Occurrence of pituitary dysfunction following traumatic brain injury.
ABSTRACT Traumatic brain injury (TBI) may be associated with impairment of pituitary hormone secretion, which may contribute to long-term physical, cognitive, and psychological disability. We studied the occurrence and risk factors of pituitary dysfunction, including growth hormone deficiency (GHD) in 50 patients (mean age 37.6 +/- 2.4 years; 40 males, age 20-60 years; 10 females, age 23-87 years) with TBI over 5 years. Cranial or facial fractures were documented in 12 patients, and neurosurgery was performed in 14. According to the Glasgow Coma Scale (GCS), 16 patients had suffered from mild, 7 moderate, and 27 severe TBI. Glasgow Outcome Scale (GOS) indicated severe disability in 5, moderate disability in 11, and good recovery in 34 cases. Basal pituitary hormone evaluation, performed once at times variable from 12 to 64 months after TBI, showed hypogonadotrophic hypogonadism in 7 (14%), central hypothyroidism in 5 (10%), low prolactin (PRL) levels in 4 (8%), and high PRL levels in 4 (8%) cases. All subjects had normal corticotrophic and posterior pituitary function. Seven patients showed low insulin-like growth factor-I (IGF-I) levels for age and sex. Results of GHRH plus arginine testing indicated partial GHD in 10 (20%) and severe GHD in 4 (8%) cases. Patients with GHD were older (p <0.05) than patients with normal GH secretion. Magnetic resonance imaging demonstrated pituitary abnormalities in 2 patients; altogether pituitary dysfunction was observed in 27 (54%) patients. Six patients (12%) showed a combination of multiple abnormalities. Occurrence of pituitary dysfunction was 37.5%, 57.1%, and 59.3% in the patients with mild, moderate, and severe TBI, respectively. GCS scores were significantly (p <0.02) lower in patients with pituitary dysfunction compared to those with normal pituitary function (8.3 +/- 0.5 vs. 10.2 +/- 0.6). No relationship was detected between pituitary dysfunction and years since TBI, type of injury, and outcome from TBI. In conclusion, subjects with a history of TBI frequently develop pituitary dysfunction, especially GHD. Therefore, evaluation of pituitary hormone secretion, including GH, should be included in the long-term follow-up of all TBI patients so that adequate hormone replacement therapy may be administered.
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ABSTRACT: Traumatic brain injury (TBI) is a common event in childhood. It is a recognised cause of hypopituitarism both in adult and paediatric patients. Routine endocrine evaluation has been proposed for adult TBI-survivors; nevertheless, incongruous data have been reported in children. The goal of this study was to describe the prevalence of pituitary dysfunction after TBI in a cohort of children. This is a cross-sectional study comprising retrospective medical record review and prospective testing. Children with brain injury discharged from the Paediatric Intensive Care Unit from year 2004 to 2009 were recruited. Height and weight were recorded, systemic examination was performed and baseline pituitary function tests were undertaken. Provocative tests were performed only if abnormal basal levels were detected. Thirty-six patients were collected; the mean age at assessment was 7.2 years and the mean interval since injury 3.3 years. All patients had skull fracture or intracranial haemorrhage; 36.6 % of them had moderate to severe TBI. No abnormalities were found on examination. Low serum IGF 1 levels were detected in four patients and two patients had low serum cortisol levels with inappropriately normal plasma ACTH concentrations. No evidence of pituitary dysfunction was observed in these patients after clinical follow-up, repeated baseline hormone levels or dynamic function tests. No endocrine sequelae have been detected in this population. The routine endocrine evaluation in children with mild to moderate TBI might not be justified, according to our findings.Journal of endocrinological investigation 02/2014; 37(2):143-8. · 1.65 Impact Factor
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ABSTRACT: Traumatic Brain Injury (TBI) initiates a cascade of neuromodulatory damage that blurs the distinctions between physical and psychological medicine. Monitoring endocrine function through labs is not part of the medical care algorithm for treatment of TBI, but the clinical symptoms are easily misidentified as they include: depression, fatigue, poor concentration, irritability and a decline in overall cognitive functioning. The reciprocal flow of change between neuroendocrine health and psychosocial health is well established within the field of neuroscience, social psychology, endocrinology and behavioral neurology, but has not translated into patient care. This paper outlines common neuroendocrine disruptions secondary to TBI and their clinical implications for treating mental health professionals. Wider adoption of the consensus guidelines on the detection and monitoring of endocrine abnormalities post-TBI may diminish the severity of functional impairment and improve quality of life.Neurorehabilitation 05/2014; · 1.74 Impact Factor
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ABSTRACT: Hypopituitarism is common after moderate and severe traumatic brain injury (TBI). Herein we address the association between mild TBI and pituitary and metabolic function in retired football players. NFL retirees aged 30-65 years with poor quality of life (QoL) were prospectively enrolled. Pituitary and metabolic syndrome testing was performed. Using a glucagon stimulation test, growth hormone deficiency (GHD) was defined with a standard cut-point of 3ng/ml and with a more stringent BMI-adjusted cut-point. Subjects with and without hormonal deficiency (HD) were compared in terms of QoL, International Index of Erectile Function (IIEF) scores, metabolic parameters and football career data. Of 74 subjects, 6 were excluded due to non-football related TBIs. Of the remaining 68 subjects (mean age 47.3±10.2 years, median NFL years 5, median NFL concussions 3, mean BMI 33.8±6.0), 28 (41.2%) were GHD using a peak GH cutoff of <3ng/ml. However, with a BMI-adjusted definition of GHD, 13 of 68 (19.1%) were GHD. Using this BMI-adjusted definition, overall HD was found in 16(23.5%) subjects: 10(14.7%) with isolated GHD, 3(4.4%) with isolated hypogonadism and 3(4.4%) with both GHD and hypogonadism. Subjects with HD had lower mean scores on the IIEF survey (p=0.016) and trended toward lower scores on SF-36 MCS (p=0.113). Metabolic syndrome was present in 50% of subjects: 5 of 6 (83%) with hypogonadism and 29 of 62 (46.8%) without hypogonadism (p=0.087). Age, BMI, median years in NFL, games played, number of concussions and acknowledged use of performance-enhancing steroids were similar between HD and non-HD groups. In summary, in this cohort of retired NFL players with poor QoL, 23.5% had HD (19% GHD (using BMI-adjusted definition), 9% hypogonadism; 50% had metabolic syndrome. Although the cause of HD is unclear, these results suggest GHD and hypogonadism may contribute to poor QoL, erectile dysfunction and metabolic syndrome in this population.Journal of neurotrauma 02/2014; · 4.25 Impact Factor
JOURNAL OF NEUROTRAUMA
Volume 21, Number 6, 2004
© Mary Ann Liebert, Inc.
Occurrence of Pituitary Dysfunction following
Traumatic Brain Injury
MARTA BONDANELLI,1LAURA DE MARINIS,2MARIA ROSARIA AMBROSIO,1
MARCELLO MONESI,1DOMENICO VALLE,1MARIA CHIARA ZATELLI,2
ALESSANDRA FUSCO,2ANTONIO BIANCHI,2MARCO FARNETI,4
and ETTORE C. DEGLI UBERTI1
Traumatic brain injury (TBI) may be associated with impairment of pituitary hormone secretion,
which may contribute to long-term physical, cognitive, and psychological disability. We studied the
occurrence and risk factors of pituitary dysfunction, including growth hormone deficiency (GHD)
in 50 patients (mean age 37.6 ? 2.4 years; 40 males, age 20–60 years; 10 females, age 23–87 years)
with TBI over 5 years. Cranial or facial fractures were documented in 12 patients, and neurosurgery
was performed in 14. According to the Glasgow Coma Scale (GCS), 16 patients had suffered from
mild, seven moderate, and 27 severe TBI. Glasgow Outcome Scale (GOS) indicated severe disabil-
ity in five, moderate disability in 11, and good recovery in 34 cases. Basal pituitary hormone eval-
uation, performed once at times variable from 12 to 64 months after TBI, showed hypogonadotrophic
hypogonadism in seven (14%), central hypothyroidism in five (10%), low prolactin (PRL) levels in
four (8%), and high PRL levels in four (8%) cases. All subjects had normal corticotrophic and pos-
terior pituitary function. Seven patients showed low insulin-like growth factor–I (IGF-I) levels for
age and sex. Results of GHRH plus arginine testing indicated partial GHD in 10 (20%) and severe
GHD in four (8%) cases. Patients with GHD were older (p ? 0.05) than patients with normal GH
secretion. Magnetic resonance imaging demonstrated pituitary abnormalities in two patients; alto-
gether pituitary dysfunction was observed in 27 (54%) patients. Six patients (12%) showed a com-
bination of multiple abnormalities. Occurrence of pituitary dysfunction was 37.5%, 57.1%, and
59.3% in the patients with mild, moderate, and severe TBI, respectively. GCS scores were signifi-
cantly (p ? 0.02) lower in patients with pituitary dysfunction compared to those with normal pitu-
itary function (8.3 ? 0.5 vs. 10.2 ? 0.6). No relationship was detected between pituitary dysfunction
and years since TBI, type of injury, and outcome from TBI. In conclusion, subjects with a history
of TBI frequently develop pituitary dysfunction, especially GHD. Therefore, evaluation of pituitary
hormone secretion, including GH, should be included in the long-term follow-up of all TBI patients
so that adequate hormone replacement therapy may be administered.
Key words: growth hormone deficiency; head trauma; pituitary function
1Department of Biomedical Sciences and Advanced Therapies–Section of Endocrinology, University of Ferrara, Ferrara, Italy.
2Institute of Endocrinology and 3Internal Medicine, Catholic University, Rome, Italy.
4Division of Neurosurgery, St. Anna Hospital, Ferrara, Italy.
consequences ranging from physical disabilities to long-
term cognitive, behavioral, psychological, and social de-
fects (Salazar, 2000). Clinical evidence has demonstrated
that TBI may cause impairment of hypothalamic-hy-
pophyseal function, which may contribute to a delayed or
hampered recovery in many of the head-injured patients
(Bondanelli et al., 2002; Cernak et al., 1999; Della Corte
et al., 1998; Edwards and Clark, 1986; Woolf et al., 1992).
Hypopituitarism may rapidly develop after TBI, with
a sudden onset of overt symptoms of cortisol, thyroid hor-
mone, and/or gonadal steroid deficiencies (Clark et al.,
1988; De Marinis et al., 1999; Edwards and Clark, 1986;
Hackl et al., 1991). However, alterations in pituitary hor-
mone secretion can develop subtly, escaping detection for
months or years (Benvenga et al., 2000). Therefore, long-
term follow-up is necessary to reveal the development of
all pituitary hormone deficiencies.
To date, few systematic studies are available in order
to define the occurrence of long-term pituitary dysfunc-
tions in head-injured patients. A recent review indicated
that hypopituitarism occurs in about 60% of head-injured
patients and may became clinically evident at any time
after trauma with a lag time of diagnosis ranging from a
few months to 40 years (Benvenga et al., 2000). In the
series reported by Kelly et al. (2000), hypopituitarism oc-
curred in 40% of 22 TBI patients studied from 3 months
to 23 years after moderate or severe head trauma.
Lieberman et al. (2001) reported pituitary abnormalities
in 69% of 70 head-injured patients examined from 1
month to 23 years after trauma.
Injury severity and secondary cerebral damage have
been suggested to be risk factors for the development of
hypopituitarism (Benvenga et al., 2000; Hackl et al.,
1991; Kelly et al., 2000). However, currently available
data are not sufficient to identify predictive and/or risk
factors for hypopituitarism following head trauma.
Dysfunctions of the growth hormone (GH) and go-
nadotrophic axes appear to be the most common deficien-
cies in patients with TBI. These pituitary cells are partic-
ularly vulnerable to a variety of insults, including trauma
(Benvenga et al., 2000; Edwards and Clark, 1986).
In the last 10–15 years, the syndrome of growth hor-
mone deficiency (GHD) in adults has been clearly de-
fined. It is characterized by significant alterations in body
composition, decreased muscular strength, exercise ca-
pacity, and bone mineral content, and impairment in the
patient’s sense of well-being and quality of life (Gilchrist
et al., 2002; Simpson et al., 2002). Moreover, growing
evidence indicates that GH plays an important role in the
RAUMATIC BRAIN INJURY (TBI) is one of the main
causes of death and disability in young adults, with
recovery of the central nervous system from experimen-
tal brain injury (Scheepens et al., 2000, 2001). Thus, it
is possible that undiagnosed GHD may contribute to the
physical, psychological, and cognitive disabilities fol-
Therefore, the purpose of the present study was to eval-
uate the occurrence of long-term pituitary dysfunction,
including GHD, in a cohort of adult patients admitted to
the Neurosurgery Sections of the Hospital of Ferrara
and of the Gemelli Hospital of Rome over 5 years
(1997–2001) after a closed or penetrating head injury. In
order to assess the occurrence of specific risk factors for
posttraumatic hypopituitarism, the relationships among
pituitary function, the overall severity and outcome of
TBI, and the time since TBI were evaluated.
MATERIALS AND METHODS
Eligible patients included adult patients who had been
admitted to the Neurosurgery Sections of the Hospital of
Ferrara or of the Gemelli Hospital of Rome over 5 years
(1997–2001) for a closed or penetrating TBI, and sur-
One hundred and twenty head-injured patients (or their
family representatives) were asked to participate in the
study, but only 76 accepted voluntarily. Among these 76
patients, 50 (40 males, 10 females) underwent all study
procedures defined in the protocol previously approved
by the local Ethical Committees. Informed consent was
obtained from subjects or next of kin.
Criteria for patient exclusion were as follows: age of ?18
years; history of preexisting metabolic, endocrine, neuro-
logical, cardiac or pulmonary diseases; liver or renal fail-
ure, or infectious diseases; alcohol and drug misuse; treat-
ment with barbiturates, or medications that could affect GH
secretion (except for the treatment administered during the
acute phase after the injury). Moreover, subjects receiving
parenteral nutrition and/or mechanical ventilation and/or
requiring corticosteroid treatment during the previous 2
months were not included.
The age of recruited patients ranged from 20 to 87
years (mean 37.6 ? 2.4 years, median 30 years), and the
body mass index (BMI) ranged from 20.0 to 33.9 kg/m2
(mean 24.6 ? 0.4 kg/m2, median 24). Patients were stud-
ied once at variable times (12–64 months after TBI) over
the 5-year period.
The severity of injury was assessed by the post resus-
citation Glasgow Coma Scale (GCS) score (severe head
injury, GSC score of 8 or less; moderate head injury, GSC
score 9–12; mild head injury, GSC score 13–15) (Teas-
dale and Jennett, 1974).
BONDANELLI ET AL.
The type of head injury was characterized by computer-
ized tomography (CT) scan according to Marshall’s classi-
fication (Marshall et al., 1992): diffuse injury I (no visible
damage); diffuse injury II (cisterns are present with mid-
line shift of 0–5 mm and/or no large lesion of ?25 cc); dif-
fuse injury III (diffuse brain swelling, cisterns compressed
with midline shift 0–5 mm, no large lesion of ?25 cc); dif-
fuse injury IV (midline shift of ?5 mm, no large lesion of
?25 cc); evacuated mass lesion (EM, any lesion surgically
evacuated); non-evacuated mass lesion of ?25 cc.
Long-term outcome was defined using the Glasgow
Outcome Scale (GOS) score (1 ? death; 2 ? persistent
vegetative state; 3 ? severe disability; 4 ? moderate dis-
ability; 5 ? good recovery) at 12 months after TBI (Jen-
nett and Bond, 1975).
In all subjects, after an overnight fast, baseline venous
blood samples were drawn, at 0800 h, for determinations
of insulin-like growth factor–I (IGF-I), thyroid stimulating
hormone (TSH), free-thyroxine (FT4), adrenocorti-
cotrophic hormone (ACTH), cortisol, luteinizing hormone
(LH), follicle-stimulating hormone (FSH), and testosterone
(T) or estradiol (E2) plasma levels. Three baseline blood
samples were drawn at 15-min intervals for prolactin (PRL)
determination. Posterior pituitary function was assessed by
measurement of serum sodium, creatinine, and osmolality,
as well as urine osmolality and specific gravity.
GHD was assessed by GH-releasing hormone (GHRH)
plus arginine (ARG) testing. On a different day, an in-
dwelling intravenous (iv) cannula was inserted in both
forearms at 0730 h after an overnight fast (10–12 h) and
kept open with a slow infusion of 0.9% saline for sepa-
rate blood sampling and drug administration. An equili-
bration period of 1 h was allowed before baseline blood
samples were obtained. GHRH (Geref, Serono, Milan,
Italy) was administered (1 ?g/kg bolus) at time 0, fol-
lowed by L-arginine hydrochloride (30 g in 60 mL of
saline) infused over a 30-min period, from time 0 to 30
min of the study. Blood samples were collected at ?30,
0, 15, 30, 45, 60, 90, and 120 min for GH measurements.
A GH response peak higher than 16.5 ?g/L was consid-
ered normal, less than 9.0 ?g/L was considered diag-
nostic for severe GHD, and between 16.5 and 9.0 ?g/L
indicative of partial GHD, as previously defined by
Aimaretti et al. (1998).
Premenopausal (n ? 5) women were studied in the fol-
licular phase of the menstrual cycle.
Blood samples were drawn into pre-cooled glass tubes
containing 1 mg/mL ethylene-diamine tetraacetic acid
disodium salt (EDTA-2Na), for hormone determinations.
They were promptly centrifuged at 3000 ? g for 15 min
at 4°C, and then the plasma was frozen at ?80°C until
analysis. All samples for each hormone were processed
in duplicate in the same assay.
GH was measured by immunoradiometric assay
(IRMA) with reagents supplied by Nichols Institute Diag-
nostics (San Juan Capistrano, CA). The limit of detection
was 0.02 ?g/L, with intra- and interassay variation coef-
ficients respectively of 4.2% and 7.2%, at concentration of
1.4 ?g/L, and of 2.8% and 4.6%, at concentration of 12.2
?g/L. Plasma IGF-I was determined by radioimmunoas-
say (RIA) using a commercially available kit (Medgenix
Diagnostic S.A, Fleurus, Belgium), after acid-ethanol ex-
traction from EDTA plasma. The sensitivity of the method
was 0.1 ?g/L. The intra- and interassay coefficients of vari-
ation were 9.6% and 6.1%, respectively, in the concentra-
tion range of 125–1050 ?g/L.
ACTH was determined by IRMA (Nichols Institute
Diagnostics). Cortisol, E2and T were determined by
RIA (Diagnostic Products Corp., Los Angeles, CA). LH
and FSH were measured with a two-site chemilumino-
metric immunoassay (ACS; Ciba Corning Diagnostic
Corp., Medfield, MA). PRL, TSH, and FT4 were mea-
sured using an automated chemiluminescence system
(ACS Centaur; Chiron Diagnostics Corp., East Wal-
pole, MA). The intra- and interassay coefficients of
variation for all methods were less than 5.8% and 7.8%,
The age-specific normal ranges for IGF-I were
135–485 ?g/L (20–30 years), 120–397 ?g/L (31–40
years), 113–306 ?g/L (41–50 years), 100–250 ?g/L
(51–60 years); and 92–229 ?g/L (?60 years). The nor-
mal ranges for the other assays were as follows: ACTH,
1.5–11.5 pmol/L; cortisol, 0.22–0.70 ?mol/L (8–10 AM);
TSH, 0.4–4.2 mIU/L; FT4, 10.3–19.4 pmol/L; PRL, 4–24
?g/L in women and 2–16 ?g/L in men; E2, 74–555
pmol/L (follicular phase) and ?180 pmol/L (menopausal
women); T, 10.1–34.7 nmol/L; LH, 2.5–10 U/L (follicu-
lar phase) and 40–104 U/L (menopausal women); LH,
1–10 U/L in men; FSH, 2.5–10 U/L (follicular phase) and
34–96 U/L (menopausal women); FSH, 1–7 U/L in men.
Serum sodium and osmolality, urinary osmolality, and
specific gravity were determined by standard methods.
Normal range values were as follows: serum sodium
135–145 mmol/L, serum osmolality 270–290 mOsm/kg,
urine osmolality 500–800 mOsm/kg, and specific grav-
ity greater than 1005.
All patients underwent magnetic resonance imaging
(MRI) of the hypothalamic-pituitary region (0.5 T and 1
T scanners, T1-weighted sequence, and 3-mm slices in
sagittal and coronal sections), before and after after in-
travenous injection of gadolinium chelate.
PITUITARY DYSFUNCTION AFTER HEAD TRAUMA
All results are expressed as the mean ? SEM. PRL
levels were obtained from the mean (?SEM) of the three
determinations. Baseline levels of GH were obtained
from the mean (?SEM) of the two values determined at
times ?30 and 0 min of the test. GH plasma concentra-
tions were expressed both as absolute values (?g/L) and
as areas under the curves from 0 to 120 min (AUC 0–120
min, ?g/L ? min) calculated by trapezoidal method, after
GHRH plus ARG administration. Comparison between
groups of continuous variables was assessed by using
Student’s t test or one-way ANOVA and the post-hoc
analysis of Student-Newman-Keuls for multiple vari-
ables. Percentage comparison was made with Fisher’s ex-
act test. Correlations between hormonal values and clin-
ical measures of trauma severity and outcome, or years
from TBI or characteristics of patients were performed
by linear regression analysis. Values were considered sta-
tistically significant when p was ?0.05.
Clinical Characteristics of Patients
Sixteen patients had mild (GCS 13–15), seven moder-
ate (GCS 9–12), and 27 severe (GCS 3–8) TBI (Fig. 1).
According to Marshall’s classification, nine patients had
no visible damage (grade I), 20 patients had diffuse injury
(grade II), and seven belonged to grade III; a mass lesion
was surgically evacuated (EM) in 14 cases. Fractures of
the skull and/or facial bones were observed in 12 cases.
GOS indicated severe disability in five patients, moderate
disability in 11 patients, and good recovery in 34 patients.
When the patients were divided into five groups (Table
1), according to the time that had elapsed since trauma,
the distribution of cases in each group was as follows:
six patients (12%; three severe, two moderate, one mild)
were evaluated ?1 year but ?2 years since TBI (group
1); 11 patients (22%; two severe, one moderate, eight
mild) were evaluated ?2 years but ?3 years since TBI
(group 2); four patients (8%; one severe, one moderate,
two mild) were evaluated ?3 years but ?4 years since
TBI (group 3); 18 patients (36%; 13 severe, three mod-
erate, two mild) were evaluated ?4 years but ?5 years
since TBI (group 4); 11 patients (22%; nine severe, one
moderate, one mild) were evaluated ?5 years but ?6
years since TBI (group 5). The mean values of GCS and
GOS as well as mean age and BMI of each group of the
patients did not significantly differ among the five
Seven patients had suffered from temporary diabetes in-
sipidus, which resolved spontaneously within a few days.
GH Response to GHRH plus ARG
As shown in Figure 2, GHRH plus ARG test demon-
strated normal GH response in 36 (72%) patients (20 se-
BONDANELLI ET AL.
Glasgow Coma Scale score: 13–15 ? mild, 9–12 ? moderate, ?8 ? severe TBI (Teasdale and Jennett, 1974); Marshall’s clas-
sification of the type of head injury by initial computerized tomography scan: I, no visible pathology; II, cisterns are present with
midline shift 0–5 mm and/or no large lesion of ?25 cc; III, diffuse brain swelling, cisterns compressed with midline shift 0–5
mm, no large lesion of ?25 cc; EM, evacuated mass lesion (Marshall et al., 1992); the presence or absence of cranial and/or fa-
cial fractures; GOS, Glasgow Outcome Scale score: 3 ? severe disability; 4 ? moderate disability; 5 ? good recovery (Jennett
and Bond, 1975).
Characteristics of 50 adult patients with a history of traumatic brain injury (TBI) during the previous 5 years. GCS,
vere, four moderate, and 12 mild TBI) with the mean
(?SEM) peak value of 31.8 ? 2.2 ?g/L. Ten (20%) sub-
jects (five severe, two moderate, and three mild TBI)
showed a GH response indicative of partial GHD, with
a mean peak value of 11.6 ? 0.4 ?g/L, and four (8%)
patients (two severe, one moderate, and one mild TBI)
had severe GHD, with a mean peak value of 4.8 ? 1.2
No significant differences were observed in GH re-
sponses to GHRH plus ARG among patients with severe
(peak 27.5 ? 3.4 ?g/L, AUC 12.4 ? 1.7 ?g/L ? min),
moderate (peak 21.9 ? 5.3 ?g/L, AUC 11.4 ? 2.6
?g/L ? min) and mild (peak 23.8 ? 2.4 ?g/L, AUC
11.1 ? 1.2 ?g/L ? min) TBI.
No significant differences were observed among the
five groups of patients divided according to the time that
had elapsed since trauma, either in the GH peak values
or in the AUCs after GHRH plus ARG.
No differences in GH response to GHRH plus ARG
were detected among patients with different GOS scores.
The mean (?SEM) BMI was not significantly differ-
ent between patients with normal GH secretion (24.2 ?
0.5 kg/m2) and those with GHD (25.5 ? 0.4 kg/m2). The
mean (?SEM) age was significantly (p ? 0.05) higher
in patients with partial or severe GHD (45.4 ? 4.7 years)
as compared to the group showing normal GH secretion
(34.9 ? 2.6 years).
Basal Hormone Values and MRI
All subjects showed spontaneously normal levels of
serum sodium and osmolality, as well as of urinary os-
molality and specific gravity.
As indicated in Table 2, seven (14%) of 50 patients
had low blood T concentrations associated with low or
normal plasma LH and FSH concentrations when com-
pared to normal range. Five (10%) patients had low
blood FT4 concentrations with low or normal TSH con-
centrations, indicating the presence of central hypothy-
roidism. Plasma PRL concentrations were slightly ele-
vated in four patients (8%; three males) and low in four
patients (8%; three males). Seven (14%) of 50 patients
showed low IGF-I concentrations when compared to
age- and sex-matched normal ranges. All patients had
plasma ACTH and cortisol levels within the normal
range. MRI revealed the presence of morphological ab-
normalities in two TBI patients (empty sella and slight
pituitary stalk dislocation).
PITUITARY DYSFUNCTION AFTER HEAD TRAUMA
TABLE 1. CLINICAL CHARACTERISTICS OF THE PATIENTS DIVIDED INTO FIVE
GROUPS ACCORDING TO THE TIME ELAPSED SINCE HEAD TRAUMA
MF(mean ? SEM)(mean ? SEM)IIIIIIEM
44.5 ? 7.2
36.5 ? 5.5
35.0 ? 8.7
36.2 ? 4.2
38.1 ? 4.6
37.6 ? 2.4
25.3 ? 1.4
25.2 ? 1.3
23.5 ? 0.3
24.0 ? 0.5
25.1 ? 0.7
24.6 ? 0.4
10.7 ? 1.9
11.9 ? 1.2
11.3 ? 1.7
7.4 ? 0.8
7.6 ? 0.9
9.1 ? 0.6
5.0 ? 0.0
4.6 ? 0.2
5.0 ? 0.0
4.2 ? 0.2
4.5 ? 0.2
4.5 ? 0.1
Group 1, ?1 year but ?2 years since TBI; ?2 years but ?3 years since TBI; ?3 years but ?4 years since TBI; ?4 years but ?5
years since TBI; ?5 years but ?6 years since TBI. Age, age at time of head injury. Values are expressed as the mean ? SEM.
plus arginine administration in 50 patients with a history of TBI
divided according to GCS score. A GH response higher than 16.5
?g/L was considered normal, ?9.0 ?g/L was considered diag-
nostic for severe GH deficiency (GHD), and between 16.5 and
9.0 ?g/L indicative of partial GHD (Aimaretti et al., 1998). GCS
score: 13–15 ? mild; 9–12 ? moderate; ?8 ? severe TBI.
GH peak concentration after GH-releasing hormone
Relationship between Pituitary Dysfunction and
Time, Outcome, or Severity of Trauma
No significant correlations were found between either
IGF-I levels or GH responses to GHRH plus ARG (GH
peak and AUC) and clinical scores of trauma severity
(GCS). Similarly, no significant correlations were pre-
sent between the indices of GH axis function and GOS
The number of years since TBI was significantly cor-
related (r ? ?0.389, p ? 0.005) with serum IGF-I lev-
els but not with either GH peak or AUC after GHRH plus
As expected, the age of patients negatively correlated
with both IGF-I levels (r ? ?0.313, p ? 0.05) and GH
responses to GHRH plus ARG (peak, r ? ?0.411, p ?
0001; AUC, r ? ?0.387, p ? 0.005).
Altogether pituitary dysfunction was observed in 27
(54%) patients. Among these 27 patients, partial or se-
vere GHD was detected in 51.8%, hypogonadism in
25.9%, hypothyroidism in 18.5%, hyperprolactinemia in
14.8%, and hypoprolactinemia in 14.8% of the patients.
Six patients showed a combination of multiple hormone
abnormalities. Two patients had partial GHD and low
PRL. One patient had LH, FSH, and TSH deficiencies.
One patient had LH, FSH, and TSH deficiencies and low
PRL. One patient had low FT4 with inappropriately nor-
mal TSH and high PRL. One patient had low T with in-
appropriately normal LH and FSH and high PRL. Only
two out of 27 (7.4%) patients with pituitary dysfunction
showed anatomic pituitary abnormalities on MRI scans
As indicated in Table 3, the mean age (39.3 ? 2.9
years) and BMI (25.3 ? 0.5 kg/m2) of the patients with
pituitary dysfunction did not significantly differ from that
observed in patients with normal pituitary hormone se-
BONDANELLI ET AL.
TABLE 2. SUMMARY OF THE CLINICAL, HORMONAL, AND PITUITARY IMAGING DATA FOR THE
27 PATIENTS WITH DOCUMENTED ABNORMALITIES OF PITUITARY HORMONE SECRETION
trauma GCS Marshall fractures GOS PRL LH FSH TSH
T FT4 IGF-I GHRH?ARG abnormalities
Age, age at time of head injury; GDH, severe growth hormone deficiency; pGHD, partial GHD; ↓, decreased; ↑, increased;
,? normal range. For other definitions, see Fig. 1 legend.
Basal hormone values
cretion (35.6 ? 2.5 years and 23.8 ? 0.3 kg/m2, respec-
tively). Moreover, the time that had elapsed since TBI
did not differ significantly between patients with (3.3 ?
0.2 years) or without pituitary dysfunction (3.4 ? 0.2
years). Considering severity of TBI, GCS scores were
significantly (p ? 0.02) lower in patients with pituitary
dysfunction (8.3 ? 0.5) compared to patients with nor-
mal pituitary function (10.2 ? 0.6). There were no sig-
nificant differences in GOS values, between patients with
(4.5 ? 0.1) or without (4.4 ? 0.1) pituitary dysfunction.
When the patients were divided according to years since
TBI, pituitary dysfunction was detected in four of six
(66.7%) patients of the group 1, six of 11 (54.5%) of the
group 2, two of four (50%) of the group 3, eight of 18
(44.4%) of the group 4, and seven of 11 (63.6%) of the
group 5 (Fig. 3).
Moreover, pituitary dysfunction was observed in six
of 16 (37.5%) patients with mild, in four of seven (57.1%)
patients with moderate, and in 16 of 27 (59.3%) patients
with severe TBI (Fig. 4).
Occurrence of pituitary dysfunction did not vary
among patients with different types of head injury ac-
cording to Marshall’s classification (55.5% grade I,
50.0% grade II, 57.1% grade III, and 50.0% grade EM)
Occurrence of pituitary dysfunction did not differ sig-
nificantly in patients with cranial and/or facial fractures
(55.3%) compared to patients without fractures (50%)
Moreover, occurrence of pituitary dysfunction was
similar among patients with different GOS scores
In the present study, pituitary dysfunction has been
documented in a substantial proportion (54%) of the pa-
tients with a history of TBI during the last 5 years. Im-
paired GH secretion was the most common abnormality,
being present in 28% of patients. The occurrence of pi-
tuitary dysfunction was 59% in the patients with severe
TBI (according to GCS) and 37.5% in those with mild
injury, suggesting that clinical severity of trauma (GCS)
may be a risk factor for developing posttraumatic hy-
popituitarism. This is supported by the observation that
GCS scores were significantly lower in patients with pi-
tuitary dysfunction compared to patients with normal pi-
tuitary function. In contrast, the type of injury (Marshall’s
classification and cranial fractures) and outcome from
trauma did not predict of developing pituitary dysfunc-
tion. Only a minority (two out of 27, or 7.4%) of the pa-
tients with pituitary dysfunction revealed morphological
alterations of the pituitary gland.
PITUITARY DYSFUNCTION AFTER HEAD TRAUMA
TABLE 3. COMPARISON BETWEEN THE PATIENTS WITH
NORMAL AND ABNORMAL PITUITARY FUNCTION
(n ? 23)
(n ? 27)
Yrs from trauma
Cranial/facial fractures (%)
35.6 ? 2.5
23.8 ? 0.3
3.4 ? 0.2
10.2 ? 0.6
4.4 ? 0.1
39.3 ? 2.9a
25.3 ? 0.5a
3.3 ? 0.2a
8.3 ? 0.5a
4.5 ? 0.1a
ap ? 0.02.
Age, age at time of head injury; BMI, body mass index; GCS,
Glasgow Coma Scale score; GOS, Glasgow Outcome Scale.
Unless otherwise indicated, values are expressed as the mean
vere GHD (for definitions, see Fig. 2 legend). ? patients with isolated GHD;
itary dysfunction; ? patients with pituitary dysfunction other than GHD.
Occurrence of pituitary dysfunction in relationship to the time elapsed since traumatic brain injury. GHD, partial or se-
patients with GHD associated with other pitu-
The relationship between head injury and subsequent
pituitary failure was first documented in 1918 (Cyran,
1918). Since 1970, several cases of pituitary dysfunction
have been described in the literature, but they are mostly
related to case reports and/or to data obtained from pa-
tients evaluated early after injury (Cernak et al., 1999;
Della Corte et al., 1998; Clark et al., 1988; De Marinis
et al., 1999; Edwards and Clark, 1986; Hackl et al., 1991;
Woolf et al., 1992). However, the incidence of pituitary
dysfunction following head trauma has only been re-
ported in three previous series (Benvenga et al, 2000;
Kelly et al., 2000; Lieberman et al., 2001). The present
study confirms data from these three reports, indicating
the presence of pituitary dysfunction in 40–69% of pa-
tients with a history of TBI (Benvenga et al., 2000; Kelly
et al., 2000; Lieberman et al., 2001).
The present data cannot define the precise time course
of development of posttraumatic pituitary dysfunction,
but they confirm the need to evaluate pituitary hormone
secretion in all patients with a TBI beyond the early pe-
riod after injury. In fact, although no statistically signif-
icant relationship was found between the occurrence of
hypopituitarism and the time elapsed since TBI, more
than 50% of the patients with a history of TBI developed
pituitary dysfunction within 4 or 5 years. Accordingly, it
has previously been shown that hypopituitarism may oc-
cur at any time after head trauma, even if it is more fre-
quently (70%) diagnosed within the first year (Benvenga
et al., 2000). This supports the view that signs and symp-
toms of hypopituitarism may frequently be unrecognized,
unless careful long-term follow-up of pituitary function
is performed in all patients with a history of TBI.
The present data show an association between the pres-
ence of a low GCS score and endocrine abnormalities,
suggesting that severity of TBI may be an important risk
factor for developing posttraumatic pituitary dysfunction.
Moreover, five out of six patients with multiple pituitary
hormone abnormalities had severe TBI (GCS 3–8), indi-
BONDANELLI ET AL.
score (for definitions, see Fig. 1 legend). GHD, partial or severe GHD (for definitions, see Fig. 2 legend). ? patients with isolated
GHD; patients with GHD associated with other pituitary dysfunction; ? patients with pituitary dysfunction other than GHD.
Occurrence of pituitary dysfunction in relationship to severity of head trauma according to Glasgow Coma Scale (GCS)
(CT) scan, according to Marshall’s classification (for definitions, see Fig. 1 legend; Marshall et al., 1992). GHD, partial or se-
vere GHD (for definitions, see Fig. 2 legend). ? patients with isolated GHD;
itary dysfunction; ? patients with pituitary dysfunction other than GHD.
Occurrence of pituitary dysfunction in relationship to the type of head injury on the initial computerized tomography
patients with GHD associated with other pitu-
cating a relationship between severity of injury and de-
gree of hypopitutarism. In contrast, Marshall’s classifi-
cation of the type of head injury, proposed for outcome
prediction (Marshall et al., 1992; Raabe et al. 1999), was
not predictive of the development of pituitary dysfunc-
tion in our patients. Moreover, the outcome from head
trauma, defined by the GOS, did not differ between pa-
tients with normal and impaired pituitary hormone se-
Greater injury severity and associated cerebral insult
have previously been suggested as risk factors for hy-
popituitarism. Kelly et al. (2000) demonstrated that dif-
fuse swelling on initial CT scans and evidence of a hy-
potensive and/or hypoxic insult occurred more frequently
in patients who developed hypopituitarism after TBI
compared to patients who continued to have normal pi-
tuitary function. Other authors reported that occurrence
of coma or unconsciousness following head trauma was
followed by hypopituitarism in 93% of patients (Ben-
venga et al., 2000). These data suggest that the clinical
severity of initial TBI may predict development of post-
traumatic hypopituitarism, but further studies are neces-
sary to clarify if the type of injury may influence long-
term hypothalamic-pituitary function.
In our study, the occurrence of skull and/or facial bone
fractures was not predictive of subsequent post-traumatic
hypopituitarism. Various reports have identified sellar
fractures in association with posttraumatic hypopitu-
itarism (Bistritzer et al., 1981; Daniel et al. 1959), but
none of our patients had this type of fracture. In Cromp-
ton’s study, the presence of anatomical lesions in the hy-
pothalamus was associated with temporal-parietal blows
and fractures of the skull base (Crompton, 1971).
Although the majority of our patients with pituitary
dysfunction had a history of severe TBI, the occurrence
of anatomical lesion demonstrated by MRI was low
(7.4%), as was the case in the study by Cytowic et al.
(1986). These findings are in agreement with the view
PITUITARY DYSFUNCTION AFTER HEAD TRAUMA
definitions, see Fig. 2 legend). ? patients with isolated GHD;
tion; ? patients with pituitary dysfunction other than GHD.
Occurrence of pituitary dysfunction and presence of cranial and/or facial fractures. GHD, partial or severe GHD (for
patients with GHD associated with other pituitary dysfunc-
Scale (GOS) (for definitions, see Fig. 1 legend). GHD, partial or severe GHD (for definition, see Fig. 2 legend). ? patients with
isolated GHD; patients with GHD associated with other pituitary dysfunction; ? patients with pituitary dysfunction other
than GHD; GOS: 3 ? severe disability; 4 ? moderate disability; 5 ? good recovery.
Occurrence of pituitary dysfunction in relationship to outcome from head trauma according to the Glasgow Outcome
that posttraumatic hypopituitarism could be due to a hy-
poxic insult that leads to functional damage at the level
of the hypothalamus or pituitary. Benvenga et al. (2000)
reported that 93% of 89 patients with posttraumatic hy-
popituitarism presented with radiological abnormalities
of the hypothalamus and/or pituitary region (mainly vas-
cular insults assessed by CT or MRI).
Gender or BMI of the patients did not influence de-
velopment of pituitary dysfunction, however a negative
correlation was present between age and GH axis func-
The most frequent alteration in endocrine function de-
tected in our study was partial or severe GHD, docu-
mented in 28% of all patients and in 52% of those
affected by any pituitary abnormalities. GHD was diag-
nosed by combined administration of GHRH plus ARG,
a potent provocative test for GH secretion (Ghigo et al.,
1990; Valletto et al., 1996). This test has been shown to
have a very high specificity and sensitivity for diagnosis
of GHD, with less inter- and intra-individual variability
than other stimulation tests. The ARG-GHRH test has
been proposed to be the best diagnostic alternative to the
ITT, especially for patients with contraindications for in-
sulin-induced hypoglycemia (Aimaretti et al., 1998;
Biller et al., 2002). Therefore, the ARG-GHRH test may
be a useful test for evaluation of patients with TBI. How-
ever, it is possible that patients with an injury limited to
the hypothalamus may have a normal response to ARG-
GHRH but not to the ITT. A recent study conducted in
the United States proposed lower peak GH criteria for
the ARG-GHRH test, due to the higher BMI of the U.S.
patients (Biller et al., 2002). However, the patients in the
present study had a normal mean BMI, which supports
our choice of the criteria proposed by Aimaretti et al.
Eight patients with partial or complete GHD presented
basal serum IGF-I concentrations within the normal
range, in agreement with previous reports (Biller et al.,
2002). One of the seven patients with low IGF-I had a
normal GH response to GHRH plus ARG administration,
indicating that low level of serum IGF-I cannot be as-
sumed as a parameter for the definition of GHD in adult
patients with a history of TBI.
We found that some patients with both partial (five out
of 10) and severe (two out of four) GHD were of mid-
dle or advanced age. It is well known that GH-IGF-I axis
function declines with normal ageing. A 15% reduction
in the 24-h GH concentrations and a 6% decrease in GH
half-life for each decade have been shown after puberty
(Giustina and Veldhuis, 1998; Zadik et al., 1985). Thus,
the daily GH secretory rate declines from a peak of about
150 ?g/kg during puberty to about 25 ?g/kg by age 55
years. However it has been amply demonstrated that the
GH response to GHRH ?ARG does not depend on age
and that this test is able to distinguish between normal
and GHD subjects with excellent reproducibility regard-
less of age (Ghigo et al., 1990; Valletto et al., 1996). The
negative relationship between age and GH axis function
suggests that aging may be a negative prognostic factor
for the development of posttraumatic GHD. Perhaps the
hypothalamic-pituitary region is more susceptible to in-
jury in older individuals. Alternatively, the reduced GH
secretory reserve in middle or advanced age may predis-
pose to GHD following TBI.
Although overall pituitary dysfunction was more fre-
quent in patients with severe TBI, the occurrence of par-
tial or severe GHD was not significantly influenced by
severity of trauma. This could be due to the particular
vulnerability of these pituitary cells to vascular insults,
which appear to be the major cause of posttraumatic hy-
popituitarism (Edwards and Clark, 1986; Kelly et al.,
Central hypogonadism was documented in 14% of all
patients and in 25.9% of those affected by any pituitary
abnormalities. This occurrence is lower than that ob-
served in some previous studies, which reported the pres-
ence of hypogonadism in almost 100% of the patients
with posttraumatic hypopituitarism (Edwards and Clark,
1986; Benvenga et al., 2000). In contrast, gonadotrophin
deficiency was uncommon in the study of Lieberman et
al. (2001). These discrepancies might be attributable to
differences among the study populations, including the
number of patients with hypopituitarism included in the
In our study, TSH deficiency was detected in 10% of
all patients and in 18.5% of patients with pituitary dys-
function. Low or high PRL levels were observed in 16%
of all patients and in 25.6% of patients with pituitary dys-
function even if no stalk abnormalities were demon-
strated on MRI in these patients. Finally, no alteration in
ACTH or cortisol levels was detected in any patient.
It is possible that undiagnosed GHD and alterations in
the secretion of other pituitary hormones may negatively
influence the recovery and the final outcome after TBI,
contributing to a diminished quality of life, or physical
and/or mental impairment (Gilchrist et al., 2002; Nyberg,
2000; Simpson et al., 2002). It is well known that GHD
in adult patients causes significant abnormalities in body
composition, reduced bone mineral content, reduced ex-
ercise capacity, and impairment in cognitive function and
sense of well being. These alterations may be improved
after GH replacement therapy (Simpson et al., 2002). In
this respect, growing evidence indicates that GH plays an
important role in promoting recovery after experimental
brain injury (Scheepens et al., 2000, 2001). However, in
the present study, no significant relationship was demon-
BONDANELLI ET AL.
strated between GH axis function and outcome follow-
ing TBI. Therefore, keeping in mind the beneficial neu-
robehavioral and physical effects of GH replacement in
GHD patients, long-term evaluation of the GH axis
should be performed after TBI, in order to make an early
diagnosis of GHD. At present, the international consen-
sus is that severe GHD should be treated with GH re-
placement therapy (Hartman, 1998). The value of GH
treatment for partial GHD remains to be established.
In conclusion pituitary dysfunction was identified in a
substantial proportion of patients with a TBI history. Al-
though the type and outcome of TBI, and time since TBI
did not predict the occurrence of pituitary dysfunction, a
greater clinical severity of TBI was associated with a
higher incidence of hypopituitarism. Partial or severe
GHD was the most common pituitary hormone dysfunc-
tion, especially in middle or advanced age patients.
Long-term prospective studies are necessary to estab-
lish the real incidence and the time of onset of pituitary
dysfunction in patients with TBI. However, the present
data confirm that an accurate evaluation of pituitary hor-
mone secretion, including the GH axis, is required for the
long-term follow-up of all patients who have suffered
from TBI, in order to detect the occurrence of posttrau-
matic hypopituitarism, independently of clinical evidence
for pituitary dysfunction, and perform adequate replace-
This work was supported by grants from the Italian
Ministry of University and Scientific and Technological
Research (60%–2002; MIUR 2002067251-003), Fon-
dazione Cassa di Risparmio di Ferrara, and Associazione
Ferrarese dell’Ipertensione Arteriosa. We are deeply in-
debted to Dr. Mark Hartman for his critical review of the
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Address reprint requests to:
Ettore C. degli Uberti, M.D.
Department of Biomedical Sciences
and Advanced Therapies
Section of Endocrinology
University of Ferrara
Via Savonarola, 9
44100 Ferrara, Italy
BONDANELLI ET AL.