Aerobic capacity and growth hormone deficiency after traumatic brain injury

CONTEXT: GH deficiency occurs in approximately 20% of all individuals who suffer from a moderate to severe traumatic brain injury. OBJECTIVE: This study determined whether GH deficiency secondary to traumatic brain injury had an effect on aerobic capacity. DESIGN: Subjects were screened for GH deficiency by the glucagon stimulation test and performed a maximal treadmill exercise test. SETTING: Patients were studied in the postacute recovery phase after traumatic brain injury. PARTICIPANTS: Thirty-five individuals were studied. Groups were formed as follows: normal GH axis, greater than 8 ng/ml response (n = 12); insufficient, GH 3-8 ng/ml response (n = 11); and deficient, less than 3 ng/ml response (n = 12). INTERVENTION: There was no intervention. MAIN OUTCOME MEASURE: Aerobic capacity was assessed by measuring expired gases during a graded treadmill exercise test. One-way and two-way ANOVAs were carried out on all peak and submaximal cardiorespiratory variables, respectively. Appropriate post hoc comparisons followed as necessary. RESULTS: Significantly higher peak oxygen consumption was found in traumatic brain injury subjects with GH normal vs. GH insufficient and deficient [26.4 +/- 6.9, 20.8 +/- 4.6, and 19.7 +/- 5.0, respectively (P < 0.05)]. Submaximal oxygen consumption was significantly higher in the GH normal group. All other variables were statistically similar. CONCLUSIONS: This study shows that individuals with traumatic brain injury with normal GH secretion have below normal aerobic capacity and those patients who have GH insufficiency/deficiency are further deconditioned. Studies of GH replacement in these subjects should be conducted to assess whether GH therapy can improve cardiorespiratory fitness and prevent secondary disability.     

Carotid artery intima-media thickness and lipid profile in adults with growth hormone deficiency after long-term growth hormone replacement

To investigate the effects of growth hormone (GH) replacement on carotid artery intima-media thickness (IMT) and lipid profile, 29 adults with GH deficiency (GHD), mean age 42.5 ± 10.1 years, were studied and compared with 29 control subjects matched for sex, age, body mass index, and smoking habits. Lipid profile (total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, apolipoproteins A and B, and lipoprotein), serum insulin-like growth factor 1 (IGF-1) levels, and ultrasonography of the carotid arteries were performed at baseline and at 6, 12, and 24 months during GH therapy on maintenance dose. At baseline, when compared with the control group, patients presented increased carotid artery IMT (P < .05) and triglyceride levels (P < .001) and lower HDL concentrations (P < .01). In a linear regression analysis, age and known mean duration of GHD were correlated with carotid artery IMT. After 24 months of GH replacement, a reduction in the mean of carotid artery IMT was observed (P < .01). The apolipoprotein B levels decreased significantly after the first 3 months of GH treatment (P < .001) and remained stable thereafter. Women also presented an increase in HDL cholesterol levels (P < .01). No differences were observed in the other lipids measured. Carotid artery IMT at baseline was inversely correlated with the change in carotid artery IMT (Δ = 24 months − baseline), r = 0.63, P < .001. In conclusion, 24 months of GH replacement therapy promoted favorable effects on carotid artery IMT and lipid profile in patients with GHD. Long-term follow-up studies are required to show whether these beneficial effects will result in reduction of morbidity and mortality from vascular disease.     

Pituitary imaging abnormalities in patients with and without hypopituitarism after traumatic brain injury

Recent evidence suggests that patients with traumatic brain injury (TBI) are at substantial risk of hypopituitarism. The pathomechanisms, however, are not completely understood yet. Little is known about the association of morphological changes in the sella region with pituitary function in TBI. In this study, we assessed morphological abnormalities of the sella region in patients with TBI and their relation to endocrine function. We studied magnetic resonance (MR) or computed tomography (CT) scans of 22 patients with TBI [17 men, 5 women, age (mean+/-SD) 43.5+/-10.6 yr, time after trauma 17.4 +/-15.0 yr]. Of these, 15 patients had some degree of hypopituitarism. We found abnormalities of the sella region in 80% of the patients with hypopituitarism and 29% of those without hypopituitarism (Fisher's exact test, p=0.032). The most common abnormality was loss of volume or empty sella, followed by native signal inhomogeneities, perfusion deficit, and lack of neurohypophyseal signal. Our results indicate that pituitary imaging abnormalities are more common in TBI patients with hypopituitarism than those without. Both immediate trauma-induced pathology as necrosis and hemorrhage as well as multifactorial mid- to long-term changes may underlie these abnormalities.     

Measurement of oxidative stress and endothelial dysfunction in patients with hypopituitarism and severe deficiency adult growth hormone deficiency

Patients with adult GH deficiency (AGHD) have a high cardiovascular risk and probably an alteration of the oxidative balance, although evidence is lacking. To evaluate the presence of endothelial dysfunction and oxidative stress in patients with AGHD. Biochemical parameters of oxidative stress and endothelial dysfunction were compared in 25 patients with previously untreated AGHD and 25 healthy controls matched by age and sex. Multivariate analysis was performed to identify independent predictors of oxidative stress. Vascular function of subcutaneous resistance arteries was also analyzed by means of wire myography in 7 patients with untreated AGHD and in 7 healthy controls with similar characteristics. The values of C-reactive protein, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-??), were higher in the AGHD group (4.6 vs. 0.2???g/L, P?=?0.02; 5.6 vs. 1.2?pg/mL, P?=?0.001; 6.7 vs. 2.1?pg/mL, P?=?0.04; respectively). The levels of type-1 vascular cell adhesion molecule, total anti-oxidant state, oxidized LDL (LDL-ox) were also greater in AGHD patients (678 vs. 423?ng/mL, P?=?0.004; 1235.6 vs. 1002.3???mol/L, P?=?0.01; 172.2.5 vs. 42.3?ng/mL, P?=?0.02; respectively). Nitric oxide (NO), reduced glutathione (GSH) and reduced/oxidized glutathione ratio (GSH/GSSG) values were lower than controls (18.7 vs. 31.6?mmol/mg protein, P?=?0.01; 372.2 vs. 756.2???mol/L, P?=?0.03; 17.2 vs. 38.4, P?=?0.04; respectively). Multiple regression analysis showed that AGHD was an independent predictor of increased LDL-ox (P?=?0.002) and decreased GSH (P?=?0.000). Furthermore, the degree of vascular relaxation to repeated exposure of acetylcholine was lower in AGHD (P?=?0.025). Patients with AGHD have an increased degree of oxidative stress and endothelial dysfunction that could already be present in early stages of the disease. Studies with a greater number of patients are needed in order to confirm our findings.     

Isolated growth hormone deficiency after severe head trauma

In a 12-yr-old boy growth arrest occurred after severe head trauma. Evaluation of pituitary endocrine function revealed isolated growth hormone (GH) deficiency. Lack of GH response to GH-releasing factor indicated that the responsible lesion was most likely to be localized in the pituitary gland. GH substitution resulted in biochemical (somatomedin increase) and clinical (catch up growth) response.     

The prevalence of severe growth hormone deficiency in adults who received growth hormone replacement in childhood

OBJECTIVE The few previous studies in which reassessment of GH status has been carried out in young adults treated with GH therapy for childhood GH deficiency concentrated on determining the incidence of ‘transient GH deficiency’. As the benefits of GH replacement therapy in adults become increasingly appreciated, it is likely that GH therapy started in childhood for GH deficiency will be continued into adult life in many of those with severe GH deficiency. The aim of this study is to determine how many patients who received GH replacement therapy in childhood until completion of growth have GH deficiency severe enough to be considered for GH replacement therapy in adult life. DESIGN Retrospective analysis of the peak GH responses to provocative stimuli performed at the time of diagnosis of GH deficiency in childhood and at the completion of growth after GH replacement therapy had been stopped. PATIENTS Eighty-eight adults (49 male, 39 female) who had received GH therapy in childhood for a diagnosis of GH deficiency. The aetiology of the GH deficiency included craniopharyngioma, radiation induced associated with either a cerebral tumour or acute lymphoblastic leukaemia, histiocytosis-X and idiopathic. MEASUREMENTS In childhood the original diagnosis of GH deficiency was based biochemically on the failure of the peak GH response to reach 20 mU/l during two provocative tests in 59 of the 88 patients and to a single test in the remaining 29. A total of 147 tests were performed, the most common being an insulin tolerance test (ITT, n= 72) and an arginine stimulation test (AST, n= 53). At reassessment in young adult life 146 tests were performed (74 ITT, 64 AST). Severe GH deficiency was defined arbitrarily as a peak GH response of less than 9 mU/l to a single (n = 33) or to two (n = 55) pharmacological stimuli. RESULTS By definition all patients were considered GH deficient at the time of initial diagnosis. A peak GH response of less than 9 mU/l was seen in 64.8% at initial assessment and 60.2% at reassessment. Analysis in aetiological terms, however, showed that between assessments the incidence of severe GH deficiency increased in the group of radiation induced (48.8 vs. 55.8%) but decreased in the idiopathic group (78.1 vs. 53.1%). Out of the 55 patients who underwent two tests at reassessment, 47.3% of those with a GH peak less than 9 mU/l at one test had a GH peak greater than 9 mU/l at the second test. Fifteen of the 55 patients had additional pituitary hormone deficiencies and all 15 had a GH peak below 9 mU/l in both tests. CONCLUSIONS Our study suggests that all children who have received GH replacement therapy in childhood should undergo reassessment of GH status in young adult life. Between 40 and 60% of such patients merit consideration for GH therapy in adult life depending on the definition of severe GH deficiency in use. Patients with isolated GH deficiency should undergo two provocative tests of GH secretion, but those with additional anterior pituitary hormone deficiencies require only one test at reassessment.     

A neurosurgical approach to traumatic brain injury and post-traumatic hypopituitarism

Purpose

Traumatic brain injury (TBI) is a common cause of mortality and major disability worldwide. The initial management often depends on the severity of the injury. Pituitary dysfunction can develop as a sequela of TBI, and can have long-term, debilitating impact on the patients. Early identification and prompt intervention of post-traumatic hypopituitarism (PTHP) is essential to prevent or minimize the adverse consequences of this condition. We hereby provide an overview of the current management of TBI from a neurosurgical standpoint. We then review the pathophysiology and risk factors of developing PTHP, as well as our recommendations for its management.

Methods

A review of current literature on TBI and PTHP, including primary research articles, reviews and clinical guidelines.

Results

The current neurosurgical approach to the management of TBI is presented, followed by the pathophysiology and risk factors of PTHP, as well as our recommendations for its management.

Conclusions

Post-traumatic hypopitutiarism is a serious and potentially debilitating condition that is likely under-recognised and under-diagnosed. From a neurosurgical perspective, we advocate a pragmatic approach, i.e. screening those considered at high risk of developing PTHP based on clinical features and biochemical/endocrinological testings; and referring them to a specialist endocrinologist for further management as indicated.

     

Treatment of growth hormone deficiency in adults

In analogy with other hormonal replacement therapy GH treatment should be commenced with a low starting dose, independent of body weight or body surface area. Hormonal replacement should mimic the normal physiology to minimize the risk of side effects in the life-long replacement of adults. We should, therefore, consider individual responsiveness and also be aware of the difference between pattern of GH under normal condition and during s.c. administration. The safety and monitoring of GH replacement therapy in adults have been addressed in the Growth Hormone Research Society Consensus Guidelines for Diagnosis and Treatment of Adults with GH Deficiency from the Port Stephens Workshop, April 1997. Besides finding better and more accurate biochemical markers for choosing correct GH replacement dose, future research should address the long-term benefits and safety with GH replacement in adults, with special emphasize on incipient risks in terms of cardiovascular disease and of neoplasia, in particular.     

The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism

OBJECTIVE A number of studies of the effect of GH replacement therapy in adult patients with GH deficlency have been published, but the definition of GH deficiency has varied considerably. In order to define severe GH deficiency more critically we have determined GH status in the context of gonadotrophin, ACTH and TSH secretion in adult patients with pituitary disease. DESIGN Analysis of peak GH response to an insulin tolerance test performed during comprehensive assessment of pituitary function. PATIENTS One hundred and ninety non-acromegalic patients (96 male) with pituitary disease whose ages ranged from 16 to 72 (mean 39·4) years. MEASUREMENTS The patients were divided into four groups according to the number of anterior pituitary hormone deficiencies demonstrated; isolated GH deficiency (GHD0), or GH deficiency plus an additional one, two or three pituitary hormone deficits (GHD1, GHD2, GHD3). RESULTS The four groups were matched for age and blood glucose nadir during the ITT. The median (interquartile range) GH peaks were GHD0, 10·0 (5·4–16); GHD1, 4·0 (2·7–7·7); GHD2, 2·0 (1–2·9); GHDB, 1·8 (1–3·2) mU/l. There was a Significant downward trend in the medians (P < 0·0001). The differences between GHD0 and GHD1, and GHD1 and GHD2, were highly significant (P < 0·0001); however, there was no difference between GHD2 and GHD3. Ninety-one per cent of patients in combined groups GHD2 and GHD3, 55% in GHD1 and 24% in GHD0 had a peak GH < 5 mU/l. CONCLUSIONS Our study has shown that GH deficiency is variable according to the degree of hypopltuitarism present and that the greater the number of pituituary hormone deficits the more severe the GH deficiency. These observations will help to clarify the diagnosis of GH deficiency In adult life.     

Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury

OBJECTIVE: Cross-sectional studies report a high prevalence of hypopituitarism after traumatic brain injury (TBI); however, no longitudinal studies on time of manifestation and reversibility exist. This study was conducted to assess hypopituitarism 3 and 12 months after TBI. DESIGN: This was a prospective, longitudinal, diagnostic study. METHODS: Seventy-eight patients (52 men, 26 women, mean age 36.0 years) with TBI grades I-III and 38 healthy subjects (25 men, 13 women, mean age 36.4 years) as a control group for the GHRH + arginine test were studied. The prevalence of hypopituitarism was assessed 3 and 12 months after TBI by GHRH + arginine test, short adrenocorticotropic hormone (ACTH) test, and basal hormone measurements in patients. RESULTS: After 3 months, 56% of all patients had impairments of at least one pituitary axis with axes being affected as follows: gonadotropic 32%, corticotropic 19%, somatotropic 9% and thyrotropic 8%. After 12 months, fewer patients were affected, but in some cases new impairments occurred; 36% still had impairments. The axes were affected as follows after 12 months: gonadotropic 21%, somatotropic 10%, corticotropic 9% and thyrotropic 3%. CONCLUSIONS: Hypopituitarism occurs often in the post-acute phase after TBI and may normalize later, but may also develop after the post-acute phase of TBI.     

Biochemical and biophysical markers of endothelial dysfunction in adults with hypopituitarism and severe GH deficiency

Adult hypopituitarism is known to be associated with reduced life expectancy related to excess vascular events, and endothelial dysfunction is present in patients with this condition. We studied the relationship between biophysical and biochemical markers of endothelial dysfunction, including E-selectin, intercellular cell adhesion molecule-1, von Willebrand factor, and thrombomodulin in 52 adult patients with hypopituitarism and severe GH deficiency (<2 ng/ml on provocative testing) compared with 54 age-, sex-, and smoking-matched normal controls. We also examined endothelium-dependent dilatation of the brachial artery to postischemic occlusion and carotid artery morphology (intima-media thickness) by high-resolution ultrasonography. The patients were stable on conventional hormone replacement therapy but not on GH therapy, and none of the subjects had a known risk factor for vascular disease. Levels of E-selectin [57 +/- 3 vs. 49 +/- 2 ng/ml (mean +/- SEM)] (P < 0.043), intercellular cell adhesion molecule-1 (308 +/- 11 vs. 266 +/- 10 ng/ml) (P < 0.001), thrombomodulin (49 +/- 3 vs. 35 +/- 2 ng/ml) (P < 0.001), and von Willebrand factor (132 +/- 7% vs. 105 +/- 5%) (P < 0.004) were significantly higher in patients than in controls. Brachial artery endothelium-dependent dilatation was significantly lower in patients than in controls [4.7% (0.00-9.77) vs. 10.5% (6.4-16.2) (median, interquartile range)] (P < 0.001). This difference in endothelium-dependent dilatation was more marked in female patients than in controls (P < 0.003), although it disappeared when estrogen-sufficient female patients were compared with controls (P = 0.31). However, the female patients who were not replaced with estrogen continued to show a striking difference compared with estrogen-deficient control females (P < 0.004). There was no difference in carotid intima-media thickness between patients of either sex and controls. On univariate analysis, brachial artery endothelium-dependent dilatation correlated inversely with intercellular cell adhesion molecule-1 (r = -0.225, P < 0.033). Intercellular cell adhesion molecule-1 correlated positively with E-selectin (r = 0.466, P < 0.0001) and negatively with IGF-I (r = -0.238, P < 0.016). E-selectin correlated with thrombomodulin (r = 0.215, P < 0.034) and von Willebrand factor (r = 0.218, P < 0.03) and negatively with IGF-I (r = -0.255, P < 009). Thrombomodulin correlated positively with von Willebrand factor (r = 0.422, P < 0.0001) and inversely with IGF-I (r = -0.266, P < 0.008). These correlations persisted after correction for age, sex, body mass index, and waist to hip ratio, with the exception of IGF-I, which now correlated with thrombomodulin only. These results confirm significant endothelial dysfunction in hypopituitarism and provide insight into the relationship of biochemical and biophysical markers of early atherosclerosis in hypopituitary GH-deficient adults. The negative correlation of IGF-I with some biochemical markers of endothelial dysfunction and the predictive nature of GH deficiency in stepwise regression analysis in this study supports the hypothesis that GH deficiency may play a role in these abnormalities. Future studies will determine whether GH treatment can reverse these abnormalities. Furthermore, the more significant endothelium-dependent dilatation abnormality in the female estrogen-deficient subjects compared with those who were estrogen replete suggests that estrogen replacement in these patients is a crucial element in protecting against vascular disease.     

Hypopituitarism after traumatic brain injury

Traumatic brain injury (TBI) is one of the main causes of death and disability in young adults, with consequences ranging from physical disabilities to long-term cognitive, behavioural, psychological and social defects. Post-traumatic hypopituitarism (PTHP) was recognized more than 80 years ago, but it was thought to be a rare occurrence. Recently, clinical evidence has demonstrated that TBI may frequently cause hypothalamic-pituitary dysfunction, probably contributing to a delayed or hampered recovery from TBI. Changes in pituitary hormone secretion may be observed during the acute phase post-TBI, representing part of the acute adaptive response to the injury. Moreover, diminished pituitary hormone secretion, caused by damage to the pituitary and/or hypothalamus, may occur at any time after TBI. PTHP is observed in about 40% of patients with a history of TBI, presenting as an isolated deficiency in most cases, and more rarely as complete pituitary failure. The most common alterations appear to be gonadotropin and somatotropin deficiency, followed by corticotropin and thyrotropin deficiency. Hyper- or hypoprolactinemia may also be present. Diabetes insipidus may be frequent in the early, acute phase post-TBI, but it is rarely permanent. Severity of TBI seems to be an important risk factor for developing PTHP; however, PTHP can also manifest after mild TBI. Accurate evaluation and long-term follow-up of all TBI patients are necessary in order to detect the occurrence of PTHP, regardless of clinical evidence for pituitary dysfunction. In order to improve outcome and quality of life of TBI patients, an adequate replacement therapy is of paramount importance.     

Management of growth hormone deficiency in adults.

Growth hormone (GH) deficiency in adults is a recognised clinical entity. There is still, however, an ongoing debate of the clinical need and the importance of replacing GH in adults with severe GH deficiency. This review will focus on the overall management of adults with GH deficiency and highlight published data on dose management and treatment goals for various age groups. The efficacy data on quality of life and well-being is discussed and available and growing experience on long-term effects of GH replacement in adults and safety in terms of diabetes mellitus, pituitary tumour recurrence/regrowth and malignancy risk will be reviewed.     

Hypopituitarism following severe traumatic brain injury.

Although hypopituitarism is a known complication of traumatic head injury, it may be under-recognized due to its subtle clinical manifestations. To address this issue, we determine the prevalence of neuroendocrine abnormalities in patients rehabilitating from severe traumatic brain injury (Glasgow Coma Scale < or = 8). 76 patients (mean age 39 +/- 14 yr; range 18-65; 53 males and 23 females; BMI 25.8 +/- 4.2 kg/m2; mean +/- SD) with a severe traumatic brain injury, an average of 22 +/- 10 months before this study (median, 20 months), underwent a series of standard endocrine tests, including TSH, free T4, T4, T3, prolactin, testosterone (males), estradiol (females), cortisol, ACTH, GH, and IGF-I. All subjects also underwent GH response to GHRH + arginine. Growth hormone deficiency (GHD) was defined as a GH response < 9 microg/L to GHRH + arginine and was confirmed by ITT (< 3 microg/L). Pituitary deficiency was shown in 24% of the patients (18/76). 8% (n = 6) had GHD (GH-peak range [GHRH + arginine]: 2.8-6.3 microg/L; GH-peak range [ITT]: 1.5-2.2 microg/L; IGF-I range: 62-174 microg/L). 17% (n = 13) had hypogonadism (total testosterone < 9.5 nmol/L and low gonadotropins in 12 males; low estradiol, and low gonadotropins in 1 female). Total testosterone levels did not correlate with BMI or age. 2 males with hypogonadism also showed a mild hyperprolactinemia (33 and 41 ng/ml). 3% (n = 2) patients had partial ACTH-deficiency (cortisol-peak [ITT] 392 and 417 nmol/L) and 3% (n = 2) had TSH-deficiency. In summary, we have found hypopituitarism in one-fourth of patients with predominantly secondary hypogonadism and GHD. These findings strongly suggest that patients who suffer head trauma must routinely include neuroendocrine evaluations.