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Transition Learning Community (B.E.M.) and Departments of Internal Medicine (S.A.L., A.L.O., C.R.G., R.J.U.) and Neurology (B.E.M.), University of Texas Medical Branch, Galveston, Texas 77555
Address all correspondence and requests for reprints to: Steven A. Lieberman, M.D., 301 University Boulevard, MRB 8.138, Galveston, Texas 77555-1060. E-mail: steven.lieberman{at}utmb.edu
Abstract
Although hypopituitarism is a known complication of head injury, it may be underrecognized due to its subtle clinical manifestations. The nonspecific symptoms may be masked by and may contribute to the physical and psychological sequelae of brain trauma. This study examines the prevalence of neuroendocrine abnormalities in patients rehabilitating from traumatic brain injury.
Seventy adults (mean age, 31.5 ± 1.1 yr; range, 18–58; 46 men and 24 women) with traumatic brain injury an average of 49 ± 8 months before the study (median, 13 months) underwent a series of standard endocrine tests, including serum levels of TSH, free T4, insulin-like growth factor I, PRL, testosterone (males), and cosyntropin stimulation. Abnormal results of these tests were followed by dynamic tests of gonadotropin, TSH, and GH secretion.
Glucagon stimulation testing in 48 subjects revealed GH deficiency (peak, <3 µg/L) in 14.6%. Free T4 (n = 6; 8.6%), TSH (n = 7; 10%), or both (n = 2; 2.9%) were low in 21.7%, whereas 87% had both TSH and free T4 below the midnormal level. Basal morning cortisol was below normal in 45.7% of subjects, whereas cosyntropin-stimulated levels were insufficient (peak, <500 nmol/L) in 7.1%. Hypogonadism and hyperprolactinemia were uncommon.
In summary, pituitary hormone deficiencies were identified in a substantial proportion of patients with previous brain injury. GH deficiency, found in 15% by glucagon stimulation testing, may compound the physical and psychological complications of traumatic brain injury and interfere with rehabilitation.
TRAUMATIC BRAIN injury produces chronic disability through a variety of mechanisms. In addition to physical and cognitive sequelae, many patients suffer psychological dysfunction, social isolation, and a diminished sense of well-being (1). Recent studies of traumatic head injury patients in the chronic recovery phase from their injuries have indicated specific deficits in their general health, vitality, and mental health (2), with depression and anxiety being particularly common (3). These psychosocial consequences often become the major impediment to successful rehabilitation (3).
Head trauma has long been recognized as a cause of neuroendocrine dysfunction (4), with case reports documenting pituitary hormone deficiencies in a variety of combinations (5). Although diabetes insipidus is easily recognized in the acute postinjury phase, the loss of other pituitary hormones may present subtly, escaping detection for months or years (5, 6). The potential importance of such deficiencies is increased by the emergence of the syndrome of GH deficiency (GHD) in adults, which is characterized by decreases in strength, aerobic capacity, and sense of well-being (7, 8). Because the symptoms accompanying these changes are subtle and nonspecific, they may be overlooked or attributed to other causes.
There have been numerous case reports and two excellent reviews of clinically overt pituitary dysfunction following head injury (5, 6). However, the frequency of chronic neuroendocrine deficits among patients with traumatic brain injury has received little systematic study. We undertook the present study to determine the prevalence of GHD and other abnormalities of pituitary hormone secretion in patients with previous traumatic brain injury who were undergoing physical, cognitive, and vocational rehabilitation.
Subjects and Methods
Subjects
Subjects were recruited from the Transition Learning Community in Galveston, TX, a community-based postacute residential rehabilitation facility for patients with a history of acquired brain injury. Patients admitted to this facility have mild to moderate cognitive dysfunction as a sequel of brain injury. Participation was solicited from all patients admitted to the Transition Learning Community without preselection. Seventy of the 87 subjects who provided informed consent and participated in the study had traumatic brain injury and are the subject of this report. The date of head injury and the Glasgow Coma Scale (GCS) score at the time of presentation with injury were recorded when available. The GCS represents a summary of the patient’s level of consciousness as indicated by scores on eye opening (1, 2, 3, 4), motor responses (1, 2, 3, 4, 5), and verbal responses (1, 2, 3, 4, 5, 6). Severity of injury is indicated by the total score: 3–8 = severe, 9–13 = moderate, and 14–15 = mild (9). The study was conducted at the General Clinical Research Center at University of Texas Medical Branch. Informed consent was obtained from the subjects.
Studies
Subjects initially underwent a series of routine endocrine tests to screen for pituitary dysfunction. The following were measured in all subjects: TSH, free T4 (FT4), PRL, and insulin-like growth factor I (IGF-I), and a short corticotropin (ACTH) stimulation test was performed (0.25 mg cosyntropin, iv, with serum cortisol measurements at 0 and 45 min). Serum total testosterone was measured in all male subjects, and a menstrual history was taken in all female subjects. Those with abnormalities in these tests underwent additional dynamic testing with GnRH stimulation (0.1 mg, iv, with measurement of LH at 0, 15, 30, 60, and 90 min) and TRH stimulation (0.5 mg, iv, with measurement of TSH at 0, 15, 30, 60, and 90 min).
Assessment of the somatotropic axis evolved during the study. IGF-I levels were measured in all subjects, and glucagon stimulation testing (1 mg, im, with measurement of GH at 0, 90, 120, 150, and 180 min) was performed in 48 subjects. Among those undergoing glucagon stimulation, additional GH stimulation with L-dopa was performed in 20 subjects (L-dopa, 500 mg, orally, with measurement of GH at 0, 30, 60, 90, and 120 min). A GH response less than 3 µg/L was considered abnormal as defined by the Growth Hormone Research Society (10). Subjects meeting the U.S. FDA criterion of less than 2.5 µg/L are also reported.
Assays
GH was measured by immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). IGF-I was measured by RIA after acid-ethanol extraction (ARUP Laboratory, Salt Lake City, UT). Free T4 (reference range, 9.7–23.8 pmol/L), TSH (reference range, 0.49–4.7 mIU/L), and LH (male basal reference range, 2–12 IU/L) were measured by microparticle enzyme immunoassay (AxSYM System, Abbott Laboratories, Chicago, IL). Cortisol (morning reference range, 193–690 nmol/L) and PRL (reference ranges: men, 0.12–0.66 nmol/L; women, 0.12–0.79 nmol/L) were measured by magnetic separation assays (Tecnicon Immuno 1 system, Bayer Corp., Tarrytown, NY). Total testosterone (male reference range, 9.7–30.5 nmol/L) was measured by RIA (Diagostics Systems Laboratories, Inc., Webster, TX).
Data analysis
For the following analyses, the standard reference ranges were used to discriminate abnormal from normal results: TSH, FT4, basal cortisol, PRL, and testosterone. Age- and gender-specific normal ranges were used for interpreting IGF-I levels. Menses within the past 42 days were considered normal. The following normal responses were employed to interpret stimulation tests: short ACTH stimulation test, stimulated cortisol 500 nmol/L or more (18 µg/dL); GH stimulation, peak GH value 3 µg/L or more; TRH stimulation, increase in TSH of 5–30 mU/L with peak TSH occurring within 60 min; GnRH stimulation (male), peak LH more than 12 IU/L and increase in LH more than 7 IU/L; and GnRH stimulation (female), peak LH more than 10 IU/L and increase in LH more than 5 IU/L.
Results
Study population
Of the 87 subjects studied, 70 (80.5%) had traumatic brain injury, whereas the remaining subjects suffered brain injury due to vascular disorders (n = 11; 12.6%), surgical complications (n = 4; 4.6%), or infection (n = 2; 2.3%). The traumatic brain injury subjects ranged from 18–58 yr of age (mean ± SEM, 31.5 ± 1.1; median, 32) and included 46 men (65.7%). Time from head trauma to study ranged from 1 month to 23 yr (mean ± SEM, 49 ± 8 months; median, 13 months), with a natural partition into 3 groups: 1–15 months (n = 37), 20–55 months (n = 18), and 97–277 months (n = 15). The mean age at the time of injury was 27.7 ± 1.2 yr. GCS scores at the time of brain injury were known for 38 subjects; 32 of these were 8 or lower, indicating severe brain injury. Before their injuries, 1 male subject had primary hypogonadism, and 1 female had a history of primary hypothyroidism. Data from the affected axes in these subjects were excluded from analysis.
Somatotropic axis
Of the 48 subjects who underwent glucagon stimulation testing, 7 (14.6%) were GH deficient (GHD) as defined by the Growth Hormone Research Society (10), i.e. a maximum GH value less than 3 µg/L. Five subjects (7.1%) met the FDA criterion of 2.5 µg/L; of note, both subjects with maximum GH responses between 2.5–3.0 µg/L had subnormal GH responses to L-dopa (peak GH, 1.47 and 1.49 µg/L) and low IGF-I levels, supporting the diagnosis of GHD in these 2 subjects. Of the 7 GHD subjects, L-dopa stimulation was performed in 5 and produced maximum GH levels less than 1.5 µg/L in all 5, confirming GHD. L-dopa produced peak GH levels less than 3 µg/L in 5 additional subjects who were normal by glucagon testing. Only 1 of these had a low IGF-I level. Overall, glucagon and L-dopa testing concurred in 15 of the 20 subjects given both tests (75%), with glucagon demonstrating a more potent stimulatory effect on GH secretion. The proportions of abnormal results on each test of the somatotropic axis were: glucagon stimulation, 7 of 48 (14.6%); L-dopa stimulation, 10 of 20 (50%); and IGF-I concentration, 9 of 48 (18.8%). We have chosen to interpret these results conservatively by requiring a subnormal response after the most potent stimulus (glucagon) to diagnose a patient with GHD. In all 7 of these subjects, GHD was corroborated by an abnormality on at least 1 of the other 2 tests.
Comparison of GHD subjects with non-GHD (i.e. GH-sufficient)
subjects is presented in Table 1
. IGF-I
levels were significantly lower in GHD compared with non-GHD subjects
and were below the normal range in 4 of 7 (57.1%) GHD subjects and 5
of 41 (12.2%) non-GHD subjects (P = 0.017, by
Fisher’s exact test). Overall, peak GH correlated with IGF-I levels
(r = 0.411; P = 0.004). GHD subjects had a higher
body mass index (BMI) than non-GHD subjects, although differences in
height and weight were not statistically significant (Table 1). The
peak GH level after glucagon showed no correlation with BMI, age,
height, weight, GCS, or time from injury.
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Free T4 and TSH levels were both below the
lower limit of normal in 2 of 69 subjects (2.9%). Additionally, 6
subjects (8.7%) had low FT4 with normal TSH, and
7 (10.1%) had normal FT4 with low TSH. Thus, 15
of 69 subjects (21.7%) had at least 1 abnormality in routine thyroid
function testing. As shown in Fig. 1, there was a global downward shift of both FT4 and
TSH levels compared with the normal range. Overall, 60 of the 69
subjects (87.0%) fell below the midnormal value for both TSH and
FT4 (P < 0.001, by
2 analysis). Of the 27 subjects who underwent
TRH stimulation testing, the increase in TSH was below normal (<5
mIU/L) in 4 (14.8%). In no case was the increase in TSH above normal
(>30 mIU/L) or the time of peak TSH response delayed (>60 min). Of
the 15 patients with frankly low FT4 and/or TSH,
6 underwent TRH testing, and 3 of these had subnormal TSH
increments.
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Basal morning cortisol levels were below the lower limit of normal
(<193 nmol/L; <7 µg/dL) in 32 of 70 subjects (45.7%). After ACTH
administration, 5 subjects (7.1%) had cortisol levels below 500 nmol/L
(18 µg/dL; range, 403–466 nmol/L, 14.6–16.9 µg/dL), and 6
subjects (8.6%) had levels between 500–550 nmol/L (18–20 µg/dL).
There was no correlation between time after injury and either basal or
stimulated cortisol levels for the group as a whole (basal: r =
0.117; P = 0.334; stimulated: r = 0.03;
P = 0.831) or for the subjects within 1.5 yr of their
injury (basal: r = 0.05; P = 0.76; stimulated:
r = 0.14; P = 0.43). As shown in Table 2, there was no difference in basal or
stimulated cortisol levels for subjects studied in the 3 time intervals
from injury.
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One man had an antecedent history of testicular failure. None of the remaining 45 men had either total or free testosterone below the normal range. PRL was mildly elevated in 6 male subjects (range, 600-2600 pmol/L, 14–60 µg/L; normal range, <565 pmol/L, <13 µg/L). Five of these were taking medications known to elevate PRL (e.g. selective serotonin reuptake inhibitors), and the other had a minimal elevation (678 pmol/L, 15.6 µg/L). All hyperprolactinemic men had normal testosterone concentrations (range, 12.9–30.2 nmol/L, 371–872 µg/L; normal range, 9.7–30.5 nmol/L, 280–880 µg/L); only 1 of these had a subnormal GnRH stimulation test.
Among the 24 female subjects, 2 had previously undergone hysterectomy. The time of the last menstrual period was known for 15 of the remaining 22; 13 had had menses in the preceding 30 days, and 1 each had menses at 37 and 92 days before the study. The latter subject was taking fluoxetine and was the only woman with hyperprolactinemia (1257 pmol/L, 28.9 µg/L; normal range, <1160 pmol/L, <26.7 µg/L).
Combined abnormalities
Overall, 22 subjects (31.4%) had no abnormalities, 36 subjects (51.4%) had a single abnormal axis (26 adrenal, 8 thyroid, and 2 GH), and 12 subjects (17.1%) had dual abnormalities (5 adrenal and thyroid, 4 adrenal and GH, 1 GH and thyroid, 1 gonadal and thyroid, and 1 adrenal and PRL). No subject was treated with desmopressin or had symptomatic polyuria. Although small numbers precluded statistical comparisons, a GCS score of 8 or less was not related to the number of abnormal pituitary axes (data not shown).
Discussion
This study found a high prevalence of neuroendocrine dysfunction in patients with a history of traumatic brain injury. The frequencies of GHD (15%) and low morning cortisol levels (46%) are striking and may have important implications for patients’ health, sense of well-being, and rehabilitation potential.
Nearly one in six subjects was found to have GHD. Although insulin-induced hypoglycemia is the preferred method for diagnosing GHD in adults (10), it is contraindicated in the setting of severe brain injury. In its place, we employed glucagon and L-dopa stimulation tests and strict criteria to avoid overestimating the prevalence of GHD in this population. The criterion of 3 µg/L for diagnosing GHD conforms to the recommendations of the Growth Hormone Research Society for the insulin tolerance test (10) and provides a specificity of more than 96% based on previous studies (11, 12). Five of the seven subjects we found to have GHD by glucagon testing underwent additional testing with L-dopa, and all five failed to respond normally, confirming GHD. Although five additional subjects with normal glucagon tests had insufficient responses to L-dopa, we conservatively interpret these five as false positive tests, yielding a GHD prevalence of 14.6% in our subjects. The subjects with GHD had lower IGF-I levels than those with normal GH responses. Because IGF-I reflects the overall secretion of GH, this difference corroborates the presence of GHD. However, as in other adult populations (13, 14), there was substantial overlap in IGF-I levels between subjects with and those without GHD. Thus, measurement of IGF-I is not able to accurately identify GHD in this population, and dynamic testing of GH secretion is required.
Differences in height and weight between subjects with GHD than those with normal GH responses were not statistically different, but the former had a significantly higher BMI than the latter. Although obesity is associated with diminished GH secretion (15, 16), it is also well recognized that both children and adults with GHD are more obese than those with normal GH secretion and that GH therapy reverses this abnormality (7, 8). In contrast, the impact of obesity on IGF-I levels has been variable in published studies (17). Thus, the interrelationship between GHD and obesity is complex (18). In the context of two abnormal stimulation tests, lower IGF-I levels in the GHD subjects, and the lack of correlation between maximum GH levels and BMI, it is likely that the greater BMI was the result of GHD during the time since traumatic brain injury, 30 months on the average.
In addition to alterations in body composition, GHD in adults is associated with decreases in strength, aerobic exercise capacity, bone mineral density, and sense of well-being (7). As reviewed by Carroll et al. (8), specific psychosocial changes include decreased energy, emotional lability, social isolation, and diminished quality of life. These effects of GHD may contribute to the psychosocial dysfunction that often follows brain injury. Several studies in GHD adults have shown improvement in psychological profiles with GH replacement, particularly with regard to energy and mood (8, 19), although not all studies show beneficial effects (20). Thus, the similarity in the psychological changes seen in patients with brain injury and patients with GHD as well as the decreased strength and exercise capacity accompanying GHD suggest potential etiological and/or therapeutic roles for GH following brain injury.
In 22% of subjects, TSH and/or FT4 values were below the normal range. In addition, there was a global downward shift of both TSH and FT4 levels, suggesting partial central hypothyroidism. The TSH response to TRH stimulation was subnormal in 15%, whereas no subjects had delayed or exaggerated responses. These findings are consistent with loss or inhibition of TSH secretion from the pituitary. Because somatostatin is known to suppress TRH-stimulated TSH secretion (21) as well as GH secretion, it may be speculated that increased hypothalamic secretion of somatostatin accounts for the abnormalities in both of these axes. Several small studies have suggested that cognitive dysfunction in patients with head injuries may result from acetylcholine deficiency (22, 23, 24). Cholinergic agonists that stimulate GH secretion (e.g. pyridostigmine) are believed to act via inhibition of somatostatin secretion (25). It is conceivable then that a loss of cholinergic neurons secondary to head injury might disinhibit hypothalamic somatostatin secretion, resulting in suppression of GH and TSH secretion.
We employed conservative diagnostic criteria for adrenal insufficiency (stimulated cortisol, <500 nmol/L, <18 µg/dL) and found a prevalence of 7%. The stimulated cortisol level ranged from 403–466 nmol/L (14.6–16.9 µg/dL) in these five patients, indicating a mildly deficient response. No subjects had overt manifestations of adrenal insufficiency. Although some subjects may have received glucocorticoids during the acute treatment for brain injury, the lack of correlation between the interval from injury and basal or stimulated cortisol levels rules out residual hypothalamic-pituitary-adrenal axis suppression as an explanation for low cortisol levels. The frequency of low basal cortisol levels (46%) is striking and requires further study; it remains to be seen whether this finding carries clinical significance.
Notable by their absence in these subjects were hypogonadism and diabetes insipidus. After GH, gonadotropin secretion is traditionally held to be the most susceptible to all varieties of pituitary damage and was reported in 5 of 21 subjects (23.8%) studied 3–6 months after major head injury (26). In their reviews of case reports of posttraumatic hypopituitarism, Edwards and Clark (5) and Benvenga et al. (6) reported hypogonadism in 95% and nearly 100% of cases, and diabetes insipidus in 26% and 31% of cases, respectively. In addition, these reviews disclosed the presence of hypothyroidism in 88% and approximately 90%, adrenal insufficiency in 92% and approximately 58%, hyperprolactinemia in 70% and approximately 45%, and GHD in 100% and approximately 23%. The discrepancies in the 2 reviews are best explained by the numbers of cases included: 53 (5) vs. 367 (6). Compared with the latter, the current study found lower rates of all pituitary abnormalities. These differences reflect the obvious difference in the population studied in the case reviews (patients with overt hypopituitarism resulting from head trauma) and the current study (patients with head trauma who may or may not have hypopituitarism). Moreover, one third of the cases reviewed by Edwards and Clark had no neurological sequelae to their injuries.
Most patients (71%) reported by Benvenga et al. (6) were diagnosed with hypopituitarism within 1 yr of injury. However, both reviews indicate a substantial number of patients diagnosed many years after injury. As pointed out, the symptoms of hypopituitarism may erroneously be "ascribed to the postconcussional syndrome and are often ignored for many years" (5). The delay in diagnosis of these patients occurred despite the fact that they suffered fully developed hormone deficiencies with overt clinical manifestations. GHD or partial deficiency of other pituitary hormones as found in the present study is typically less obvious, and recognition of these deficiencies may be obscured more easily by the physical, cognitive, and psychosocial sequelae of traumatic brain injury.
The morbidity of acquired brain injury in enormous. More than 80,000 Americans are severely disabled from traumatic brain injuries every year (27). Despite advances in their acute management and rehabilitation, patients are often left with physical and/or mental impairment and a diminished quality of life. This study has found a high prevalence of neuroendocrine abnormalities in patients with traumatic brain injury undergoing rehabilitation months to years after injury. As in patients with other causes of hypopituitarism, these abnormalities may contribute to a diminished quality of life. These findings strongly suggest that patients who suffer head trauma should be tested routinely for deficiency of GH and other pituitary hormones.
Footnotes
1 This work was supported by grants from the Moody Endowment and
grants from the NIH National Center for Research Resources General
Clinical Research Center program (M01-RR-00073). 
Received July 18, 2000.
Revised December 28, 2000.
Revised February 1, 2001.
Accepted February 12, 2001.
References
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