17 patients had isolated GHD.
Low IGF-I levels (<84 ng/ml) or the presence of pituitary hormone deficiencies other than GH may have a diagnostic value similar to that of dynamic tests (12). Based on these findings, we did not perform any dynamic test, and GHD was defined according to IGF-I levels in the acute phase of TBI. Although the acute phase GH and IGF-I analyses were compatible with peripheral GH resistance, subgroup analysis of acute phase GH levels revealed that IGF-I levels lower than 84 ng/ml were caused by decreased GH secretion, which reflects GHD. Ten patients had IGF-I levels lower than 84 ng/ml in the acute phase. Only three of them had GHD 12 months after trauma. Therefore, IGF-I levels lower than 84 ng/ml in the acute phase have an estimated value for GHD as 33% 1 yr after TBI. Additionally, 12 months after TBI, only one GHD patient had an IGF-I level lower than 84 ng/ml.
When we compared GH-sufficient and GHD patients, mean age and body mass index (BMI) were significantly higher in GHD patients. Marked obesity is associated with blunted GH secretion after provocative stimuli (33). We could not find any correlation between age and BMI in GHD patients, suggesting that an impaired GH response in GHD patients truly reflects GHD.
We found ACTH deficiency in 19% of the patients, which was the second most common hormone deficiency. Basal ACTH and cortisol evaluations detected ACTH deficiency in less than 10% of the subjects (7, 15, 30). Agha et al. (32) reported that 22.5% of TBI patients had a low cortisol response to glucagon, and 12.7% also failed to respond to the insulin tolerance test. The main reason for the higher prevalence of secondary adrenal insufficiency in the present study might be the low-dose ACTH test that we used for the diagnosis of ACTH deficiency. Because cortisol is a vital hormone, using a sensitive test such as the low-dose ACTH stimulation test would be important in avoiding the underdiagnosis of subclinical cases.
Recently, it was reported that 3 months after TBI, 40% of the patients show fully normal pituitary function. Twelve months after TBI, nearly 60% show fully normal pituitary function, suggesting that pituitary function may improve or recover over time (15). Conversely, there are reports that 5.5% of TBI patients with normal pituitary function at 3 months developed hormone deficits at 12 months (15). The percentages of pituitary hormone deficiencies at 12 months in the Italian study and the present study are summarized in Table 6. In the present study, when we analyzed recovery rates and new-onset cases for each hormone, the percentages were substantially higher than in the study by Aimaretti et al. (15). The main reason for this difference is that the initial evaluation in our group was in the early phase.
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In conclusion, our data clearly demonstrate that most hormonal changes in the very early phase after TBI were transient, and the acute phase pituitary hormone deficiencies did not generally predict the hormone deficiencies after 1 yr. IGF-I levels lower than 84 ng/ml in the acute phase may have a predictive value for GHD at 12 months. After screening the TBI patients prospectively, pituitary function may improve or worsen in a considerable number of patients. GHD is the most common pituitary deficit at 12 months after TBI. Taken together, 50.9% of the patients had at least one anterior pituitary hormone deficiency. Therefore, screening of pituitary function is crucial after severe, moderate, and mild TBI.
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Footnotes |
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Abbreviations: BMI, Body mass index; fT3, free T3; GCS, Glasgow Coma Scale; GHD, GH deficiency, GH deficient; GHRP, GH-releasing peptide; IRMA, immunoradiometric assay; PRL, prolactin; TBI, traumatic brain injury.
Received November 11, 2005.
Accepted February 28, 2006.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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