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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0901
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 3861-3868
Copyright © 2007 by The Endocrine Society

Posttraumatic Hypopituitarism Is Associated with an Unfavorable Body Composition and Lipid Profile, and Decreased Quality of Life 12 Months after Injury

M. Klose, T. Watt, J. Brennum and U. Feldt-Rasmussen

Department of Medical Endocrinology (M.K., T.W., U.F.-R.), University Hospital of Copenhagen, Rigshospitalet, 2100 Copenhagen, Denmark; and Department of Neurosurgery (J.B.), Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark

Address all correspondence and requests for reprints to: Marianne Christina Klose, M.D., Department of Medical Endocrinology, PE2131, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: mcklose{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective: Our objective was to describe body composition, lipid profile, and health-related quality of life (HRQL) in patients with traumatic brain injury (TBI) in relation to the development of posttraumatic hypopituitarism.

Design: This is a cross-sectional evaluation with a nested prospective substudy.

Patients: The cross-sectional cohort included 104 hospitalized patients with TBI [26 females/78 males; median age 41 yr (range 18–64); body mass index (BMI) 25 kg/m2 (range 17–39); and severity, mild (Glasgow Coma Scale score (GCS) 13–15) n = 44, moderate (GCS 9–12) n = 20, and severe (GCS <9) n = 40)]. A nested cohort of 46 patients was followed prospectively.

Measurements: BMI, waist circumference, lipid profile, total- and regional-fat mass were assessed 3 and 12 months (prospective) or only 12 months (cross-sectional) posttraumatically. HRQL questionnaires (Nottingham Health Profile, EuroQoL-5D, and the GH deficiency (GHD) specific instrument, Quality of Life Assessment of GHD in Adults) were completed "pre-traumatically," 3 and 12 months (prospective), or only 12 months (cross-sectional) posttraumatically.

Results: Patients with posttraumatic hypopituitarism had higher age-, gender-, and BMI-adjusted 12-month low-density lipoprotein-cholesterol, waist circumference, and total fat mass (P < 0.05 in all cases), and a higher increase in total cholesterol (P = 0.01) during follow-up compared with sufficient patients. These findings were unrelated to 12-month IGF-I and IGF-I SD scores. Hypopituitary patients also had worse age, BMI, and TBI severity adjusted overall EuroQoL-5D visual analog scale (P = 0.03) and Quality of Life Assessment of GHD in Adults (P = 0.01) scores, and worse Nottingham Health Profile dimension scores of sleep (P = 0.03), energy (P = 0.02), and social isolation (P = 0.04), compared with patients with an intact pituitary function.

Conclusion: Posttraumatic hypopituitarism was an independent predictor of the classical phenotypical features of hypopituitarism, including an unfavorable lipid and body composition profile, as well as worsened HRQL.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
TRAUMATIC BRAIN INJURY (TBI) is associated with a high morbidity causing a broad spectrum of limitations in everyday life, including physical and psychosocial functioning. The negative consequences are most marked in patients with cerebral lesions, and include emotional and cognitive dysfunction (1), and restriction of participation in life activities (2). Several studies have shown a steady improvement within the first months after injury, which thereafter usually stabilizes below the pretrauma level (1, 3, 4). Intensive neurorehabilitation seems promising in terms of amelioration, reduction, or alleviation of symptoms. However, various physiological and psychological dysfunctions may interact in generating posttraumatic problems. Over the last years, increasing evidence has suggested that posttraumatic hypopituitarism is of clinical importance in patients with moderate and severe TBI (5). Whether pituitary dysfunction influences the health-related quality of life (HRQL) in TBI patients remains poorly described, although posttraumatic GH deficiency (GHD) was recently reported to be associated with depression and an overall diminished quality of life (6, 7).

Hypopituitarism is associated with a reduced HRQL but is also associated with an unfavorable body composition and lipid profile, features that tend to improve when relevant insufficiencies are treated (8, 9, 10).

We have previously reported prevalence and predictors of posttraumatic hypopituitarism (11), and in the present study, we describe body composition, lipid profile, and HRQL in patients with TBI in relation to the development of hypopituitarism. Part of the study was conducted as a nested prospective study to ascertain the temporal sequence between the head trauma and outcome measures.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and healthy controls

A total of 104 patients with TBI were included for cross-sectional evaluation at a median of 13 months (range 10–27) after injury. A nested subgroup of 46 patients was included for longitudinal follow-up with assessment in the early aftertraumatic phase [median 3 d (range 0–12) after injury], 3 and 12 months after injury. The 46 patients included for follow-up did not differ from the other 58 patients in the cross-sectional cohort concerning age and gender distribution, trauma cause, TBI severity [defined by post-resuscitation Glasgow Coma Scale score (GCS)], days of hospitalization, and the percentage of patients with isolated or multiple pituitary dysfunction but included a lower percentage of patients with pathological trauma-related cerebral computerized tomography imaging (P = 0.01) (Table 1Go). A total of 30 age and body mass index (BMI) group-matched healthy controls (15 women), median age 36 yr (range 21–64), with BMI 24 kg/m2 (range 19–30) were included.


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  		TABLE 1. Characteristics of the cross-sectional cohort and of those included or not included in the nested cohort with prospective follow-up

 
Methods

In the prospective cohort, lipid profile and body composition were assessed 3 and 12 months after injury, whereas HRQL questionnaires were completed in the early posttraumatic phase, and 3 and 12 months after injury. Lipid profile, body composition, and HRQL were assessed at a median of 13 months posttraumatically in the TBI patients included for cross-sectional evaluation. The study was approved by the local ethical committee (Journal no. 01-107/03), and all participants gave their written informed consent. In case of altered consciousness, significant others (closest relatives) gave written informed consent, which was confirmed by the patient at follow-up.

Lipid profile

Fasting morning blood samples were collected for analyses of triglycerides, and total-, low-density lipoprotein (LDL)-, and high-density lipoprotein (HDL)-cholesterol. All participants were tested in a supine position with sampling after 15 min rest after inserting an indwelling catheter in a large forearm vein. Plasma samples were analyzed on the day of sampling.

Body composition

Body weight was measured to the nearest 0.1 kg with patients wearing light indoor clothing without shoes. Height was measured barefoot to the nearest 0.5 cm. BMI was calculated as weight (kg)/height (m)2. Waist circumference was ascertained by tape measure to the nearest 0.5 cm with the subject in a standing position, and was measured midway between the lower rib and iliac crest during expiration. Dual-energy x-ray absorptiometry (model XP-26/XR-46; Norland Medical Systems, Fort Atkinson, WI) was performed as whole body scans with separate assessment of the three compartments: total fat mass (FM), total lean tissue mass, and total bone mineral content. Data on the regional distribution of body components were obtained for abdomen. The in-house intraoperator coefficient of variation (CV) was 5%. The same technician assessed all body composition measures.

Quality of life (HRQL)

HRQL was assessed using two generic questionnaires [EuroQoL-5D (EQ-5D) (12) and Nottingham Health Profile (NHP) (13, 37, 38)] and one specific for GHD [Quality of Life Assessment of GHD in Adults (QoL-AGHDA) (14)]. All questionnaires were completed at each visit. Significant others filled in the acute-phase questionnaires in 17 of 46 patients followed prospectively. The acute-phase questionnaires were completed in accordance with the health status before the incident.

EQ-5D includes a descriptive system and a visual analog scale (VAS). We analyzed the VAS only, which measures overall health status on a scale, scored 0–100, with 100 denoting the best imaginable health. EQ-5D has had concurrent validity with other standard generic quality of life measures and good reliability (15).

The NHP is a generic questionnaire, measuring health in six dimensions: emotional reactions (nine items), energy (three items), physical mobility (eight items), pain (eight items), sleep (five items), and social isolation (five items). Each item represents a problem that is scored dichotomously, acknowledging or denying the problem. The score for each of the six dimensions is calculated as the percentage of problems present (i.e. positively answered items) within each dimension score. Thus, a high score denotes a poor HRQL. An acceptable validity and reliability across several diseases has been shown (16, 17).

QoL-AGHDA is a GHD specific questionnaire, measuring the impact of GHD in one overall dimension (14). Each of the 25 items represents a problem and is scored dichotomously, acknowledging or denying the problem. Summating positively scored items derives the overall score, thus ranging from 0–25, with higher scores representing worse HRQL. Concurrent validity with the NHP and the Psychological General Well-Being schedule, and high reliability coefficients has been demonstrated (14).

Diagnostic criteria for hypopituitarism

All patients were tested by baseline hormone evaluation and dynamic testing, including an insulin tolerance test (ITT) (86% of the patients in the cross-sectional cohort and 96% with prospective follow-up), or alternatively by a GHRH + arginine (arg) test and a Synacthen test. One patient with panhypopituitarism included in the prospective substudy received replacement therapy at the 12-month evaluation, including hydrocortisone (10 + 5 + 5 mg), androgens, and desmopressin. In this patient, hypothalamic-pituitary-adrenal-axis assessment was performed at least 12 h after the last dose of hydrocortisone. None of the other patients received replacement therapy at testing. One patient diagnosed as hypopituitary was treated with antiepileptic drugs, whereas none of the other patients were treated with any drug known to influence the test results.

Secondary adrenal insufficiency was defined as peak or 30 min cortisol less than 500 nmol/liter, in response to the ITT, as well as to the 250 µg ACTH test. Secondary hypothyroidism was suspected in patients with a subnormal serum free T4 (<12 pmol/liter) associated with an inappropriately low TSH. Hypogonadotropic hypogonadism in postmenopausal women was defined as inappropriately low gonadotropins for age: in premenopausal women as the presence of amenorrhea or oligomenorrhea, associated with persistently low estradiol and inappropriately low gonadotropins; and in men as a low serum total testosterone (<10 mmol/liter) associated with inappropriately low LH. Severe GHD was defined as peak GH less than 7.8 mU/liter (3 µg/liter) in response to hypoglycemia (18) and as peak GH less than 23 mU/liter (9 µg/liter) (19) in response to a GHRH + arg test. Partial GHD was defined by a peak GH response ≤13 mU/liter (5 µg/liter) but ≥7.8 mU/liter (3 µg/liter) in response to ITT, or ≤43 mU/liter (16.5 µg/liter) but ≥23 mU/liter (9 µg/liter) in response to the GHRH + arg test. Antidiuretic hormone deficiency was considered in cases of reported polyuria and polydipsia, and diagnosed if the patient proved an insufficient water deprivation test. All insufficiencies were confirmed by retesting within 1–3 months. The 12-month prevalence of hypopituitarism in the cross-sectional and prospective cohort is given in Table 1Go. One patient with posttraumatic hypopituitarism had evidence of a pituitary stalk transection at magnetic resonance, whereas magnetic resonance did not reveal any obvious damage in the remaining hypopituitary patients.

Assays

Plasma total cortisol, TSH, free T4, prolactin, LH, FSH, testosterone, and estradiol were analyzed by ElectroChemiLuminescens-ImmunoAssay (Modular Analytics E170; Roche Diagnostics GmbH, Mannheim, Germany). The local long-term maximal total assay variations were: cortisol, 9.2% nmol/liter; TSH, 5.3%; free T4, 6.1%; prolactin, 7.0%; LH, 11.9%; FSH, 7.9%; testosterone, 9.5%; and estradiol, 8.2%. GH was analyzed by a flouroimmunometric assay (AutoDelfia; PerkinElmer Life And Analytical Sciences, Inc., Waltham, MA). Intraassay and interassay CVs given by the manufacturer were 2.2–5.1% and 1.4–2.5%, respectively. The hormone assays were under ongoing certification by Deutsche Vereinte Gesellschaft für Klinische Chemie und Laboratoriumsmedizin (Bonn, Germany). IGF-I was determined by competitive RIA. The local intraassay CVs were 10.3 and 6.1% at a concentration of 29.5 and 215 ng/ml, respectively. Lipids were analyzed by ElectroChemiLuminescens-ImmunoAssay. The local total CVs were: 5% (total cholesterol) at concentrations of 3.1 and 7.6 mmol/liter, respectively; 5% (HDL-cholesterol) at concentrations of 0.9 and 2.2 mmol/liter, respectively; 5% (LDL-cholesterol) at concentrations of 1.9 and 4.5 mmol/liter, respectively; and 5% (triglycerides) at concentrations of 1.0 and 2.2 mmol/liter, respectively.

Statistical analyses

Data are presented as mean (± SD) if normally distributed and otherwise as median (range). Comparison of categorical data was performed by the {chi}2 test or Fisher’s exact test in tables with expected frequencies less than five. Between-group comparisons were analyzed by unpaired t tests for normally distributed data, otherwise by the Mann-Whitney U test. Univariate and multivariate regression analyses were conducted to analyze the association between outcome measures (body composition, lipid, and HRQL measures) and covariates (hypopituitarism, gender, age, etc.). Multivariate analyses were conducted with backward elimination. Because peak GH in response to the GHRH + arg test was highly influenced by BMI, additional analyses were conducted only including patients tested with the ITT.

Within-subject changes during follow-up were analyzed by paired t tests or by Wilcoxon’s matched pairs test. Comparisons of follow-up changes between diagnostic groups were made by analysis of covariance (20), including the 12-month data as the outcome measures and the corresponding 3-month data and the binary variable "hypopituitarism" as covariates. Cronbach’s {alpha} (21) and Spearman’s {rho} were calculated for the comparison of HRQL scales. In all cases a difference was considered significant when P < 0.05. Statistical analyses were performed by SAS version 9.1 (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Lipid profile and body composition

Patients with posttraumatic hypopituitarism were older (P = 0.02), and had higher age and gender-adjusted 12-month mean total- and LDL-cholesterol, higher triglycerides, similar HDL-cholesterol, higher mean BMI, waist circumference, and total and abdominal FM compared with patients who had an intact pituitary function (Fig. 1Go). Further adjustment for BMI and TBI severity showed that hypopituitarism was an independent predictor for higher LDL-cholesterol (P < 0.05), total FM (P = 0.03), and waist circumference (P = 0.04), whereas hypopituitarism was only weakly related to higher total cholesterol (P = 0.06). Analyses restricted to patients tested with the ITT showed a nonsignificant gender, age, and BMI-adjusted tendency toward higher total FM (P = 0.06) and waist circumference (P = 0.08). Total body, femoral, and lumbar (L2–L4) spine bone mineral content and BMD were not significantly different comparing insufficient and sufficient patients.


Figure 1
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  		FIG. 1. Lipid profile and body composition in healthy controls (n = 30) and patients included in the cross-sectional cohort with pituitary sufficiency (n = 87) or insufficiency (n = 16). The boxes illustrate mean ± SEM, and the whiskers the mean ± SD. Age- and gender-adjusted P values are given in case of significant differences. Analyses were performed by the Student’s t test (after log transformation if indicated). W/H, Waist to hip.

 
In the prospective cohort, pituitary insufficient as opposed to sufficient patients had significantly higher BMI, waist circumference, and total FM at late (12 months) relative to early (3 months) follow-up (P < 0.05 in all cases), and showed a higher age, gender, and TBI severity adjusted increase in total cholesterol, BMI, waist circumference, and total lean tissue mass (P < 0.05 in all cases) (Table 2Go). Hypopituitarism remained independently related to a higher increase in total cholesterol after further adjustment for BMI (P = 0.01). The changes in body composition between 3 and 12 months did not correlate significantly with serum IGF-I or IGF-I SD scores.


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  		TABLE 2. Total cholesterol and body composition measured 3 and 12 months after injury in the pituitary sufficient and insufficient patients included for prospective follow-up (n = 46)

 
HRQL

In the cross-sectional cohort, 12-month age-adjusted EQ-5D VAS scores (P < 0.001), QoL-AGHDA scores (P < 0.01), and the NHP scores in the dimensions of emotional reaction (P = 0.001), sleep pattern (P < 0.01), energy level (P < 0.001), and physical mobility (P < 0.05) were significantly worsened in both pituitary sufficient and insufficient patients relative to healthy controls (Fig. 2Go).


Figure 2
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  		FIG. 2. Mean EQ-5D VAS, QoL-AGHDA, and NHP dimension scores in healthy controls (white bars) and in TBI patients assessed in the pretrauma setting [gray checkered bars (n = 46)] and 12 months after injury divided into those with pituitary sufficiency [gray bars (n = 87)] and insufficiency [black bars (n = 16)]. A low HRQL is denoted by high QoL-AGHDA and NHP scores, whereas by low EQ-5D VAS scores. a, P < 0.05 comparing sufficient and insufficient patients (adjusted for age, BMI, and TBI severity). c, P < 0.05 compared with controls (adjusted for age); ns, nonsignificant compared with controls.

 
Age, BMI, and TBI severity adjusted EQ-5D VAS score (P = 0.03), QoL-AGHDA score (P = 0.01), and NHP score in the dimensions of sleep (P = 0.03), energy (P = 0.02), and social isolation (P = 0.04) were, furthermore, significantly worsened in the hypopituitary patients relative to TBI patients with a preserved pituitary function (Fig. 2Go), whereas the NHP dimensions of physical mobility, pain, and emotion were similar comparing the two groups.

Pretrauma HRQL was assessed in the 46 patients included in the prospective cohort. Median pretrauma EQ-5D VAS scores, QoL-AGHDA scores, and NHP dimension scores were similar in the TBI patients compared with the controls (P > 0.3 in all cases) (Fig. 2Go). There were no significant differences in the median pretrauma score from questionnaires completed by the patients or significant others.

Analyses on age and TBI severity adjusted temporal changes in HRQL showed that patients developing hypopituitarism had a tendency toward a more prominent deterioration of the EQ-5D VAS score and the QoL-AGHDA score from "pre-trauma" to 12 months after injury. Pituitary insufficient patients were prone to develop scores up to 43 points lower (i.e. worse) on the VAS and up to 10 points higher (i.e. worse) on the QoL-AGHDA scale relative to pituitary sufficient patients. Hypopituitary patients were also prone to acknowledge up to 50% more items, compatible with more problems within the sleep dimension. However, none of the temporal changes was significant.

The temporal changes in body composition were not identified as independent predictors for the overall HRQL measures 12 months after injury (P > 0.5).

The acceptable reliability estimates for the HRQL scales used were reproduced in our cohort. Internal consistency reliability coefficients (Cronbach’s {alpha}) in insufficient patients were 0.96 (QoL-AGHDA) and above 0.81 (NHP dimensions), and in sufficient patients 0.90 (QoL-AGHDA) and above 0.7 (NHP dimensions, except physical mobility).

The EQ5D VAS score was significantly correlated with the QoL-AGHDA score in both insufficient (Spearman’s {rho} = –0.70) and sufficient ({rho} = –0.54) patients.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
This study demonstrates that patients with posttraumatic hypopituitarism seem to develop the classical phenotypical characteristics of hypopituitarism, including an adverse lipid profile, unfavorable body composition, and worsened perceived overall HRQL with a lowered energy level, worsened sleep, and increased social isolation, relative to TBI patients with a preserved pituitary function.

The observed unfavorable lipid profile was characterized by increased total cholesterol, LDL-cholesterol, and triglycerides relative to TBI patients with normal pituitary function. Higher BMI per se could potentially explain the observed dyslipidemia. However, hypopituitarism remained independently related to higher LDL-cholesterol and borderline related to higher total-cholesterol after adjustment for BMI. Our data also showed that posttraumatic hypopituitarism was related to a higher increase in total cholesterol over the 3–12-month follow-up. Although some inconsistencies exist between studies, our present findings are in overall agreement with previous studies on GHD patients not receiving GH replacement therapy. However, interaction with untreated hypogonadism or hypothyroidism cannot be excluded because only one of the six patients with multiple insufficiencies in our study received appropriate replacement therapy.

The altered body composition included increased BMI, waist circumference, total and abdominal FM. A general tendency toward a further increase in these body composition markers during follow-up was only observed in hypopituitary patients. These findings are in line with alteration in body composition seen in untreated GHD patients (8), probably reflecting a decreased lipolytic activity (8) and an increased 11ß-hydroxysteroid dehydrogenase 1 activity (22). However, as for the changes in lipid profile, the body composition changes might also be related to untreated hypothyroidism and hypogonadism. On the other hand, a relation to supraphysiological glucocorticoid substitution seems unlikely because the only treated patient received a rather moderate dosage of hydrocortisone.

Because BMI is an important confounder for the diagnosis of GHD (23, 24), there was a potential risk of a falsely skewed BMI and FM distribution in patients diagnosed as GH sufficient or insufficient. This could represent a potential problem in patients with isolated GHD in particular. However, hypopituitarism remained an independent predictor of LDL-cholesterol, waist circumference, and total FM, even after adjustment for BMI, indicating a true association, which may nevertheless remain difficult to interpret, particularly in patients tested with the GHRH + arg test.

The negative consequences of TBI in terms of HRQL were clear, causing a substantially decreased overall HRQL, with altered sleep, increased emotional reactions, decreased energy and physical mobility. This was an expected finding and is in overall accordance with previous studies on HRQL in TBI patients (1, 25). For the comparison, the HRQL levels were similar to those observed in patients with, for example, lung cancer (26) and severe chronic obstructive pulmonary disease (27).

In addition to the influence by TBI in itself, we were able to show that the overall HRQL was further worsened in the pituitary insufficient relative to sufficient patients, which was independent of age, TBI severity, and BMI. Focusing on some of the specific areas evaluated by the chosen questionnaires, hypopituitary patients had a lowered energy level, worsened sleep, and increased social isolation, which is in keeping with some of the most frequently reported problems in GHD patients (28, 29, 30, 31, 32). Hypopituitary patients also had a tendency toward a more pronounced deterioration during follow-up in most of the HRQL scores relevant to GHD, which was, however, insignificant, probably caused by the lack of statistical power. From placebo-controlled studies performed in GHD patients, it appears that initiation of GH replacement therapy causes an improvement in overall general health (33, 34), energy level (30, 32, 33), physical mobility, emotional and social functioning (33), reduced depression (30), and improved sleep (32). To our knowledge, no trials on GH replacement have yet been conducted in TBI patients, but future studies will hopefully show us whether introduction of GH replacement therapy in addition to replacement of other pituitary hormone deficiencies could hasten and potentially improve the rehabilitation process and diminish the neuropsychological sequelae in patients with posttraumatic hypopituitarism. Although hypopituitarism may explain some of the neuropsychological sequelae, treatment will certainly need to be performed in collaboration with neuropsychiatrists in most patients.

Decreased HRQL has been shown in GHD patients by both generic and disease-specific questionnaires, whereas the relation to other insufficiencies remains poorly described, although these are probably even more important.

We included the EQ-5D VAS to provide a general overall HRQL measure. It has previously never been used in hypopituitarism. We found a moderately strong relation between the EQ-5D VAS and QoL-AGHDA scores, indicating that the EQ-5D VAS does reflect the problems experienced by our patient population, and was also sensitive enough to differentiate between pituitary sufficient and insufficient patients. Therefore, its use may be justified in hypopituitarism. As for the NHP, it furthermore provides a scale allowing for comparison between diseases. The NHP was included to provide a more detailed general questionnaire describing different aspects of the patients’ health status. It has often been used in hypopituitarism (14, 28, 29, 30) and has shown a reasonably high correlation with the disease-specific QoL-AGHDA. QoL-AGHDA was chosen because it is the only disease-specific questionnaire translated into Danish. Although sensitive, the specificity of the QoL-AGHDA is questionable because TBI patients with an intact pituitary function had median scores comparable to those previously reported in non-TBI GHD patients (14), reflecting the very unspecific symptoms in GHD overlapping other chronic diseases.

Some concerns related to the indirect assessment of the pretrauma status should be addressed. First, pretrauma HRQL was assessed 0–12 d after injury, which could cause recall bias. Our patients were not suspected to differ from a healthy background population, and the pretrauma scores were indeed similar in TBI patients and controls. Second, some of the patients were not able to respond in the acute phase, which necessitated HRQL responses from proxy respondents (i.e. significant others). We have no reason to believe that the use of proxy respondents has caused any significant bias because the overall scores reported by the patients able to respond and the proxy respondents were comparable (35). This finding also supports the validity of the pretrauma scoring as such.

Yet another concern could be the potential invalidity of the late posttraumatic HRQL scores. The cerebral lesions in TBI patients often involve the frontal lobe region, and, therefore, the patients may lack awareness and insight into their own dysfunctions. HRQL items reporting on these dysfunctions may consequently be underestimated (36). We did not collect late posttraumatic HRQL scores from significant others and, therefore, were not able to correct for this potential bias.

Extracranial injuries could affect most of the outcome measures evaluated. Similar scores in the pain and physical mobility dimensions were recorded, indicating that physical disabilities were comparable in insufficient and sufficient patients, minimizing the influence of this potential confounder.

The primary strength of this study is the inclusion of closely matched control groups, including patients with comparable exposure not developing hypopituitarism. Adjusting for age, BMI, and trauma severity, these patients only differed in terms of pituitary status and thereby provided optimal controls. However, whether the unfavorable characteristics reported are a consequence of hypopituitarism or GHD exclusively, or of additional hypothalamic damages is unknown. None of our patients reported hyperphagia, but a hypothalamic syndrome cannot be excluded. Another strength is the inclusion of a cohort with prospective follow-up, which allowed for the evaluation of temporal changes. Comparing pituitary sufficient and insufficient patients, we were not able to identify significant temporal changes in HRQL, which is likely to be explained by the lack of statistical power.

In conclusion, patients with posttraumatic hypopituitarism developed the classical phenotypical characteristics of hypopituitarism, including an adverse lipid profile, unfavorable body composition, and worsened perceived overall HRQL, including a lowered energy level, worsened sleep, and increased social isolation. Intervention studies are awaited to demonstrate whether these unfavorable changes could be alleviated or at least ameliorated.


   Footnotes
 
The study was supported by an unrestricted grant from Novo Nordisk, the A. P. Møller Foundation for the Advancement of Medical Science, and King Christian the 10th Foundation. M.K. was supported by a fellowship from Copenhagen University, Denmark.

The study protocol has been submitted to www.clinicaltrials.gov (ID: KF-01-107/03).

Disclosure Statement: M.K., T.W., and J.B. have nothing to declare. U.F.-R. has received lecture fees from Novo Nordisk and Pfizer and an unrestricted grant from Novo Nordisk for the present study.

First Published Online July 24, 2007

Abbreviations: arg, Arginine; BMI, body mass index; CV, coefficient of variation; EQ-5D, EuroQoL-5D; FM, fat mass; GCS, Glasgow Coma Scale score; GHD, GH deficiency; HDL, high-density lipoprotein; HRQL, health-related quality of life; ITT, insulin tolerance test; LDL, low-density lipoprotein; NHP, Nottingham Health Profile; QoL-AGHDA, Quality of Life Assessment of GHD in Adults; TBI, traumatic brain injury; VAS, visual analog scale.

Received April 24, 2007.

Accepted July 13, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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