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Anterior Pituitary Dysfunction in Survivors of Traumatic Brain Injury

Academic Department of Endocrinology (A.A., B.R., M.S., P.O., C.J.T.) and Departments of Neurosurgery (J.P.) and Clinical Chemistry (W.T.), Beaumont Hospital, Dublin 9, Ireland

Address all correspondence and requests for reprints to: Dr. Christopher J. Thompson, Department of Endocrinology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland. E-mail: chris.thompson{at}beaumont.ie.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Recent data suggest that anterior pituitary dysfunction after traumatic brain injury (TBI) is common. We sought to confirm the results of earlier studies in a larger cohort of patients with dynamic testing of pituitary function.

We studied 102 consecutive TBI survivors (85 males; median age 28, range 15–65 yr) who had survived severe or moderate TBI (initial Glasgow Coma Scale score 3–13) at a median of 17 months (range 6–36) post event. GH and ACTH reserves were initially assessed using the glucagon stimulation test (GST). Normative data on GH and cortisol responses to the GST were obtained from 31 matched healthy controls. Patients with subnormal GH or cortisol responses were further evaluated, using the insulin tolerance test (ITT) or arginine + GHRH test for GH assessment and the ITT or 250-µg short synacthen test for the assessment of ACTH reserve. Patients were considered to be GH or ACTH deficient if they failed both the GST and the second provocative test. Baseline thyroid function, prolactin, IGF-I, gonadotropins, testosterone, or estradiol was performed in all patients and compared with local reference ranges.

In controls, normal response to the GST was a stimulated GH peak of greater than 5 µg/liter and cortisol peak greater than 450 nmol/liter (16 µg/dl). Eighteen TBI patients (17.6%) had GH response to the GST less than 5 µg/liter, 11 of whom also failed the ITT or the arginine + GHRH tests. GH-deficient patients had significantly higher body mass index (P = 0.003), and lower IGF-I concentrations (P < 0.001), than GH-sufficient patients. Twenty-three patients (22.5%) had cortisol responses to GST less than 450 nmol/liter, 13 of whom also failed the ITT or short synacthen test. GH or ACTH deficiencies were not related to age, Glasgow Coma Scale score, or the presence of other pituitary hormone abnormalities (P > 0.05). Twelve patients (11.8%) had gonadotropin and one (1%) had thyrotrophin deficiencies. Twelve patients (11.8%) had hyperprolactinemia. Twenty-nine patients (28.4%) had at least one anterior pituitary hormone deficiency.

This is the largest study, to date, of hypopituitarism after TBI and confirms a high prevalence of undiagnosed anterior pituitary hormone abnormalities in survivors of TBI. Hypopituitarism is a treatable cause of morbidity after TBI. In addition to conventional pituitary hormone replacement, the potential of GH treatment to enhance recovery needs to be examined in a prospective study.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
TRAUMATIC BRAIN INJURY (TBI) is increasingly common, and 180–250 persons per 100,000/yr die or are hospitalized in industrialized countries as a result (1). It is the leading cause of death and disability among young adults (2, 3), and survivors are often left with significant adverse physical and/or psychological sequelae (1, 3).

Posttraumatic hypopituitarism was recognized more than 80 yr ago (4), but it was thought to be a rare occurrence (5), despite autopsy results showing pituitary gland necrosis in up to one third of patients who suffered fatal head injury (6). Recent data suggest that pituitary hormone deficiency is not infrequent among TBI survivors, with as many as 40–50% of patients studied reported having some degree of pituitary dysfunction (7, 8). Because the majority of TBI survivors are young adults with near-normal life expectancy, the implications of undiagnosed posttraumatic pituitary dysfunction can be serious and may contribute to the significant morbidity associated with TBI. To determine the true prevalence of anterior hypopituitarism, further research in large cohorts of TBI survivors is needed. In this study, we report on the frequency of posttraumatic anterior hypopituitarism in a large cohort of patients who survived severe or moderate TBI.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

One hundred two TBI patients (85 males), median age 28 yr, range 15–65 yr, who were admitted to the neurosurgical unit in Beaumont Hospital between September 2000 and September 2002, were studied. Beaumont Hospital is the national neurosurgical center for the Republic of Ireland and has a catchment area of 3.5 million people. Patients were identified from the Beaumont Hospital head trauma database. Patients were eligible for inclusion in the study if they suffered severe or moderate TBI (see below), were between 15 and 65 yr of age, were 6 months or longer past their injury, and were discharged alive from the neurosurgical unit. Exclusion criteria were: patients over 65 or under 15 yr of age at the time of testing, patients who had suffered a prolonged hypotensive episode (defined as a systolic blood pressure <90 mm Hg for >30 min), pregnant women, and patients on glucocorticoid therapy. One hundred twenty-eight patients were eligible for inclusion in the study. Twenty-six patients were excluded for the following reasons: four died since leaving hospital, 13 had left Ireland or were uncontactable, four were too ill to participate, and five declined to participate.

All patients had suffered severe or moderate head trauma according to the initial postresuscitation and presedation Glasgow Coma Scale (GCS) score (9). Fifty-seven patients had documented severe head injury, as defined by a GCS score of 8/15 or less, and 42 subjects had documented moderate injury, defined by a GCS score of 9/15 to 13/15 (10). The three remaining patients had no documented GCS scores but were admitted to the intensive care unit (ITU) and therefore were assumed to have a GCS of 13 or less. The median GCS score was 8/15.

The causation of TBI was road traffic accidents in 44 patients, falls in 30 patients, assault in 13 patients, and other mechanisms in 15 patients. Assessment of outcome post TBI was done using the Glasgow Outcome Scale (GOS) score (11). All patients, except one, had computerized tomography (CT) evidence of brain injury. CT appearance was classified as showing focal brain injury (extradural, subdural, or intracerebral hematomas) or diffuse brain injury (shearing axonal injury), with or without cerebral edema (12). Eighty-six patients had focal brain injury and 15 patients had diffuse brain injury. Seventy-two patients (70.6%) had CT evidence of cerebral edema. Fifty-five patients (54%) underwent operative mass evacuation. Eighty-four patients (82.4%) had received intracranial pressure monitoring and were sedated and ventilated in the neurosurgical ITU. The duration of ITU stay was 14 ± 10 d. Thirty-two patients had additional non-TBI trauma.

Methods

Patients were tested at a median of 17 months (range 6–36) after injury. Testing was performed in the pituitary investigation day ward. Testing started at 0800 h after an overnight fast. Undiluted blood samples were drawn from a heparinized cannula inserted in an antecubital vein.

Assessment of somatotrophic and corticotrophic function

The im glucagon stimulation test (GST) was used initially as a screening test for somatotrophic and corticotrophic function (13, 14, 15, 16, 17, 18). Patients with subnormal GH response to GST were further assessed using either the insulin tolerance test (ITT) (19, 20, 21, 22, 23, 24) or, if they had a history of seizures or heart disease, the arginine + GHRH test (24, 25). Patients with subnormal serum cortisol responses to the GST were further evaluated using the ITT (19, 26), or, if they had a history of seizures or heart disease, the 250-µg short synacthen test (SST) (27, 28, 29) was used.

For the GST, a baseline serum sample for GH and cortisol and a plasma sample for ACTH were obtained after which, 1 mg glucagon (Novo Nordisk, Bagsvaerd, Denmark) was injected into the deltoid muscle (1.5 mg if body weight was more than 90 kg). Clotted serum samples for GH and cortisol were then obtained at times 90, 120, 150, 180, 210, and 240 min (30).

For the ITT, a baseline serum GH and/or cortisol samples were obtained, followed by the iv administration of 0.15 U/kg Actrapid (Novo Nordisk) to achieve a nadir plasma glucose of less than 2.2 mmol/liter (40 mg/dl). Clotted serum samples for GH and cortisol were then withdrawn at times 15, 30, 45, 60, 90, and 120 min (31).

For the arginine + GHRH test, a basal serum sample for GH was obtained, followed by a 30-min iv infusion of 0.5 g/kg arginine (up to a maximum dose of 30 g), together with an iv bolus dose of 1 µg/kg GHRH (GEREF, Serono, Italy). Serum samples for GH were then obtained at times15, 30, 45, 60, and 90 min (25).

For the SST, 250 µg tetracosartin (Novartis, Surrey, UK) were injected iv, with cortisol samples collected basally and 30 min after injection (27).

Other anterior pituitary hormones

Baseline clotted serum samples were withdrawn for measurements of FSH, LH, free T₄ (FT4), TSH, prolactin, IGF-I, and testosterone in males or estradiol levels in females. In all females, menstrual history was obtained.

Other assessments

Assessment of outcome post-TBI was done using the GOS score (11). Quality of life (QoL) was assessed using the assessment of GH deficiency in adults (AGHDA) questionnaire (32).

Definition of abnormalities

Because normal GH and cortisol responses to the GST are not well established, we performed the GST in 31 healthy subjects (22 males) who were matched for age, sex, and body mass index (BMI) to the patient population.

GH response

All 31control subjects had a GH response to glucagon more than 5 µg/liter (median 13.7, range 5.8–50 µg/liter). We therefore took a cut-off of 5 µg/liter (12.5 mU/liter) to define a normal response. TBI patients with GH responses to GST less than 5 µg/liter were further assessed using either the ITT or arginine + GHRH test. For ITT, GH deficiency was defined as a GH peak less than 5 µg/liter (12.5 mU/liter) and severe deficiency as a response less than 3 µg/liter (7.5 mU/liter) (20, 24). For the arginine + GHRH, severe GH deficiency was defined as a peak response less than 9 µg/liter (22.5 mU/liter) (25).

Cortisol response

Twenty-eight of 31 normal subjects showed a peak serum cortisol response to the GST exceeding 450 nmol/liter (16 µg/dl). Three subjects had a flat cortisol response to glucagon, giving a false-positive (nonresponder) rate of 9%, similar to that quoted in other studies (15). Accepting this well-recognized false-positive result, we defined a normal serum cortisol response to the GST as a peak plasma cortisol of more than 450 nmol/liter. Patients who failed the GST had either ITT or SST testing. For the ITT, the normal response in our laboratory is a peak cortisol more than 500 nmol/liter (18 µg/dl) and for the SST a 30-min cortisol more than 500nmol/liter (33, 34).

Other hormone abnormalities

In males, gonadotropin deficiency was defined by a low serum testosterone with inappropriately low gonadotropin level, in premenopausal females by amenorrhea in the presence of low serum estradiol level without a rise in gonadotropin level, and in postmenopausal females by serum gonadotropin concentration in the premenopausal range (35, 36). TSH deficiency was defined by low serum FT4 level (after excluding artifactual causes) without appropriate elevation in serum TSH (35, 36). Hyperprolactinemia was defined as a basal level greater than the locally derived normal assay reference range.

Analytical methods

Serum GH was assayed using a noncompetitive immunoradiometric assay (IRMA) method, (DiaSorin, Vercelli, Italy), with an intraassay coefficient of variation (CV) of 1.9, 1.9, and 3.9% at GH means of 18.4, 8.2, and 1.71 µg/liter, respectively. The interassay CV was 5.5, 4.5, and 2.3% at GH means of 17.5, 7.7, and 1.69 µg/liter, respectively. The conversion factor was 1 µg/liter = 2.5 mU/liter.

Serum cortisol was measured using a fluoroimmunoassay (AutoDELFIA, Perkin-Elmer, Turku, Finland) with an intraassay CV of 3.6, 2.7, and 3% and an interassay CV of 1.6, 1.1, and 1.5% at serum cortisol concentrations of 210, 517, and 781 nmol/liter, respectively.

Serum IGF-I was measured using HCl-ethanol extraction RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). Serum testosterone, LH, FSH, FT4, TSH, prolactin, and estradiol were measured using fluoroimmunoassay, AutoDELFIA (Perkin-Elmer, Turku, Finland). Normal reference ranges were as follows: testosterone, male = 10.3–34.5 nmol/liter (300–1000 ng/dl); estradiol more than 100 pmol/liter (27.2 ng/liter), FT4 = 8–21 pmol/liter (0.62–1.62 ng/dl); TSH = 0.5–4.2 mIU/liter; prolactin, males = 83–414 mIU/liter (2.3–11.5 ng/ml) and females = 90–523 mIU/liter (2.5–14.6 ng/ml). Plasma ACTH was measured using a two-site IRMA (CIS Bio International, Paris, France). Plasma glucose was measured using the hexokinase method.

All GH and cortisol samples from any single individual were assayed in the same batch.

Statistical analysis

Continuous data (age, BMI, IGF-I, basal cortisol) were assessed for normality based on skewedness and kurtosis and also assessed for equality of variances between groups. As a result of these tests, the data were log transformed before testing for significance using a two-sample t test. However, for descriptive purposes, data are expressed as untransformed mean ± SD. Variables that used a scoring system (GCS and AGHDA scores) were analyzed using a Wilcoxon rank-sum test for nonparametric measurements, and categorical data were compared using the Fisher exact test. Multifactorial logistic regression models were developed to assess the effect of appropriate variables in the presence of other confounding variables in the development of pituitary hormone abnormalities. The dependent variables for the models were GH, ACTH, and gonadotropin deficiencies; the independent variables were age, gender, BMI, GCS score, CT scan appearance, cerebral edema, operative mass evacuation, and other anterior pituitary hormone abnormalities. Significance of results were determined according to a two-tailed alternative hypothesis, and results were deemed significant for P < 0.05. All of the analyses were performed using the statistical software package STATA (version 8, STATA Corp., College Station, TX). Serum IGF-I SD scores (SDSs) were calculated according to the formula: IGF-I SDS = In (IGF-I) – [5.9 – (0.0146 x age in years)]/0.272.

Ethics

The study was approved by the ethics section of Beaumont Hospital Medical Research Committee. The purpose of the study was explained carefully to patients and relatives, who were provided with written information on the background to the study. After an interval of 1 wk, patients who agreed to participate signed written consent for inclusion in the study; written consent was given by next of kin, where appropriate.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Fifty-seven patients (55.9%) had recovered well after TBI (GOS score = 5), 33 patients (32.3%) had moderate disability (GOS score = 4), and 12 patients (11.8%) had severe disability (GOS score = 3). Completed studies were performed in all patients. No serious adverse reactions to any of the tests were observed.

GH-IGF-I axis

Eighteen patients (17.6%) had a GH response to glucagon less than 5 µg/liter, including 13 (12.7%) with a response less than 3 µg/liter; the results are summarized in Table 1. Fourteen of the 18 patients had the ITT, all achieving adequate hypoglycemia (nadir glucose <2.2 mmol/liter); nine had a GH response less than 5 µg/liter, including six with a response less than 3 µg/liter (Table 1 and Fig. 1). Four patients had the arginine + GHRH test, two of whom had a GH response less than 9 µg/liter (Table 1 and Fig. 1). Defining GH deficiency as failing two different stimulation tests, 11 patients (10.7%) had GH deficiency including eight (7.8%) with severe deficiency.

View larger version (24K): [in this window] [in a new window]   FIG. 1. Dynamic screening and confirmatory testing for GH and ACTH deficiencies in 102 patients with traumatic brain injury.

Twenty-three patients (22.5%) had a serum cortisol response to GST less than 450 nmol/liter (16 µg/dl). Of these, 15 patients had the ITT (all achieved nadir glucose <2.2 mmol/liter), with 10 achieving a peak serum cortisol less than 500 nmol/liter (18 µg/dl) (Table 3 and Fig. 1). Of the other eight patients who had the SST, three had a peak serum cortisol less than 500 nmol/liter (Table 3 and Fig. 1). None of the 23 patients who failed the GST had elevated basal plasma ACTH levels. Diagnosing ACTH deficiency by failure of two provocative tests, 13 patients (12.7%) were defined as ACTH deficient.

Twelve patients (11.8%, 10 males) had gonadotropin deficiency, which was associated with hyperprolactinemia in four patients (three males). Comparisons between gonadotropin-deficient and -sufficient patients are presented in Table 5. Multifactorial logistic regression analysis showed that gonadotropin deficiency to be associated with older age (P = 0.006) but was unrelated to hyperprolactinemia (P = 0.786), gender (P = 0.375), BMI (P = 0.728), GCS scores (P = 0.561), CT scan appearance (P = 0.064), cerebral edema (P = 0.896), or mass evacuation (P = 0.357).

View larger version (28K): [in this window] [in a new window]   FIG. 2. The frequency and pattern of different anterior pituitary hormone deficiency in 102 patients with severe or moderate TBI. GT, Gonadotropins

Overall results

Twenty-nine patients (28.4%) had at least one anterior pituitary hormone deficiency. Twenty-three patients (22.5%) had isolated hormone deficiencies and six (5.9%) has multiple hormone deficiencies. The breakdown pattern of the hormone deficiencies is shown in Fig. 2.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Our data show that in a large, unselected population of survivors of moderate or severe TBI who are studied well after the initial trauma, there is a significant prevalence of undiagnosed hypopituitarism. This is the largest study, to date, to examine anterior pituitary function in survivors of TBI, and, although we deliberately used stringent criteria for the identification of pituitary hypofunction, our data are broadly in agreement with earlier, smaller studies.

Because 29% of our patients had a documented history of seizure disorder, we used the GST (13, 14, 15, 16, 17, 18) for the initial assessment of somatotrophic and corticotrophic function. Normal serum GH and cortisol responses to the GST are not well defined; therefore, we defined these responses in our healthy controls. In patients who failed the GST, we used a second provocative test for GH and cortisol to make our data more reliable because of potential false-positive cortisol responses to the GST and because of the need to define clinically significant GH deficiency. We used the ITT, which is highly reliable and has well-established cut-off values for both GH (20, 24) and cortisol (33, 34) responses. Where the ITT was contraindicated, we used the arginine + GHRH (24, 25) as an alternative for assessing GH secretion, as suggested by the Growth Hormone Research Society (24), and the SST (27, 28, 29) for the assessment of adrenal function. We took a conservative approach to define GH and ACTH deficiency by requiring the patient to fail both provocation tests.

GH deficiency was common, with 10.7% of patients failing both provocative tests; 8.8% had severe GH deficiency. Seven of the 18 patients who failed the GST passed either the ITT or arginine + GHRH, showing some discordance between these provocative tests of GH secretion. There have been very few studies comparing the ITT to the GST, and the results are conflicting (13, 22, 37). No study, in adults, has compared the GST with the arginine + GHRH test. In our laboratory we define normal GH response to ITT using the conservative cut-off as 5 µg/liter, in common with other centers (20, 24), although some studies have shown higher values of GH response to ITT in normal subjects (37, 38). In our laboratory, we use the cut-off of 9 µg/liter to define severe GH deficiency by the arginine + GHRH test, as reported by Aimaretti et al. (25). We recognize that another well-conducted study identified a cut-off of 4.1 µg/liter as appropriate for defining GH deficiency using the arginine + GHRH test. However, the last study used an immunochemiluminometric assay for GH measurements, whereas in this study and that reported by Aimaretti et al., the same IRMA was used. Even if we had used the lower cut-off of 4.1 µg/liter, only one patient would be reclassified as having normal GH reserve.

The prevalence of GHD in our series is slightly lower than that reported by Kelly et al. (7), who studied a smaller cohort of 22 patients with moderate or severe TBI, using the ITT. Four patients (18%) had subnormal GH responses, but it was not reported how many had clinically significant deficiency (peak response <3 µg/liter). In addition, all four patients had sustained a hypotensive or a hypoxic insult at the time of TBI, which may have contributed to the development of somatotrophic dysfunction. The higher prevalence of GH deficiency in this study may also reflect the smaller cohort studied, but equally we used very conservative diagnostic criteria by requiring patients to fail two dynamic tests of GH secretion.

Our results are more comparable with those of Lieberman et al. (8), who performed glucagon stimulation on 48 TBI patients recruited from a transition learning community. Seven patients (14%) had a GH response to GST of less than 3 µg/liter. Five of the seven subjects also had the L-dopa test and had subnormal responses. Unfortunately, the L-dopa test is not reliable for the diagnosis of adult GH deficiency; in one study, the majority of healthy control subjects (68%) had a response less than 3 µg/liter (39).

In contrast, Bondanelli et al. (40) studied a small cohort of 16 TBI patients using three different stimuli for GH release: GHRH, arginine + GHRH, and somatostatin infusion withdrawal. Overall, GH response was not significantly different between the TBI group and healthy controls with any stimulus. However, the authors did not report whether individual TBI patients had subnormal GH responses, which may have been masked by analyzing the groups as a whole.

The TBI patients in this study who had subnormal GH responses to the GST did show biochemical and somatic features of GHD, in that they also had lower serum IGF-I levels and higher BMI than those with normal GH responses. Elevation of BMI is a recognized feature of GH deficiency (41). Indeed, the mean BMI in our GH-deficient group was similar to that reported for a large cohort of GH-deficient patients (42). Although obesity, particularly marked obesity, is associated with blunted GH secretion in response to provocative stimuli (22), serum IGF-I concentrations remain normal (43). Four of the subjects we identified as GH deficient had grade 1 obesity (BMI 30–35 kg/m²). However, all four had severe impairment of GH response to two different provocative tests and had serum IGF-I values below, or near the lower limit of, the normal range; two of them also had ACTH deficiency. All of these features are in keeping with genuine GH deficiency, rather than attenuated GH responses due to obesity.

There was no difference in the AGHDA scores between GH-deficient and -sufficient subjects, which is likely to reflect other influences on QoL scores, such as severity of head injury, stage of rehabilitation, and the presence of other hormone defects.

As with GHD, we were fairly conservative in our definition of ACTH deficiency, requiring patients to fail both the GST and one other provocative test. Because the normal cortisol response to the GST has not previously been well established, we studied a cohort of normal subjects, such that we defined our own local normal cortisol response to GST as that exceeding 450 nmol/liter (16 µg/dl). Most U.K. endocrinologists will regard a normal serum cortisol response to the ITT or SST as a peak of 500 nmol/liter (18 µg/dl) or more (34), which justifies our use of this cut-off to define normal response to these stimuli.

Only four of the 13 ACTH-deficient patients had morning serum cortisol less than 200 nmol/liter (7 µg/dl), indicating that the majority had partial ACTH deficiency. The practical clinical significance of this finding is debatable. We have recently shown (44) that, under unstressed conditions, hypopituitary patients with partial ACTH deficiency have a cortisol day profile similar to that of healthy controls. We have suggested that lower than conventional doses of glucocorticoid or even no glucocorticoid treatment may be justified under unstressed conditions. However, under stressed conditions, such as intercurrent illness, mild untreated ACTH deficiency may become life threatening. Therefore, it is important that patients with any degree of posttraumatic adrenal insufficiency are identified so that appropriate management can be offered during intercurrent illness, when partial glucocorticoid deficiency may become clinically significant.

Our data contrast with the results of Lieberman et al. (8), who reported that 45.7% of TBI patients tested had a morning cortisol of less than 7 µg/dl (193 nmol/liter), although only 7.1% failed the SST. Our results also contrast with those of Kelly et al. (7), who found only one patient with blunted cortisol response to hypoglycemia, although in this last study, the 95% confidence limit for the area under the curve for cortisol responses was used to define normality, rather than the more conventional peak cortisol response. We would defend our data on the basis of the larger size of our cohort, the use of two separate dynamic tests of glucocorticoid secretion, and our rigorous definition for ACTH deficiency.

The discordance between the GST and ITT results in five of the 15 patients who failed the GST can be explained by the well-recognized false-fail results associated with the GST. The 10 patients who failed both the GST and ITT were clearly ACTH deficient. However, it is not possible to be certain that the five patients who failed the GST but passed the SST have intact corticotrophic function because of well-reported false-pass results with the latter test (45, 46, 47, 48). It has been suggested that raising the cut-off for the diagnosis of ACTH deficiency, by the SST, from 500 to 600 nmol/liter increases the sensitivity of the test to 90% (28), in which case seven of the eight patients will have failed both the GST and SST. Using these criteria would have identified 16.6% of our cohort as being ACTH deficient. It is important to acknowledge that most patients with pituitary disease who pass the standard 250-µg SST do well without glucocorticoid replacement (29).

Four of the 12 patients with gonadotropin deficiency had hyperprolactinemia, which may have been responsible for this abnormality. However, the relationship between hyperprolactinemia and gonadotropin deficiency was not statistically significant. We did not use the GnRH test for the assessment of gonadotrophic function because this test lacks both sensitivity and specificity and rarely adds any helpful additional information (35, 36). Patients with gonadotropin deficiency were more likely to be older, although their ages ranged from 18 to 64 yr. It is well recognized that serum testosterone levels decline with age (49). Separating the effect of age from the effect of TBI is not possible from this study. Kelly et al. (7) assessed gonadal function using the GnRH test, and found a higher rate of subnormal responses, in four of 18 men, and one of four females. All the males, however, had normal testosterone levels, but the female patient had a low estradiol level and menstrual irregularity. In contrast, Lieberman et al. (8) found no evidence of secondary hypogonadism among male patients and only one female patient with possible pituitary hypogonadism, which may have been the result of coexisting hyperprolactinemia.

TSH deficiency was uncommon in this study. The frequency of TSH deficiency with relation to other anterior pituitary hormone abnormalities, in pituitary disorders, is variable (50, 51). Because the thyrotrophs are located more medially within the adenohypophysis in the protected territory of the short hypophyseal vessels (7, 52), they may be less susceptible to traumatic injury than the rest of the anterior lobe, which receives its blood supply predominantly from the more vulnerable long hypophyseal vessels (7). Our results are comparable with those of Kelly et al. (7), who found only one patient (4.5%) with low T₄ and TSH levels, who also showed a blunted response to TRH stimulation. In contrast, Lieberman et al. (8) found 11.6% of patients to have low free FT4 without elevated thyrotropin levels, suggesting TSH deficiency.

Hyperprolactinemia occurred in 12% of our patients. Hypothalamic and pituitary stalk lesions have been reported at autopsy in patients who died after TBI (6), and lesions in either area could be responsible for the significant proportion of patients with hyperprolactinemia. We found similar rates of hyperprolactinemia to those reported by Lieberman et al. (8), who found 10% of patients to have hyperprolactinemia, although their figures did include patients taking medications known stimulate prolactin secretion.

We did not observe an association between the presence of hormone abnormalities and the severity of the head injury, as measured by the either the GCS score or CT scan appearance. Although the data from Lieberman et al. (8) seem to suggest no association between the GCS score and posttraumatic hypopituitarism, the GCS scores were available for only some of the patients, and the authors cautioned that the small numbers preclude valid statistical comparisons. In the smaller study of Kelly et al. (7), all four patients with GH deficiency had CT appearances of diffuse brain swelling, although all four had either hypotensive or hypoxic insults, which could have caused these radiological abnormalities. An association between the severity of TBI and pituitary dysfunction cannot be completely ruled out because patients with more severe TBI may have died early after the event or may been left with severe disabilities that precluded participation in the study. Although our patient sample was representative of survivors of TBI admitted to our unit, only a small number of our patients had long-term severe disability.

Pituitary insufficiency may have serious consequences and may aggravate the physical and neuropsychiatric morbidity observed after head injury. Glucocorticoid deficiency can be life threatening, particularly in acutely ill patients, and may impair recovery and rehabilitation in the post-TBI period due to lethargy, muscle fatigue, and poor exercise capacity. GH deficiency is associated with reduced lean body mass (53), decreased exercise capacity (54), impaired cardiac function (55), and reduction in bone mineral density (56), which may be of particular significance in immobilized patients, as well as sleep disturbances, social isolation, reduced physical mobility, and general well-being (57). In addition to these effects, which have direct consequences for post-TBI patients, GH deficiency has been associated with adverse metabolic changes that increase the risk of cardiovascular disease and possibly overall mortality (58). Testosterone deficiency in males leads to reduced lean body mass and reduced bone mineral density; estrogen deficiency in females predisposes them to premature osteoporosis. Deficiency in thyroid hormones leads to anergia, muscle weakness, and neuropsychiatric disorders. All these effects can have the potential to impair recovery and rehabilitation and may contribute to the significant morbidity associated with TBI.

We have confirmed in the largest series to date the gathering evidence that undiagnosed pituitary hormone dysfunction is common post TBI. Because hypopituitarism may impair recovery from TBI and because the benefit of replacement of hormone deficiencies is well established, identification of post-TBI hypopituitarism offers the potential to improve the chances of rehabilitation and enhance QoL. This study raises important questions, therefore, about the need for pituitary function assessment after TBI. Because assessment of GH and ACTH reserves requires provocative testing, a close liaison between the endocrine and neurosurgical services is needed. The optimal timing for such assessment remains unclear. We have reported a high frequency of pituitary hormone deficiency early on after TBI (59), but the natural history of posttraumatic hypopituitarism is largely unknown, and early hormone deficiencies may spontaneously recover, as is the case with post-TBI diabetes insipidus. Further studies are required to identify the optimum timing for pituitary assessment and treatment. The effect of GH replacement in posttraumatic GH deficiency needs to be examined in a randomized controlled study. Notwithstanding these important questions, there seems little doubt that traumatic brain injury is a common cause of undiagnosed hypopituitarism.

	Acknowledgments

 
The authors thank Professor Dermot Kenny and the staff of the RCSI Clinical Research Centre, Dublin, Ireland, where part of this study was conducted. The authors are indebted to Sister Siobhan Leydon and her staff for their assistance with the study.

	Footnotes

 
This work was supported by an unrestricted educational grant, obtained in open competition, from Pfizer International Research Grants.

Abbreviations: AGHDA, Assessment of GH deficiency in adults; BMI, body mass index; CT, computerized tomography; CV, coefficient of variation; FT4, free T₄; GCS, Glasgow Coma Scale; GOS, Glasgow Outcome Scale; IRMA, immunoradiometric assay; ITT, insulin tolerance test; ITU, intensive care unit; QoL, quality of life; SDS, SD score; SST, short synacthen test; TBI, traumatic brain injury.

Received March 16, 2004.

Accepted July 8, 2004.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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