Pituitary Function and Functional Outcome in Adults afterSevere Traumatic Brain Injury: The Long-Term Perspective

Trandur Ulfarsson,1,2 Gudni Arnar Gudnason,3 Thord Rosen,3 Christian Blomstrand,1,2

Katharina Stibrant Sunnerhagen,2,4 Asa Lundgren-Nilsson,2,4 and Michael Nilsson1

Abstract

Post-traumatic hypopituitarism (PTHP) has been linked to disability and decreased quality of life. However, no studies

have addressed the long-term consequences of PTHP in adults with severe traumatic brain injury (TBI) only. In this study,

we evaluated the relationship between pituitary function, quality of life, and functioning in 51 patients (16–65 years of

age) with severe TBI who were admitted to Sahlgrenska University Hospital, Gothenburg from 1999 to 2002. The patients

were assessed once, 2–10 years after trauma. Data from the time of injury were collected retrospectively to adjust for

injury severity. Outcome measures included hormonal testing, the Short Form-36 Health Survey, the Glasgow Outcome

Scale–Extended, and a self-report questionnaire specifically designed for this study and based on the International

Classification of Functioning, Disability and Health. Of 51 patients, 14 (27.5%) presented with PTHP, and 11 (21.6%) had

isolated growth hormone deficiency. Patients with PTHP were more often overweight at follow-up ( p = 0.01); the higher

body mass index was partially explained by PTHP (R2 change = 0.07, p = 0.001). Otherwise no significant correlation was

found among PTHP, functioning, or patient-reported quality of life. This study—which is unique in the homogeneity of

the patients, the long follow-up time, and the use of injury severity as an outcome predictor—did not confirm results from

previous studies linking PTHP to a worse outcome. Therefore, screening for PTHP might be restricted to specific

subgroups such as overweight patients, indicating growth hormone deficiency.

Key words: functioning; hypopituitarism; long-term outcome; quality of life; TBI

Introduction

Traumatic brain injury (TBI) is associated with a high

morbidity, causing a broad spectrum of limitations in physical

and psychosocial functioning and participation in life activities.1–6

The initial severity of the TBI explains only a proportion of the

variation in late outcome, a relationship that may weaken over

time.3,4,6 Intensive neurorehabilitation can reduce or alleviate

symptoms.7 However, physiological and psychosocial dysfunc-

tions may lead to problems even years after injury.3,4,6 The rela-

tionships among physical, cognitive, emotional, and social

outcome measures are relevant, because factors might be identified

that are amenable to intervention to alleviate late disability.

Several studies from the last decade have shown that TBI puts

patients at substantial risk of subsequent post-traumatic hypopitu-

itarism (PTHP).8–15 Researchers have begun to investigate the ef-

fect of PTHP on outcome after TBI, with a particular focus on

neuropsychological sequelae.16 However, such studies have mea-

sured outcome in a heterogeneous group of patients with a wide

range of TBI severity.17–29 Few studies have considered the relative

contribution of injury severity to outcome.16

A worse functional outcome (e.g., greater functional depen-

dency and activity limitation) and worse cognitive functions (e.g.,

greater deficits in attention, executive functioning, memory, and

emotion) has been reported in TBI patients with PTHP, particularly

those with growth hormone deficiency (GHD), than in those

without PTHP.20,21,28 A few studies have also reported a worse

health-related quality of life (HRQL) in patients with PTHP, par-

ticularly those with GHD (e.g., poorer sleep and energy levels and

an increased sense of social isolation).18,23,25,29

All of the studies described evaluated patients up to 2 years after

the injury. However, in one study of TBI patients with long-lasting

cognitive disorders followed for a mean of 6.5 years after the initial

injury, late functional outcomes, activity performance, and cogni-

tive function after TBI were worse in patients with PTHP, espe-

cially those with GHD. However, the impact of PTHP on functional

outcome, cognitive disorders, and HRQL is controversial.22 Few

studies have shown results that have questioned the current opinion

1Center for Brain Repair and Rehabilitation (CBR), 4Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience andPhysiology, University of Gothenburg, Gothenburg, Sweden.

2Rehabilitation Medicine and 3Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.

JOURNAL OF NEUROTRAUMA 30:271–280 (February 15, 2013)ª Mary Ann Liebert, Inc.DOI: 10.1089/neu.2012.2494

271

on hypopituitarism after TBI. They reported no evidence for an

association between impaired cognitive function and GHD in adult

TBI patients, between neuropsychological impairments, HRQL

and PTHP, or between TBI, fatigue, and GHD.19,17,27

Given the discrepancies in the limited data on PTHP and out-

come, the clinical importance of PTHP needs to be examined fur-

ther in a well-defined group of patients with severe brain injury and

a long follow-up time. In this study, we retrospectively evaluated

the relationship between pituitary function and outcome in a series

of patients 2–10 years after severe TBI. The patients underwent

hormonal testing and clinical examination and completed self-

report questionnaires measuring functioning and HRQL.

Methods

Patient enrollment and retrospective evaluation

The catchment region of the Sahlgrenska University Hospitalincludes * 1,500,000 inhabitants in the Vastra Gotaland region inwestern Sweden, including roughly 500,000 in the city of Go-thenburg. Between January 1, 1999, and December 31, 2002, 419patients with TBI (International Statistical Classification of Dis-eases and Related Health Problems, 10th revision [ICD 10] diag-nostic codes S06.1–S06.9) were admitted to the neonatal intensivecare unit at Sahlgrenska University Hospital, Gothenburg, Sweden.We retrospectively reviewed the medical files of these patients tocollect data on the level of consciousness upon arrival at the hos-pital. Consciousness was evaluated with the Reaction Level Scale(RLS), a hierarchically ordered scale with eight categories (‘‘re-action levels’’), where higher scores denote worse responsiveness,and a score ‡ 4 denotes a nonresponsive patient.30 RLS scores wererecoded into Glasgow Coma Scale (GCS) scores, where RLS ‡ 4 isequivalent GCS £ 8.31,32

The inclusion criteria were: 1) age 16–65 years; 2) GCS score£ 8, indicating a severe TBI; (3) survival to discharge from theNICU; and (4) residence in the Vastra Gotaland region at the timeof follow-up. The exclusion criteria were a known pituitary insuf-ficiency or recent or ongoing glucocorticoid, growth hormone, orthyroxine replacement therapy at the time of follow-up.

Of the 419 patients, 288 were excluded because they did notmeet the criteria for age or severity of TBI, died in the NICU, orlived outside the Vastra Gotaland region at follow-up. Therefore,131 patients were eligible to participate in the study. Each patientwas sent a letter inviting him or her to participate in the study.Those who did not respond within 1 month received another letter,a phone call, or both. Seventeen patients declined, 37 did not re-spond to the invitation, 24 had died after discharge from the NICU,and 2 could not be located. Therefore, 51 patients were included inthe study (Fig. 1). These patients did not differ in age or genderfrom the 80 patients lost to follow-up.

Data collection

All patients were assessed once, between September 2004 andJune 2010, 2–10 years after sustaining their TBI. Data from the timeof injury were collected retrospectively from medical files. Patientswere assessed in the endocrinology department by a doctor and anurse who did not have knowledge of their hormonal status, in aquiet setting over a 2–3 h period.

Comorbidity and sociodemographic and injurycharacteristics

Data on comorbidity and sociodemographic characteristics atthe time of injury were recorded from the medical files at the time ofinjury and from the specifically designed questionnaire, the clinicalexamination, and the medical history at the time of follow-up. The

injury characteristics were recorded from the acute care medicalfiles, including age, sex, major extracranial injury, RLS score, andpupillary status after arrival to hospital. The CT findings (recordedfrom patients’ first and second CT scans) were registered as cranialfracture and type, diffuse brain swelling, evacuated/unevacuatedhematoma, visible petechiae, midline shift of > 5 mm, basal cisterncompression, and subarachnoidal hemorrhage.

To provide a valid comparison of the injury characteristics asoutcome predictors versus hormonal status, we combined the pre-dictive value of some of the clinical parameters and CT findingsinto a validated and generalizable prognostic model of TBI calledCorticosteroid Randomization after Significant Head Injury(CRASH).33 For this to be done, RLS scores were recoded intoGCS scores.

Measures of functions, activity,participation, and HRQL

The primary outcome measures were assessment of functioning,disability, and HRQL. Body functions, activities, and participationwere assessed with a patient-report questionnaire specifically de-signed for this study, using the framework of the InternationalClassification of Functioning, Disability and Health. The ques-tionnaire consists of 38 ‘‘yes–no’’ questions about physical andpsychological functions, 12 questions about personal and instru-mental activities of daily living. The questionnaire also gatherssociodemographic information, including household, work, andstudies, and the need of support (personal, economical, or techni-cal) and information on comorbidities, medications, smoking, al-cohol, and drug abuse.

HRQL was assessed with the Short Form-36 Health Survey (SF-36), a widely used health outcome measure, validated for the TBI

Identified = 419

All patients with TBI admitted to NICU, Sahlgrenska

University Hospital between Jan 1st 1999 – Dec 31st 2002

Eligible = 131

Severe TBI(GCS score of < 8)

16 - 65 years of age

Survival to discharge from the NICU

Living in the VästraGötaland region

Not included = 288

Included = 51

Patients tested and interviewed

2 – 10 years after the TBI

Data from the acute settings

gathered retrospectively

Loss to follow up = 80

24 died before follow up

17 declined participation

37 did not respond to invitation

2 could not be located

FIG. 1. Flow chart of derivation of cohort.

272 ULFARSSON ET AL.

population.34 The 36 questions are designed to measure patient-reported health-related functioning and well-being along eightsubscales. The scales range is 0–100 (worst to best). Despite theordinal nature of the SF-36, it has been recommended that thesubscales of the SF-36 be aggregated into summary scores thatrepresent the two main dimensions of health: the physical com-ponent summary and the mental component summary, calculated asweighted sums of the subscales scores.34

Another outcome measure was the eight-point Glasgow Out-come Scale–Extended (GOS-E), in which the specifically designedquestionnaire was interpreted in light of the results of the physicalexamination and medical history, according to the study protocolobtained by a physician specialized in endocrinology or rehabili-tation medicine.35 The physician completed the questionnaires byinterviewing the patient, or if that was not possible, a relative orpersonal assistant of the patient.

Anterior and posterior pituitary hormonal testing

All patients arrived in the morning after fasting since midnight.Fasting blood samples were obtained between 8 and 9 a.m. for testsof anterior pituitary function, including free thyroxine (f-T4),thyroid stimulating hormone (TSH), cortisol, adrenocorticotrophichormone (ACTH), testosterone (males), estrogen (females), sexualhormone binding globulin (SHBG), luteinizing hormone (LH),follicle-stimulating hormone (FSH), prolactin, insulin-like growthfactor-1 (IGF-1) and GH in connection to an arginine-growthhormone-releasing hormone (arginine-GHRH) stimulation test.Urine osmolality and history of increased thirst and/or increasedurine volumes were obtained for all patients, and a history ofmenstrual status was obtained for all females.

Arginine-GHRH stimulation test. A bolus dose of GHRH1 lg/kg (maximum 100 lg) was given intravenously, followed byan infusion of arginine 0.5 g/kg (maximum dose 30 g). Samples forserum GH were taken at - 15, 0, + 15, 30, 45, 60, and 90 min. Themaximal GH-response was evaluated according to the patient’sbody mass index (BMI) level and was considered subnormal if theGH maximum level was < 11.5 lg /L (BMI < 25 kg/m2), < 8.5 lg /L(BMI 25–30) and < 4.2 lg /L (BMI > 30).

Co-syntropin stimulation test. If the initial serum cortisollevel was < 350 nmol/L, a follow-up co-syntrophin stimulation testwith ACTH (0.25 mg sc) was performed at a later occasion. Amaximal cortisol response < 500 nmol/L at + 30 min or + 60 minwas then considered subnormal.

BMI was calculated at follow-up. If available, BMI at the time ofinjury was obtained from the medical files.

Biochemical assays. Serum IGF1 concentration, until June2004, was determined using a hydrochloric acid–ethanol extractionradioimmunoassay (RIA) (Nichols Institute Diagnostics, San JuanCapistrano, CA). Inter- and intra-assay coefficients of variation(CVs) were 5.4 and 6.9% respectively, at a mean serum IGF1 levelof 126 lg/L, and 4.6 and 4.7% respectively, at a mean serum IGF1level of 327 lg/L. From June 2004 to August 2006, serum IGF1concentration was determined using a chemiluminescence immu-noassay (Nichols Advantage; Nichols Institute Diagnostics). FromSeptember 2006, serum IGF1 level was determined using an au-tomated chemiluminescent assay system (IMMULITE 2500, Di-agnostic Products Corp., Los Angeles, CA). The standard used forcalibration of the IGF1 assays was the World Health OrganizationNational Institute for Biological Standards and Control First In-ternational Reference Reagent (WHO NIBSC 1st IRR) 87/518throughout the study period.

Serum GH concentration, until January 2008, was determinedusing Wallac DELFIA human growth hormone (hGH) Perkin Elmer.

Inter- and intra-assay CVs were 14%, 7%, and 5%, respectively, at amean serum GH level of 0.5 mU/L, 10 mU/L, and 30 mU/L, re-spectively. From February 2008, serum GH concentration wasdetermined using Access2, Beckman Colulter. The inter-and intra-assay CVs were 10%, 7%, and 6%, respectively, at a mean serum GHlevel of 0.200 lg/lL, 3.0 lg/L, and 11 lg/L, respectively.

Serum SHBG concentration, until March 2006, was determinedusing IRMA, Orion Diagnostic. The inter- and intra-assay CVswere 7% and 5%, respectively, at a mean serum SHBG level of40 nmol/L, and 60 nmol/L, respectively. From April 2006, serumSHBG concentration was determined using Architect, AbbottScandinavia AB, with the inter-and intra assay CVs being 7%, 7%,and 9%, respectively, at a mean serum SHBG concentration of20 nmol/L, 40 nmol/L, and 100 nmol/L, respectively.

Serum LH concentration, until November 2004, was determinedusing IRMA, LH MAIA clone, Serono. The inter- and intra-assayCVs were 11%, 8%, and 7%, respectively, at a mean serum LHlevel of 2.6 IU/L, 8 IU/L, and 20 IU/L, respectively. FromDecember 2004, the serum LH concentration was determined usingArchitect, Abbott Scandinavia AB, with the inter-and intra assayCVs being 11%, 8%, and 7%, respectively, at a mean serum LHconcentration of 3 IU/L, 20 IU/L, and 60 IU/L, respectively.

Serum FSH concentration, until May 2004, was determinedusing RIA, DPC, Diagnostic Product Corporation. The inter- andintra-assay CVs were 9%, 6%, and 4%, respectively, at a meanserum FSH level of 9 IU/L, 20 IU/L/L, and 90 IU/L, respectively.From June 2004, the serum FSH concentration was determinedusing Architect, Abbott Scandinavia AB, with the inter-and intraassay CVs being 9%, 6%, and 6%, respectively, at a mean serumFSH concentration of 5 IU/L, 25 IU/L, and 75 IU/L, respectively.

From 2004, serum prolactin concentration was determined usingArchitect, Abbott Scandinavia AB. The inter- and intra-assay CVswere 6%, 6%, and 6%, respectively, at a mean serum prolactin levelof 200 mIU/L, 400 mIU/L, and 900 mIU/L, respectively. FromDecember 2009 the serum prolactin concentration was determinedin lg/L, still using Architect, Abbott Scandinavia AB, with theinter-and intra assay CVs being 6%, 6% and 6%, respectively, at amean serum prolactin concentration of 10 ug/L, 20 ug/L, and 45 ug/L,respectively.

Serum cortisol concentration from 2004 to August 2008 wasdetermined using Advia Centaur, Abbott Scandinavia AB. Theinter- and intra-assay CVs were 11%, 15%, and 13%, respectively,at a mean serum cortisol level of 100 nmol/L, 500 nmol/L, and800 nmol/L, respectively. From September 2008, the serum cortisolconcentration was determined using Molecular and Cobas 6000/8000, Roche Diagnostic Scandinavia, with the inter-and intra assayCVs being 11%, 15%, and 13%, respectively, at a mean serumcortisol concentration of 100 nmol/L, 500nmol/L, and 800 nmol/L,respectively.

From 2004, urine cortisol concentration was determined usingRIA, Orion Diagnostica. The inter- and intra-assay CVs were 14%,9%, and 11%, respectively, at a mean urine cortisol level of50 nmol/L, 100 nmol/L, and 400 nmol/L, respectively.

Plasma ACTH concentration was determined using ELSA-ACTH, a solid phase two site immunoradiometric assay (CisbioBioassays). The inter-assay CVs were 9.5% and 6.8%, respectively,at a mean plasma ACTH level of 2.4 pmol/L and 112 pmol/L, re-spectively, and the intra-assay CVs were 5.8 % and 3.7% at2.8 pmol/L and 95 pmol/l, respectively.

Serum free T4 concentration from 2004 to May 2005, was de-termined using Architect, Abbott Scandinavia AB. The inter- andintra-assay CVs were 10%, 10%, and 9%, respectively, at a meanserum free T4 level of 6 pmol/L, 12 pmol/L, and 28 pmol/L, re-spectively. From June 2005, the serum free T4 concentration wasdetermined using Molecular and Cobas 6000/8000, Roche Diag-nostic Scandinavia, with the inter-and intra assay CVs being 10%,10%, and 9%, respectively, at a mean serum free T4 concentrationof 6 pmol/L ug/L , 12 pmol/L, and 28 pmol/L, respectively.

POSTTRAUMATIC HYPOPITUITARISM: LONG-TERM OUTCOME 273

Serum TSH concentration from 2004 to May 2005, was deter-mined using Architect, Abbott Scandinavia AB. The inter- andintra-assay CVs were 7%, 6%, and 5%, respectively, at a meanserum TSH level of 0,4 mIU/L, 6 mIU/L, and 28 mIU/L, respec-tively. From June 2005, the serum TSH concentration was deter-mined using Molecular and Cobas 6000/8000, Roche DiagnosticScandinavia, with the inter-and intra assay CVs being 7%, 6%, and5%, respectively, at a mean serum TSH concentration of 0.4 mIU/L,6 mIU/L, and 28 mIU/L, respectively.

Serum testosterone concentration from 2004 to August 2008,was determined using Advia Centaur, Scandinavia AB. The inter-and intra-assay CVs were 10%, 10%, and 10%, respectively, at amean serum testosterone level of 3 nmol/L, 15 nmol/L, and25 nmol/L, respectively. From September 2008, the serum testos-terone concentration was determined using Access 2, BeckmanCoulter, with the inter-and intra assay CVs being 10%, 10%, and10%, respectively, at a mean serum testosterone concentration of5 nmol/L, 20 nmol/L, and 40 nmol/L, respectively.

Serum estrogen concentration from 2004 to 2008, was deter-mined using RIA, DiaSorin. The inter- and intra-assay CVs were16% and 10%, respectively, at a mean serum estrogen level of0.04 nmol/L and 0.4nmol/L, respectively. From 2009, the serumestrogen concentration was determined using Architect, AbbottScandinavia AB, with the inter-and intra assay CVs being 16% and10%, respectively, at a mean serum estrogen concentration of121 pmol/L and 2047 pmol/L, respectively.

Statistical analysis

Patients were categorized as being deficient or not in one or morehormonal axes, and functioning, disability, and health in the twogroups were compared. All statistical analysis was performed withPASW (Chicago, IL), version 18.0. Factor analysis was used toanalyze data from the specifically designed questionnaire on func-tional impairment and activity limitation. Principal componentsanalysis with Varimax rotation based on the correlation matrix wasused to make informed decisions on reducing the number of vari-ables, while retaining as many variables as needed to describe per-formance and dependency. Principal component analysis gives thenumber of variables (components) needed to capture most of thevariance in the original data set. The determination of the specificvariables to be extracted is both a statistical and a qualitative decisionof the researcher. The correlation matrix was used to determinewhich variables clustered together in a meaningful way, and maymeasure aspects of the same underlying dimension (factor). Com-ponents were extracted according to Kaiser’s criterion; therefore, thevariables with loading values > 0.6 were extracted from the rotatedcomponent matrix. Fisher’s exact test and independent samples t testwere used to compare groups with and without hormonal deficit. Todetermine whether hormonal status independently predicted out-come, multivariate analyses were performed; multiple linear re-gression was used to control for the outcome predictors of injuryseverity (e.g., clinical status, age, and CT characteristics) and forgender, BMI, epilepsy, alcoholism, and drug abuse

Ethics

The study was approved by the regional ethical review board ofthe University of Gothenburg. The aim of the study was carefullyexplained to the patients at the time of their inclusion, and again atthe time of the patient assessment. Informed consent was obtainedfrom each patient or the next of kin.

Results

Hormone deficiency

There were 51 patients in the study (13 females and 38 males). A

pituitary insufficiency was diagnosed in 14 (1 woman, 27.5%). All

hypopituitary patients had isolated deficiencies; 11 (21.6%) had

GH deficiency, 2 (both men, 3.9%) had gonadotrophic deficiency,

and 1 (a man, 2%) had a thyrotrophic deficiency.

Three patients (one with GH-deficiency and two with a normal

pituitary function) had subnormal IGF-1 levels. Two patients had a

mildly elevated serum prolactin concentration (491 and 541 mIU/L)

with otherwise normal hormone levels. Three patients with low

serum cortisol levels underwent a co-syntropin stimulation test with

a concomitant normal rise of serum cortisol in all cases.

Comorbidity and sociodemographic and injurycharacteristics

A pituitary insufficiency was found in one third of the men, but

in only 1 of 13 women (Table 1). Patients with GHD at follow-up

were older at the time of injury (Table 1). This correlation persisted

after we controlled for possible effect of gender, BMI, and injury

severity (R2 change = 0.12, p = 0.015). Patients with GHD were

more often overweight and had a higher BMI at the time of injury

than those without GHD (Table 1). The most common causes of

TBI were traffic accidents (53%), falls (29%), and assault (12%).

No differences were found in the causes of TBI between the groups.

Patients with hormonal deficiencies at follow-up had a more severe

TBI according to the CRASH prognostic model at the time of

injury; however, this difference was not significant (Table 1).

Functioning and quality of life

There were no statistical differences in patient-reported quality

of life measured by the SF-36 in patients with and those without

pituitary deficiency (Table 2). Interestingly, when multivariate

analyses were performed with multiple linear regression control-

ling for other outcome predictors, PTHP and GHD partly explained

a better global outcome measured by GOS-E even though the

fraction of variance explained was small (Table 3).

Patients with or without hypopituitarism showed no statistically

significant differences in perceived problems with cognitive,

emotional, or physical functions, dependence in activities, and

participation in work (Tables 4 and 5). PTHP and BMI were sig-

nificantly associated at follow-up but not at the time of injury

(Table 5). Patients with PTHP and within that group, patients with

GHD, were more often overweight at the time of follow-up. The

groups did not differ in weight gain after trauma. When multivar-

iate analyses were performed, PTHP partly explained a higher

BMI, although the fraction of variance explained is small (Table 3).

TBI patients with PTHP, and especially those with GHD, more

often had cardiovascular disease or diabetes mellitus (Table 5). No

association was found between PTHP and smoking, alcoholism,

drug abuse, epilepsy, or use of antiepileptic drugs (Table 5).

Discussion

In contrast to most previous studies of PTHP and outcome, our

findings in this study do not support the hypothesis that PTHP

causes disability and decreased quality of life in patients with se-

vere TBI.18,20–26,28,29 Our TBI patients with hypopituitarism did

not report worse psychological, cognitive, or motor functions, all of

which are important predictors of activity level and participation. In

our study approximately 25% of the patients had PTHP, most

commonly deficiencies of GH and gonadotrophins, which is in

accordance with the prevalence published in previous studies.14,16

All of our patients had a severe TBI and received similar acute

care in a modern NICU at a university hospital, where all severe

274 ULFARSSON ET AL.

TBI patients are admitted within the Vastra Gotaland region. For

this relatively homogenous group of patients, we were able to

provide a valid comparison of injury characteristics as outcome

predictors versus hormonal status by combining the predictive

value of some of the clinical parameters and CT findings into the

validated and generalizable CRASH prognostic model of TBI.

Predictors of patient injury severity, including age, were con-

trolled for, as were gender, substance abuse, epilepsy, and BMI,

allowing an estimation of hormonal status as an independent

outcome predictor.

Table 1. Demographic Data, BMI, and Injury Characteristics of the Patients at the Time of the Traumatic Brain Injury

All patients(n = 51)

PTHP(n = 14)

No PTHP(n = 37)

95% CI /p valuea

GHD(n = 11)

No GHD(n = 40)

95% CI /p valuea

Age (yr) 37.9 (16–64) 48.3 (29–63) 34.1 (16–64) 4.9–23.6 52.3 (34–63) 34.0 (16–64) 8.5 – 28.0b

Gender 13 F/38 M 1 F/13 M 12 F/25 M p = 0.08 1 F/10 M 12 F/28 M p = 0.25BMI (n = 40) 24.0 (18–29) 25.3 (21–28) 23.5 (18–29) - 4.1–0.46 25.8 (23–28) 23.5 (18–29) 0.7–4.0b

BMI > 25 16/40 (40%) 7/10 (70%) 9/30 (30%) p = 0.06 7/9 (78%) 9/31 (29%) p = 0.02b

RLS (1–8) 5.2 (4–8) 5.4 (4–8) 5.1 (4–8) - 1.1–0.54 5.4 (4–8) 5.2 (4–8) - 1.1–0.72Pathological pupil (n = 50) 14 (28%) 4 (29%) 10/36 (28%) p = 1.00 2 (18%) 12/39 (31%) p = 0.71Extracranial injury 24 (47%) 7 (50%) 17 (46%) p = 1.00 5 (46%) 19 (48%) p = 1.00

CT findingsSkull fracture 27 (53%) 9 (64%) 18 (49%) p = 0.36 8 (73%) 19 (48%) p = 0.18General edema 31 (61%) 9 (64%) 22 (60%) p = 1.00 6 (55%) 25 (63%) p = 0.73Petechiae 41 (80%) 10 (71%) 31 (84%) p = 0.43 8 (73%) 33 (83%) p = 0.67Obliterated cisterns 22 (43%) 7 (50%) 15 (41%) p = 0.75 5 (46%) 17 (43%) p = 1.00Midline shift (n = 50) 15 (30%) 6 (43%) 9/36 (25%) p = 0.31 5 (46%) 10/39 (26%) p = 0.27SAH 18 (35%) 6 (43%) 12 (32%) p = 0.53 6 (55%) 12 (30%) p = 0.67Unevacuated hematoma 32 (63%) 9 (64%) 23 (62%) p = 1.00 7 (64%) 25 (63%) p = 1.00Evacuated hematoma 17 (33%) 7 (50%) 10 (27%) p = 0.18 5 (46%) 12 (30%) p = 0.47

Unfavorable outcome riskc 63.1% 71.5% 60.0% - 26.3 - 3.2 74.0% 60.0% - 29.5–2.3Unfavorable outcome

risk > 75%c23 (45%) 9 (64%) 14 (38%) p = 0.12 7 (64%) 16 (40%) p = 0.19

The patients are categorized as pituitary deficient or not and GH deficient or not, at follow up, 2 – 10 years after the injury. Data are given as mean(range) or absolute number (%).

a95% confidence interval of the difference between the groups/p-value.bA significant difference between the groups.cRetrospectively analyzed, according to the CRASH prognostic model. Unfavorable outcome, Glasgow Outcome Scale–Extended score 1–4.PTHP, post-traumatic hypopituitarism; GHD, growth hormone deficiency; M, male; F, female; BMI, body mass index; RLS, Reaction Level Scale;

SAH, subarachnoidal hemorrhage; CRASH, Corticosteroid Randomization after Significant Head Injury.

Table 2. Outcome Measured by GOS-E and SF- 36 at the Time of Follow-up, 2–10 Years after TBI

All (n = 51)PTHP

(n = 14)No PTHP(n = 37)

95% CI/p valuea

GHD(n = 11)

No GHD(n = 40)

95% CI/p valuea

Months to follow- up 68.0 (30–131) 74.0 (41–124) 66.0 (30–131) - 24.6–8.4 74.2 (41–124) 66.6 (30–131) - 25.6–10.4Age at follow-up (yr) 43.7 (19–75) 54.7 (36–73) 49.6 (19–75) 5.2–24.9b 58.6 (42–73) 39.6 (19–75) 8.7–29.0b

GOS-E (1–8)c 5.3 (3–7) 5.3 (3–7) 5.3 (3–7) - 0.92–0.94 5.4 (3–7) 5.3 (3–7) - 1.1–0.9Unfavorable

outcome ( £ 4)13 (26%) 4 (29%) 9 (24%) p = 0.73 3 (27%) 10 (25%) p = 1.00

SF-36 (0–100)d (n = 51– 49)Physical health score 45.4 (17–61) 47.0 (30–61) 45.0 (17–60) - 8.7–5.3 48.6 (34–61) 44.5 (17–60) - 11.6–3.4Mental health score 42.7 (8–63) 44.8 (15–61) 42.0 (8–63) - 11.7–6.2 43.8 (15–61) 42.5 (8–63) - 11.0–8.3Physical functioning 74.8 (0–100) 75.9 (0–100) 74.3 (0–100) - 20.2–17.0 80.1 (28–100) 73.1 (0–100) - 27.7–12.5Role - physical 58 (0–100) 73.2 (0–100) 52.1 (0–100) - 49.3–7.0 72.8 (0–100) 53.8 (0–100) - 49.6–11.9Bodily pain 75.3 (12–100) 78.0 (31–100) 74.2 (12–100) - 21.8–14.1 81.7 (32–100) 73.4 (12–100) - 27.6–11.1General health 66.7 (15–100) 65.8 (25–100) 67.0 (15–100) - 13.5–15.9 68.4 (42–100) 66.2 (15–100) - 18.1–13.7Vitality 52.7 (0–100) 55.0 (20–100) 51.6 (0–95) - 18.7–11.9 58.2 (25–100) 51.0 (0–95) - 23.7–9.3Social functioning 71.5 (0–100) 76.8 (25–100) 79.4 (0–100) - 27.5–12.8 73.9 (25–100) 70.1 (0–100) - 25.0–18.9Role-emotional 68.7 (0–100) 80.1 (0–100) 63.9 (0–100) - 44.0–9.9 78.8 (0–100) 65.9 (0–100) - 42.4–16.5Mental health 71.5 (12–100) 68.9 (28–96) 71.1 (12–100) - 12.1–16.7 69.5 (28–100) 70.8 (12–100) - 14.2–17.0

Patients are categorized on as pituitary deficient or not, and GH deficient or not, at follow up. Data on follow-up time and age are given as median(range). Data measured by GOS-E and SF-36 are given as mean (range) or absolute number (%).

a95% confidence interval of the difference between the groups/p-value.bSignificant difference between the groups.c1 = dead, 2 = vegetative state, 3 = lower severe disability, 4 = upper severe disability, 5 = lower moderate disability, 6 = upper moderate disability,

7 = lower good recovery, 8 = upper good recovery.dHigher scores indicate a better health-related quality of life.PTHP, post-traumatic hypopituitarism; GHD, growth hormone deficiency; GOS-E, Glasgow Outcome Scale -Extended; SF-36; Short Form Health Survey-36.

POSTTRAUMATIC HYPOPITUITARISM: LONG-TERM OUTCOME 275

The results showed no significant correlation between hypopi-

tuitarism and patient-reported quality of life and functioning in the

severe TBI patients.

Changes in outcome can continue for many years after TBI, and

many factors, possibly including pituitary function, may influence

the global outcome in patients with TBI.3,4,6,36 The time from in-

jury to follow-up in this study is much longer than in most studies

linking PTHP to disability and decreased quality of life (2–10 years

versus 6 months to 2 years) and might partially explain the dif-

ference in outcome. However, in a recent study of TBI patients with

persistent cognitive and/or behavioral disorders who underwent

cognitive testing and were followed as long as our patients, cog-

nitive function and activity performance were worse in patients

with PTHP.22

There are discrepancies in the limited data on PTHP and out-

come. Several studies have described worse outcomes in patients

with hypopituitarism, but these findings were not confirmed in

others.17,19,27 Although associations are interesting, they do not

Table 3. Parameter Measurements of Pituitary Function and Somatotroph Axis Function and Their pValues

Explanatory variables at follow-up

Post-traumatic hypopituitarism Growth hormone deficiency

Unstandardizedcoefficients

Unstandardizedcoefficients

Outcome at follow-up B Standard error p-value

Fraction ofvariance explained

(R2 change) B Standard error p-value

Fraction ofvariance explained

(R2 change)

BMI 2.67 0.62 < 0.01a 0.066 1.03 0.91 0.27 0.008Physical functions 0.37 0.62 0.55 0.005 0.045 0.68 0.95 < 0.001Psychological functions - 0.17 0.60 0.77 0.002 0.237 0.65 0.72 0.003ADL - 1.68 1.32 0.21 0.031 - 1.88 1.44 0.20 0.033SF-36 Physical health score 5.09 4.08 0.22 0.032 7.24 4.39 0.11 0.054SF-36 Mental health score 2.76 5.39 0.61 0.006 0.28 5.91 0.96 < 0.001GOS-E 0.95 0.45 0.04 0.062 1.11 0.49 0.03 0.070

The results show how pituitary and somatotroph axis function explains the outcome measures when adjusted for gender, injury severity, age, epilepsy,,alcoholism and drug abuse. For BMI at follow-up we additionally adjusted for BMI at the time of injury.

aPituitary function partly explains a high BMI.BMI, body mass index; ADL, activities of daily living; SF-36, Short Form Health Survey-36; GOS-E, Glasgow Outcome Scale –Extended.

Table 4. Functioning, Disability, and Environmental Factors at the Time of Follow-up

MeasuresaAll

(n = 51)PTHP

(n = 14)No PTHP(n = 37)

95% CI /p valueb,c

GHD(n = 11)

No GHD(n = 40)

95% CI /p valueb,c

Functional impairmentGeneral 0–12 (n = 49) 4.3 (0–11) 4.9 (0–11) 4.0 (0–11) - 2.7–0.9 4.5 (0–11) 4.2 (0–11) - 2.2–1.8Physical 0–7 2.1 (0–7) 2.4 (0–7) 2.0 (0–6) - 1.7–0.9 1.8 (0–6) 2.1 (0–7) - 1.1–1.7

Psychological 0–5 2.3 (0–5) 2.6 (0–5) 2.2 (0–5) - 1.4–0.7 2.6 (0–5) 2.2 (0–5) - 1.6–0.7

Activity/particip limitatADL 0–12 (n = 48) 3.0 (0–12) 2.9 (0–10) 3.0 (0–12) - 2.2–2.5 2.5 (0–10) 3.1 (0–12) - 2.0–3.1P-ADL 0–7 (n = 50) 1.7 (0–7) 1.6 (0–6) 1.8 (0–7) - 1.3–1.7 1.5 (0–5) 1.8 (0–7) - 1.3–1.9I-ADL 0–5 (n = 49) 1.4 (0–5) 1.3 (0–5) 1.5 (0–5) - 0.9–1.3 1.1 (0–5) 1.5 (0–5) - 0.8–1.7Probl with ADL% 33 (69%) 12 (86%) 21/34 (62%) p = 0.17 10 (91%) 23/37 (62%) p = 0.14Not working% 30 (59%) 8 (57%) 22 (60%) p = 1.00 6 (55%) 24 (60%) p = 0.74Not working full time% 41 (80%) 12 (86%) 29 (78%) p = 0.71 9 (82%) 32 (80%) p = 1.00

Environmental factorsSingle (n = 50) 21 (42%) 6 (43%) 15/36 (42%) p = 1.00 3 (27%) 18/39 (46%) p = 0.31SupportPers/tech support% 22 (43%) 7 (50%) 15 (41%) p = 0.75 6 (55%) 16 (40%) p = 0.50

Major 18 (35%) 5 (36%) 13 (35%) p = 1.00 4 (34%) 14 (35%) p = 1.00Minor 7 (14%) 2 (14%) 5 (13%) p = 1.00 2 (18%) 5 (12%) p = 1.00

Economic supp syst% 39 (77%) 11 (79%) 28 (76%) p = 1.00 9 (82%) 31 (75%) p = 1.00

Data are given as mean (range) or absolute number (%). Patients are categorized as pituitary deficient or not, and GH deficient or not, at follow-up.aQuestionnaire specifically designed for the study, using the framework of International Classification of Functioning, Disability, and Health; clinical

examination. Higher scores denote more impairment or limitation.b95% confidence interval of the difference between the groups/p-value.cNot a significant difference between the groups.PTHP, post-traumatic hypopituitarism; GHD, growth hormone deficiency; P-ADL, personal activities of daily living; I-ADL, instrumental activities of

daily living.

276 ULFARSSON ET AL.

prove causality, and there may well be common risk factors for both

PTHP and impaired well-being.

Few studies used a similar approach to ours, examining the

relative contribution of the injury severity and PTHP to outcome.

One of them, relating neuropsychological complaints to pituitary

function and to CT scan findings at the time of injury, showed no

significant difference in neuropsychological complaints and HRQL

between the groups, measured with patient-reported question-

naires.17 The other studies described worse global and functional

outcome and HRQL in patients with PTHP than in those with

normal pituitary function.22,26,29

GHD is associated with a reduced HRQL37–39 However, it is

unclear whether pituitary dysfunction influences HRQL in TBI

patients. A few studies have reported a worse HRQL in patients

with PTHP, with poorer sleep and energy levels and an increased

sense of social isolation.18,23 Both prospective studies and cross-

sectional studies have described poorer HRQL in TBI patients with

GHD.18,23,25,29 All of these studies evaluated patients up to 1 year

after the injury.

Studies have now related PTHP to cognition and functional

outcome in TBI patients tested within 1 year or up to 2 years after

injury.20,21,28

TBI patients with GHD have been reported to experience greater

deficits in attention, executive functioning, memory, and emotion

than GH-sufficient TBI patients.21,22,28

Hypopituitarism is associated with an unfavorable body com-

position and lipid profile, features that tend to improve when rel-

evant insufficiencies are treated.40–43

Table 5. Disease, Symptoms and Signs at the Time of Follow-up

MeasuresaAll

(n = 51)PTHP

(n = 14)No PTHP(n = 37)

95%CI /p valueb

GHD(n = 11)

No GHD(n = 40)

95% CI /p valueb

Disease, sympt, signsFatigue 42 (82%) 12 (86%) 30 (81%) p = 1.00 10 (91%) 32 (80%) p = 0.67Irritability 23 (45%) 3 (21%) 20 (54%) p = 0.06 2 (18%) 21 (53%) p = 0.08Sleep disturbances 19 (37%) 6 (43%) 13 (35%) p = 0.75 4 (37%) 15 (38%) p = 1.00Concentration problems 37 (73%) 10 (71%) 27 (73%) p = 1.00 8 (73%) 29 (73%) p = 1.00Memory problem 36 (70%) 11 (79%) 25 (68%) p = 0.51 9 (82%) 27 (68%) p = 0.48Speech problem 23 (45%) 6 (43%) 17 (46%) p = 1.00 4 (36%) 19 (48%) p = 0.73Depression 25 (49%) 7 (50%) 18 (49%) p = 1.00 6 (54%) 19 (48%) p = 0.74Anxiety 17 (33%) 6 (43%) 11 (30%) p = 0.51 5 (46%) 12 (30%) p = 0.48Arm motor impairment 19 (37%) 5 (36%) 14 (38%) p = 1.00 3 (27%) 16 (40%) p = 0.51Leg motor impairment 18 (35%) 5 (36%) 13 (35%) p = 1.00 3 (27%) 15 (38%) p = 0.73Problem swallowing 6 (11%) 3 (21%) 3 (8%) p = 0.33 2 (18%) 4 (10%) p = 0.60Problem talking (n = 50) 17 (33%) 7 (50%) 10 (28%) p = 0.19 5 (46%) 12 (31%) p = 0.48Impaired touch sense 17 (33%) 5 (36%) 12 (32%) p = 1.00 3 (27%) 14 (35%) p = 0.73Dizziness 15 (29%) 6 (43%) 9 (24%) p = 0.30 5 (46%) 10 (25%) p = 0.26Visual impairment 17 (33%) 6 (43%) 11 (30%) p = 0.58 6 (55%) 11 (28%) p = 0.15Hearing impairment 18 (35%) 4 (29%) 14 (38%) p = 0.74 3 (27%) 15 (38%) p = 0.73Impaired smell sense 14 (28%) 4 (29%) 10 (27%) p = 1.00 4 (37%) 10 (25%) p = 0.47Headache (n = 50) 5 (10%) 2 (14%) 3 (8%) p = 0.61 0 (0%) 5 (13%) p = 0.58Other chronic pain 18 (35%) 5 (36%) 13 (35%) p = 1.00 3 (27%) 15 (38%) p = 0.73Diabetes/cardiovascular

disease11 (22%) 6 (43%) 5 (14%) p = 0.05c 6 (55%) 5 (13%) p = 0.01c

Epilepsy 10 (20%) 4 (29%) 6 (16%) p = 0.43 1 (9.1%) 9 (23%) p = 0.43Alcoholism 11 (22%) 5 (36%) 6 (16%) p = 0.15 3 (27%) 8 (20%) p = 0.69Substance abused 14 (28%) 6 (43%) 8 (22%) p = 0.17 3 (27%) 11 (28%) p = 1.00Smoking 16 (31%) 4 (29%) 12(32%) p = 1.00 3 (27%) 13 (33%) p = 1.00Symptoms of hormonedeficiencye

33 (65%) 11 (79%) 22 (60%) p = 0.33 9 (82%) 24 (60%) p = 0.29

Gain weight(self reported)

21 (41%) 7 (50%) 14 (38%) p = 0.53 5 (46%) 16 (40%) p = 0.74

Gain weight (kg; n = 39) 2.9 ( - 13–21) 2.6 ( - 8–14) 3.1 ( - 13–20) - 4.7–5.7 2.6 ( - 8–14) 3.1( - 13–20) - 4.7–5.7Reduced libido (n = 50) 18 (35%) 7 (50%) 11 (31%) p = 0.33 6 (55%) 12 (31%) p = 0.17Impotence (men)

(n = 38)14 (37%) 6 (46%) 8 (32%) p = 0.49 5 (46%) 9 (32%) p = 0.45

Irregular menses(women) (n = 12)

1 (8%) 0 (0%) 1 (9%) p = 1.00 0 (0%) 1 (9%) p = 1.00

BMI (n = 50) 25.4 (19–42) 27.8 (23–42) 24.5 (19–31) 0.9–5.6c 26.9 (23–32) 24.9 (19–42) - 4.5–6.1BMI > 25 (n = 50) 22 (43%) 10 (77%) 12 (32%) p = 0.01c 9 (82%) 13/39 (33%) p = 0.01c

Data are given as mean (range) or absolute number (%).The patients are categorized as pituitary deficient or not and GH deficient or not, at follow-up.aQuestionnaire specifically designed for the study, using the framework of ICF; clinical examination.b95% confidence interval of the difference between the groups/p-value.cA significant difference between the groups.dAlcoholism and drug abuse.eGaining weight, reduced libido, impotence, and irregular menstrual cycles.PTHP, post-traumatic hypopituitarism; GHD, growth hormone deficiency; BMI, body mass index; M, male; F, female.

POSTTRAUMATIC HYPOPITUITARISM: LONG-TERM OUTCOME 277

Our study confirms the findings of previous studies that the mean

BMI was greater for the hormonally deficient patients than for those

without hormonal deficiency at the time of follow-up. Studies of

body composition reported that BMI, total abdominal fat mass, and

LDL cholesterol and triglycerides were higher in TBI patients with

PTHP.20,23,29,44

Our findings suggest that pituitary function partially explains a

high BMI in this group of patients even though the fraction of

variance explained is small. Furthermore, the patients with PTHP in

our study were more often overweight at the time of follow-up.

Many factors may act as confounders and contribute to these

findings, including physical activity, appetite and food intake,

medications, and common comorbidities of TBI such as epilepsy,

alcoholism, and drug abuse, partly controlled for in the current

study. In addition, it has been established that spontaneous and

stimulated secretion of GH is lower in obese than in normal weight

individuals, and even though specific BMI-related cutoff limits

were assumed in our study, the patients with a high BMI might have

a higher risk of a false- positive test for PTHP caused by metabolic

changes.45–47

The fact that most of the patients with PTHP were overweight

suggests that BMI in TBI patients should be monitored more clo-

sely, and that greater effort should be made to help them lose

weight. GH replacement therapy could be an important supplement

to other interventions to reduce weight (e.g., lifestyle changes, a

healthier diet, and increased physical training).

The TBI patients with GHD in our study were older than those

with normal GH secretions. This is an interesting finding, which

indicates a possible predisposing factor for the development of

GHD after TBI. Discrepancies in published data on the association

between age and PTHP suggest that this issue needs to be studied

more extensively.23,29 Hypopituitarism increases the risk of pre-

mature death, mainly because of an increased prevalence of car-

diovascular disease.48,49 GHD is the most likely explanation for

this finding.50–52 An important finding in our study was that the TBI

patients with PTHP, and especially those with GHD, more often

had cardiovascular disease and/or diabetes mellitus. These findings

linking PTHP to important health issues that might cause functional

impairments and premature death suggest that even though the

study did not support its effects on functional outcome and quality

of life as measured here, a longer follow-up time would be needed

to measure the effects of these health issues.

Limitations

A limitation of the study was the relatively small sample size.

The patients who were excluded or lost to follow-up might have

differed from the study population in regard to injury severity,

comorbidity, psychosocial status, and, possibly, even hormonal

status. Therefore, our findings cannot be generalized to all patients

with severe TBI. However, multivariate analyses gave no indica-

tion of a worse functional outcome in our PTHP patients. Another

limitation of the study is that only a patient-report instrument was

used to measure functioning; therefore, the results are not as reli-

able as if both patient-reports and functional tests had been used.

Finally, the assessment of global outcome in our study included

functions, activities, participation, and HRQL. As hormonal status

was evaluated 2–10 years after the injury, we have not been able to

predict whether important determinants of global outcome, pre-

mature death, substance abuse, and serious illness that would hin-

der participation in our study, might be more common in patients

with PTHP.

Conclusion

Despite the homogeneous patient population, long follow-up

time, and consideration of injury severity as an outcome predictor,

this study did not confirm results from previous studies linking

PTHP to disability and decreased quality of life. Our study does

suggest that screening for PTHP might be restricted to specific

subgroups such as overweight patients. The finding that patients

with PTHP are often overweight needs to be studied more

extensively.

Acknowledgments

This study was based on data from the Sahlgrenska University

Hospital. The authors acknowledge research support from ALF

Goteborg, AFA Insurance, Sten A Olsson Foundation for Research

and Culture, the Swedish Cancer & Traffic Injury Society Fund,

and the Lansforsakringar Alliance. The authors gratefully ac-

knowledge the participants and their next of kin for their partici-

pation in the study. They also thank Ingrid Morberg at the

Rehabilitation Medicine, Olof Ehn and Olof Strandberg at the

Department of Endocrinology, and Helene Seeman-Lodding at the

NICU, the Sahlgrenska University Hospital, for their support and

practical assistance, as well as Anna Ekmans for statistical advice.

Author Disclosure Statement

Thord Rosen has received honoraria for lecturing for the phar-

maceutical companies Pfizer, Novo Nordisk, and Bayer Schering

Pharma. He has received a grant from Pfizer and the insurance

company Lansforsakringar Alliance. No competing financial in-

terests exist for Trandur Ulfarsson, Gudni Arnar Gudnason,

Christian Blomstrand, Katharina Stibrant Sunnerhagen, Asa

Lundgren-Nilsson, and Michael Nilsson.

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Address correspondence to:

Trandur Ulfarsson, MD

Department of Rehabilitation Medicine

Sahlgrenska University Hospital

Box 30110

SE- 40043 Goteborg

Sweden

E-mail: trandur.ulfarsson@vgregion.se

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