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Growth Hormone & IGF Research 18 (2008) 472478 www.elsevier.com/locate/ghir

Growth hormone decient patients after traumatic brain injury Baseline characteristics and benets after growth hormone replacement An analysis of the German KIMS database
I. Kreitschmann-Andermahr a,*,1, E.M. Poll a, A. Reineke a, J.M. Gilsbach a, G. Brabant b,1, M. Buchfelder c,1, W. Fabender d,1, M. Faust e,1, P.H. Kann f,1, H. Wallaschofski g,1
a

Department of Neurosurgery, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany b Department of Endocrinology, Christie Hospital, Manchester, UK c Department of Neurosurgery, University of Erlangen, Germany d Department of Internal Medicine Kempen, Germany e Department of Internal Medicine II, University of Cologne, Germany f Division of Endocrinology & Diabetology, Philipps University Marburg, Germany g Department of Gastroenterology, Endocrinology and Nutrition, University of Greifswald, Germany Received 22 April 2008; revised 8 August 2008; accepted 17 August 2008

Abstract Objective: In recent years, traumatic brain injury (TBI) has been identied as a signicant cause of growth hormone deciency (GHD). The aim of the present study was to characterize adult TBI patients with GHD to elucidate the eect of human growth hormone (hGH) replacement in TBI patients as documented in the German Pzer International Metabolic (KIMS) database. Design: As of October 2006, 84 TBI patients had been included in the German KIMS database (n = 28 childhood-onset and 54 adult-onset GHD). All 84 TBI patients were matched with 84 patients with GHD due to non-functioning pituitary adenoma (NFPA) also included in this database. Analysis of clinical and outcome variables was performed, with comparisons of childhood vs. adult TBI, and TBI vs. NFPA patients, at baseline and one-year follow-up. Results: TBI patients with GHD were signicantly younger at the onset of pituitary disease and exhibited a signicantly longer time span between GHD diagnosis and KIMS entry than NFPA patients. Those KIMS patients who had sustained their TBI in childhood were of signicantly shorter stature than adult-onset TBI patients. At 1-year follow-up, insulin-like growth factor I (IGF-I) standard deviation score levels had returned to the normal range and quality of life (QoL), as measured by QoL- Assessment of Growth Hormone Deciency in Adults (AGHDA) questionnaire, improved signicantly in TBI as in NFPA patients. Conclusion: This analysis provides preliminary data that TBI patients with GHD benet from hGH replacement in terms of improved QoL in a similar fashion as do NFPA patients. Moreover, it suggests that belated diagnosis and treatment in childhood-onset GHD due to TBI might be related to a shorter nal height in these children. 2008 Elsevier Ltd. All rights reserved.
Keywords: Traumatic brain injury; Hypopituitarism; Quality of life; Growth hormone deciency; Pituitary

1. Introduction
Corresponding author. Tel.: +49 241 8088483; fax: +49 241 8082564. E-mail address: ikreitschmann-andermahr@ukaachen.de (I. Kreitschmann-Andermahr). 1 On behalf of the German KIMS board. 1096-6374/$ - see front matter 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ghir.2008.08.007
*

Recently, the importance of brain damage due to traumatic brain injury (TBI) as a major and formerly underestimated cause of hypothalamic-pituitary dysfunction

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has been highlighted. From 2000 to October 2007, 10 clinical studies evaluating endocrine function in a total of 809 adult patients in the chronic phase after hospitalisation for TBI (at least 5 months after trauma) have indicated some degree of hypopituitarism, with a pooled frequency of 27.5% (95% CI 22.8%28.9%) in these TBI survivors [111]. In most cases, only one pituitary axis was aected and panhypopituitarism was a rarity. Several studies have identied severe growth hormone deciency (GHD) as the most frequent pituitary abnormality following the head trauma [for an overview see [11]]. Because of the similarity of some TBI sequelae, such as lack of energy and a diminished quality of life (QoL), to those of untreated hypopituitarism, it is frequently postulated that hormone decits may contribute to the chronic disability of TBI survivors. In this context, a recent study has shown that GH-insucient TBI patients have higher levels of fatigue than GH-sucient TBI patients 69 months after the trauma [12]. Nevertheless, testing for endocrine dysfunction in TBI survivors is still not a matter of clinical routine and data on the benet of hormone replacement in this patient group are scarce. One observational study, published in March 2005, has compared 51 patients with adult-onset GHD due to TBI to 688 GH-decient patients with non-functioning pituitary adenoma (NFPA) using data from KIMS (Pzer International Metabolic Database) [13], an international pharmacoepidemiologic survey designed to monitor the safety and outcome of human growth hormone (hGH) replacement therapy in GH decient adults. This study showed that adult-onset GH-decient TBI patients were signicantly shorter in height and had a signicant reduction in pituitary GH reserve as compared to NFPA patients (as assessed by indirect parameters, such as blood glucose, and direct parameters, such as insulinlike growth factor I (IGF-I) levels, as well as higher GH dose requirements to maintain IGF-I levels) and were diagnosed and treated after considerable delay. However, this cohort was drawn from the multinational KIMS database and therefore reects diagnostic and treatment modalities from dierent countries. It was the aim of the present investigation to characterize TBI patients presently treated with hGH in Germany only and to elucidate the eect of hGH replacement in this patient group as documented in the German section of KIMS.

bined into one group, subsequently termed TBI. These patients were matched as closely as possible, according to gender and age at KIMS enrollment, with 84 patients with GHD due to NFPA who were also included in KIMS. 12 of the patients included in this assessment had also been included in the observational study of GH-decient adults mentioned above [13]. Patients who had never received hGH replacement before KIMS entry were called true nave (TBI n = 43, NFPA n = 60), those who had been treated with hGH but in whom hGH-treatment had been discontinued for at least six months before entry to KIMS were called semi-nave (TBI n = 19, NFPA n = 4) and those patients with continuous hGH-treatment before and after KIMS entry were called non-nave (TBI n = 22, NFPA n = 20).

2.1. Assessments To characterize patients with GHD due to TBI, this patient group was divided into those with onset of GHD before (n = 28, mean age 9.5 years) and after (n = 56, mean age 33.6 years) the age of 18 years (childhood-onset GHD vs. adult-onset GHD). GH provocative tests and number and type of pituitary decits were recorded in all patients. The two subgroups were compared for the following clinical characteristics at entry into KIMS: height, body mass index (BMI), waist-hip ratio (WHR), IGF-I standard deviation score (IGF-I SDS), fasting lipid prole (triglycerides, low density lipoprotein (LDL)- and high density lipoprotein (HDL)-cholesterol), latency between the onset of pituitary disease and start of hGH treatment in KIMS (KIMS entry), GH-dose and quality of life (QoL) assessed by means of the Quality of Life-Assessment of Growth Hormone Deciency in Adults (QoLAGHDA) questionnaire [14]. All biochemical measurements were conducted in a single central laboratory. Serum IGF-I was determined by radioimmunoassay after acid-ethanol precipitation of the binding proteins (Nichols Institute Diagnostics, San Juan Capistrano, Ca, US). Long-term reproducibility, measured during a time period of more than 1 year, was CV <9% in the concentration range 130850 lg/L. The assay detection limit was about 30 lg/L. The reference range for the IGF-I assay was adjusted for age. Lipid measurements were all performed in the same central laboratory. Serum concentrations of total cholesterol [15], HDL-cholesterol [16] and triglycerides [17] were measured directly and expressed as mmol/L. Serum concentrations of LDL-cholesterol were estimated using Friedewalds formula: LDL-cholesterol = total cholesterol minus HDL-cholesterol minus 0.45 triglycerides [18]. The accuracy of this formula decreases when the triglycerides level is above 4.5 mmol/L. The conversion

2. Patients and methods In October 2006, the German KIMS database (which contained, as of November 27th, a total of 2208 patients) was searched for the diagnoses perinatal head injury, head trauma and TBI, resulting in identication of a total of 84 patients (TBI n = 55, perinatal head injury n = 15, head trauma n = 14). Because of the relatively small group sizes, the three subgroups were com-

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factors are: 1 mmol/L = 38.46 mg/dL for cholesterol and 1 mmol/L = 90.90 mg/dL for triglycerides. To analyze the eect of hGH replacement therapy in TBI patients, data were obtained from all TBI patients who had at least a 1 year follow-up in KIMS (n = 61). Baseline ndings and values obtained after 1 year of hGH replacement therapy were compared for all investigated parameters except height and latency between the onset of pituitary disease and start of the hGH treatment. To check for possible dierences in the eect of hGH-treatment in TBI patients compared with other patients with an indication for hGH, the same analysis was performed in the matched NFPA patients. SPSS for Windows version 14.0 (SPSS Inc., Chicago, IL) was used to perform the data analyses. Descriptive statistics of interval-scaled data are expressed as mean standard deviation (SD) unless otherwise mentioned. To test for group dierences, Students t-tests were calculated.

3. Results 3.1. Baseline characteristics of TBI and NFPA patients Table 1 gives the clinical characteristics of TBI and NFPA patients included in the present analyses. There were no signicant dierences within the two groups with respect to the reported parameters (t-test, ns; gender compared by chi2-test ns) except that TBI patients were signicantly younger at onset of pituitary disease and latency between onset and KIMS-entry was longer. Moreover, adult-onset TBI patients and adult-onset NFPA patients did not dier in absolute height (pooled for males and females) as well as in standard deviations from the applicable median height for male and female

patients [19] (TBI absolute height = 174.59 cm, SD = 0.36; NFPA absolute height = 172.80 cm, SD = 0.36; t-tests ns). In NFPA patients, the insulin tolerance test (ITT) was used most often for GHD diagnosis (n = 39) followed in frequency by the arginine (ARG) test (n = 31), the growth hormone releasing hormone (GHRH) test (n = 18) and the GHRH-ARG-test (n = 8), whereas in TBI patients the order of frequency was ARG (n = 49), ITT (n = 31), GHRH (n = 16) and GHRH-ARG (n = 4). In 9 TBI and 6 NFPA patients, no other deciencies besides GHD were recorded, whereas 16 TBI and 14 NFPA patients exhibited one additional, 11 TBI and 12 NFPA two additional and 44 TBI and 28 NFPA patients three other hormone decits. Decits of all 4 anterior and posterior pituitary axes were observed in 4 TBI and 24 NFPA patients. The main dierence between the two groups was that NFPA patients presented with ADH deciency signicantly more frequently than TBI patients (p < 0.001, chi2-test). The distribution of the pituitary hormone deciencies other than GHD in TBI and NFPA patients is given in Fig. 1. 3.2. Childhood-onset vs. adult-onset GHD in TBI patients Patients with childhood-onset GHD due to TBI were signicantly shorter than those with adult-onset GHD (mean 162.7 cm vs. 174.6 cm, p < 0.001, see Table 2). This also is the situation when controlling for gender, when not the absolute height but standard deviations from the applicable median height for male and female patients are compared (1.34 SD vs. 0.36 SD, p < 0.001). Patients with childhood-onset TBI also exhibited signicantly lower IGF-I SDS levels at baseline (mean 4.4 vs. 1.2, p = 0.001). Mean time span between TBI and KIMS entry was 21.0 years in the

Table 1 Baseline characteristics of 84 patients with GHD due to TBI and 84 matched patients with NFPA, enrolled in the German KIMS database TBI group (n = 84) Age at enrollment (years) Males/females Body mass index (kg/m2) Adult onset GHD Isolated GHD Time since diagnosis of pituitary disease and KIMS entry (years)a Age of onset of pituitary diseaseb True nave/semi-nave/non-nave IGF-I SDS score GH starting dose (mg) QoL AGHDA scorec 36.7 10.8 58/26 25.9 5.4 56 (66.7%) 9 (10.7%) 11.2 11.3 25.5 14.3 43/19/22 2.6 2.9 0.3 0.3 8.8 6.3 NFPA group (n = 84) 37.3 10.3 49/35 26.7 4.5 76 (90.5%) 6 (7.1%) 5.0 5.0 32.2 12.2 60/4/20 1.9 2.2 0.3 0.2 8.7 6.6 p .715 chi2 ns .265

.000* .001* .259 .161 .898

Values are mean SD. a p = 0.028* if only true nave patients are considered. b Within KIMS terminology this refers to the rst date on which the clinical symptoms of hypopituitarism occur (based on clinical records and the judgment of the treating physician). c A high score depicts a poor quality of life. * Indicates statistical signicance.

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ACTH TSH LH/FSH ADH 0

8,3 * * 36,9 *

63,1 76,2 69 70,2 81 76,2

TBI NFPA

1 year follow-up: mean = 6.95, p = 0.041, t-test). No signicant eect was observed with respect to the other investigated parameters (Table 3). Since data were not available for all parameters at both time points, group sizes of the dierent statistical analyses vary (group sizes are given in Table 3). 3.4. One-year follow-up in 67 GH-decient NFPA patients

25

50

75

100

Fig. 1. Pituitary hormone deciencies other than GHD in TBI and NFPA patients (%) (* indicates a signicant dierence (chi2-test)).

childhood-onset group and 6.2 years in the adult-onset group (p < 0.001). It must, however, be considered that patients with childhood-onset GHD may have been treated and followed up in other databases (i.e. KIGS) before KIMS entry. An overview is given in Table 2. 3.3. One-year follow-up in 61 GH-decient TBI patients In the longitudinal investigation, GH dose increased signicantly as did IGF-I SDS. Quality of life (available as QoL-AGHDA scores at baseline and follow-up in 19 patients) improved signicantly (baseline: mean = 9.47,

In the group of matched NFPA patients, 67 data-sets were available for follow-up investigation. The results are presented in Table 4. In close agreement with ndings in GH-decient TBI patients, GH dose and IGF-I SDS increased signicantly after 1 year and QoL, as measured by QoL-AGHDA, improved signicantly. Additionally, LDL-cholesterol decreased signicantly in NFPA patients only.

4. Discussion The present study population, from the KIMS international pharmacoepidemiologic survey that enrolled adults with GHD, represents the largest cohort of patients with GHD due to TBI from a single country.

Table 2 Baseline data from patients at KIMS entry with childhood-onset and adult-onset GHD due to TBI (mean, SD) Childhood onset N Age at KIMS entry Time since diagnosis of pituitary disease and KIMS entry (years) Height (cm) Weight (kg) Body mass index (kg/m2) Waist-hip-ratio IGF-I SDS score QoL-AGHDA True nave/semi-nave/non-nave
*

Adult onset 56 39.8 6.2 9.4 174.6 9.1 81.7 19.8 26.6 5.3 0.9 0.1 1.2 2.2 10.0 6.4 38/5/13

p .000* .000* .000* .000* .072 .882 .001* .215

28 30.5 21.0 8.1 162.7 11.5 64.2 14.2 24.3 5.5 0.9 0.1 4.4 2.9 7.4 6.2 5/14/9

Indicates statistical signicance.

Table 3 Descriptive data from 61 GH-decient TBI patients at KIMS entry and one-year follow-up (mean, SD) KIMS entry GH dose Weight (kg) Waisthip-ratio IGF-I SDS score Triglycerides Total cholesterol HDL-cholesterol LDL-cholesterol QoL-AGHDA
a *

One year later 0.41 0.3 73.23 17.3 .89 0.1 .90 1.9 1.83 1.2 5.68 1.1 1.26 0.4 3.66 1.0 6.95 6.7

na 58 52 38 26 25 25 25 23 19

p .023* .781 .806 .018* .402 .683 .304 .576 .041*

0.31 0.3 73.04 18.1 .89 0.1 2.38 2.6 1.63 1.0 5.63 0.9 1.32 0.5 3.58 0.9 9.47 6.6

Data were not available for all parameters at both time points. Indicates statistical signicance.

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Table 4 Descriptive data from 67 GH-decient NFPA patients at KIMS entry and one-year follow-up (mean, SD) KIMS entry Dose Weight (kg) Waisthip-ratio IGF-I SDS score Triglycerides Total cholesterol HDL-cholesterol LDL-cholesterol QoL-AGHDA
a *

One year later 0.36 0.2 79.87 16.4 0.91 0.1 0.17 2.0 1.88 1.2 5.49 1.2 1.42 0.4 3.41 1.2 4.86 5.3

na 67 56 27 24 22 22 22 20 22

p .002* .512 .269 .000* .543 .058 .947 .015* .027*

0.27 0.2 79.54 16.1 0.89 0.1 1.80 2.6 1.70 1.0 5.95 1.3 1.42 0.3 3.92 1.1 7.18 4.9

Data were not available for all parameters at both time points. Indicates statistical signicance.

In comparison to a NFPA group, matched for age at entry into KIMS, TBI patients with GHD were signicantly younger at the onset of pituitary disease and had a signicantly longer time between diagnosis and KIMS entry. This may be due to a higher number of patients with childhood-onset GHD receiving previous hGH-treatment in the TBI group compared to the NFPA group. When comparing adult-onset to childhood-onset TBI patients, the latter had a signicantly shorter stature and a longer time between onset of pituitary disease and enrollment into KIMS than the adult TBI group (Table 2). One year follow-up data showed that in TBI, as well as in NFPA patients, a GH dose adjustment was performed, IGF-I levels (SDS) had returned to the normal range and QoL, as measured by QoL-AGHDA, had improved signicantly. In contrast to the study by Casanueva et al. [13] published in 2005, who evaluated 51 patients with adultonset GHD due to TBI from KIMS, this analysis of the German KIMS data also includes data from 28 patients who had sustained their head trauma and were diagnosed to have GHD before the age of 18. The topic of brain injury-induced hypopituitarism has received more attention from endocrinology specialists in recent years, and thus, more patients are diagnosed and treated. This might be the reason why the number of adult-onset TBI patients we identied in the German section of the KIMS database alone is larger than the total TBI population in the KIMS worldwide study [13]. The present data also suggest that despite the increased attention, it remains that only a subset of trauma patients are selected for hGH replacement, as TBI patients included in KIMS Germany presented with a high number of additional hormone decits. This extensive degree of neuroendocrine dysfunction in TBI patients as documented in KIMS is not reected in the literature, which most frequently describes insuciencies of one, or at most, two pituitary hormone axes in brain trauma patients [for an overview see [20]]. However, many patients reported here were diagnosed with pituitary disease several years ago, at a time before TBI was recognised as aetiology for GHD,

and were probably not tested routinely for GHD. Therefore, patients in this cohort might have been evaluated for GHD simply because they already had other pituitary deciencies, providing another explanation for why more than half of the TBI patients in the present study had more than two pituitary deciencies. In analogy to Casanuevas nding [13], there was a considerable latency in our cohort, with a mean of 11.2 years between the age of onset of pituitary disease and enrollment in KIMS observed in patients after TBI, which was signicantly longer than that in the matched NFPA group. This time delay may be due to the protracted diagnosis of hypopituitarism as a sequel of TBI, but may also, in both Casanuevas and the present data, be confounded by the fact that not all patients were treatment-nave at the time of enrollment into KIMS. This holds especially true for the childhoodonset TBI patients who may have been treated and followed up in other databases before entering KIMS. One important piece of information that can be derived from the 1-year follow-up of TBI patients is that, as in the NFPA patients, hGH replacement after TBI was associated with a signicantly improved QoL after 1 year of treatment. This improvement was not connected to a change in other pharmacological treatment as documented in KIMS, especially new substitution of other hormone axes or initiation of antidepressant therapy. Since there was a considerable time delay between the initial injury and the improvement in QoL-AGHDA score as documented in KIMS, this improvement in QoL cannot be attributed to general recovery from the trauma but can be regarded as a treatment eect. This hypothesis is conrmed by data published in 2006 which show that TBI patients with GH insuciency (GHI) exhibit more depression and a reduced QoL in comparison to TBI patients without GHI [12]. Therefore, further studies of the eect of hGH replacement in brain trauma patients are called for and should include QoL as one endpoint. In this analysis, the nding by Casanueva et al. [13] that patients with adult-onset GHD due to TBI were of signicantly shorter stature than NFPA patients

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could not be conrmed. However, the German KIMS TBI patients with childhood-onset GHD were signicantly shorter than those with adult-onset GHD. Moreover, patients with childhood-onset TBI and GHD also had signicantly lower IGF-I SDS-levels than patients with adult-onset TBI and GHD. This may be a general characteristic of childhood-onset GHD since childhoodonset GHD patients and even patients with adult-onset GHD at younger ages demonstrate lower IGF-I SDS than those who become aected later in life [2124]. However, there might also be a possibility that this difference in height and initial IGF-I SDS scores is a consequence of belated GHD diagnosis and therapy after childhood TBI. As the incidence of TBI in infancy and childhood is high, and recent publications indicate that neuroendocrine dysfunction is also common in this patient group [25,26], the data suggest that childhood TBI patients should undergo testing for GHD and be treated after diagnosis without undue delay. Last but not least, the present data analysis gives an overview of the spectrum of endocrinological tests used in the diagnosis of TBI-related GHD in Germany. The ITT, here the second most frequently used test (n = 31), has been said to be contraindicated in patients with TBI [2] due to the possible (but so far in the literature undocumented) risk of provoking epileptic seizures. While it is true that this test should not be used in patients with severe cardiovascular morbidity or uncontrolled epileptic seizures, it must be kept in mind that it is considered the gold standard for assessment of GH and the adrenal axis and oers the opportunity to evaluate hypothalamic as well as pituitary decits. This view seems to be shared by practising endocrinologists in Germany. Moreover, recent data indicate discrepancies in results between the GHRH-ARG test and the ITT in patients with brain trauma [27]. In summary, this evaluation of the German KIMS data suggests that TBI patients with GHD benet from hGH-replacement therapy in terms of an improved QoL in a similar fashion as do NFPA patients. Moreover, it suggests, that belated diagnosis and treatment of childhood-onset GHD due to brain trauma might be related to a shorter nal height in these children. Although the total number of 84 TBI patients treated for GHD reects increasing awareness of brain-injury induced hypopituitarism, it remains an issue that a large number of patients with hypopituitarism after TBI still are unrecognized and untreated.

authors are very grateful to the nurses, study coordinators and to the 62 centers and investigaters who included patients in this KIMS substudy for their patience and their cooperation in making this analysis possible. The authors thank Dr. Maria Koltowska-Haggstrom for her helpful comments on the manuscript. The Pzer International Metabolic Database (KIMS) is sponsored by Pzer Inc. Editorial support was provided by RxCommunications Ltd. and sponsored by Pzer Inc. References
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Acknowledgements I. Kreitschmann-Andermahr, G. Brabant, M. Buchfelder, W. Fassbender, M. Faust, P.H. Kann and H. Wallaschofski are members of the German KIMS board and submit the manuscript on behalf of this board. The

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