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2 - Patients with Severe Head Injury Should Have Hormone Assessment as Part of Routine Care according to the 86th Annual Meeting of the Endocrine Society.  June 21, 2004 -  Neuroendocrine abnormalities occur early and with high frequency in survivors of traumatic brain injury (TBI) and may have significant implications with respect to rehabilitation and recovery, according to the results of a prospective study presented at the 86th annual meeting of The Endocrine Society in New Orleans, Louisiana. "We have observed that some patients after head injury will present with symptoms that are similar to those that we observe in patients with hormone deficiency secondary to a pituitary gland underfunction," lead author Amar Agha, MD, from the Department of Endocrinology at Beaumont Hospital in Dublin, Ireland, told Medscape. "There is strong evidence that this is a common and treatable problem...[and] very much underdiagnosed." To evaluate the presence of pituitary dysfunction in early-stage TBI, the investigators tested for hormone abnormalities 50 consecutive patients admitted to the neurosurgical unit with severe or moderate TBI as determined by the Glasgow Coma Scale (GCS). Results showed a high frequency of hormonal abnormalities. "This research gives us an insight into one of the potential causes of morbidity in patients with head injury, and in some of these patients that [involves] hormone deficiencies which might adversely affect their recovery and rehabilitation," said Dr. Agha. "We feel that all patients with significant head injury should undergo hormone assessment as part of routine clinical care, so that we can identify those patients with hormone deficiencies in whom treatment may influence their recovery and rehabilitation and improve their quality of life.   Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study. Am J Psychiatry.  2002; 159(8):1315-21 . Koponen S;  et al. Department of Psychiatry, Turku University Central Hospital, Finland. OBJECTIVE: Patients who had suffered traumatic brain injury were evaluated to determine the occurrence of psychiatric disorders during a 30-year follow-up. METHOD: Sixty patients were assessed on average 30 years after traumatic brain injury. DSM-IV axis I disorders were diagnosed on a clinical basis with the aid of the Schedules for Clinical Assessment in Neuropsychiatry (version 2.1), and axis II disorders were diagnosed with the Structured Clinical Interview for DSM-III-R Personality Disorders. Cognitive impairment was measured with a neuropsychological test battery and the Mini-Mental State Examination. RESULTS: Of the 60 patients, 29 (48.3%) had had an axis I disorder that began after traumatic brain injury, and 37 (61.7%) had had an axis I disorder during their lifetimes. The most common novel disorders after traumatic brain injury were major depression (26.7%), alcohol abuse or dependence (11.7%), panic disorder (8.3%), specific phobia (8.3%), and psychotic disorders (6.7%). Fourteen patients (23.3%) had at least one personality disorder. The most prevalent individual disorders were avoidant (15.0%), paranoid (8.3%), and schizoid (6.7%) personality disorders. Nine patients (15.0%) had DSM-III-R organic personality syndrome. CONCLUSIONS: The results suggest that traumatic brain injury can cause decades-lasting vulnerability to psychiatric illness in some individuals. Traumatic brain injury seems to make patients particularly susceptible to depressive episodes, delusional disorder, and personality disturbances. The high rate of psychiatric disorders found in this study emphasizes the importance of psychiatric follow-up after traumatic brain injury. Prevalence of hypopituitarism and growth hormone deficiency in adults long-term after severe traumatic brain injury. Clin Endocrinol (Oxf) 2005 May;62(5):525-32/ Leal-Cerro A; et al.  Division of Endocrinology, Vorgem del Rocio University Hospital, Sevilla, Spain. OBJECTIVE: Traumatic brain injury (TBI) has been associated with hypopituitarism and GH deficiency. However, TBI-mediated hypopituitarism may be more frequent than previously thought. The present work, performed in patients with severe TBI at least 1 year before, had three aims: (i) to evaluate the prevalence of hypopituitarism, (ii) in particular to evaluate the prevalence of GH deficiency, and (iii) to compare three different tests of GH reserve in this cohort. DESIGN AND PATIENTS: From a nonselected group of 249 patients admitted to our Clinical Centre for severe TBI over the last 5 years, 200 of them answered a custom made questionnaire of symptoms of hypopituitarism enclosed in the invitation letter to participate in the study. A total of 170 (99 men and 14 women), accepted to participate in the study (study cohort); 57 had normal questionnaires and were not further studied, 14 discontinued the study, and 99 attended the hospital for dynamic tests of pituitary hormone deficiencies. From these, 44 subjects with IGF-I in the lower range were tested with GHRH+GHRP-6; ITT; and glucagon tests of GH reserve, on three different occasions. MEASUREMENTS: Pituitary hormones plus IGF-I and target gland hormones were analysed. RESULTS: With regard to the initial cohort of 170 subjects (100%), three (1.7%) showed diabetes insipidus; 10 (5.8%) TSH deficiency, 11 (6.4%) ACTH deficiency and 29 (17%) gonadotrophin deficiency. In 10 subjects (5.8%), GH deficiency was diagnosed by strict criteria. Finally, 15 (8.8%) showed combined deficit of several hormones. CONCLUSION: After severe head trauma, gonadotrophin deficiency was the most common pituitary deficit. GH deficiency showed a prevalence similar to ACTH and TSH deficits, i.e. near 6% of the cohort. Taken together, 24.7% of the subjects studied showed any type of pituitary hormone deficiency. Anterior hypopituitarism following traumatic brain injury. Brain Injury.  2005; 19(5):349-58. Urban RJ; Harris P; Masel B. Department of Internal Medicine, Division of Endocrinology, University of Texas Medical Branch, Galveston, TX, USA. PRIMARY OBJECTIVES: To review evidence that there exists a substantial sub-population of patients with endocrine disorders as a result of traumatic brain injury (TBI) and to underscore the importance of screening patients with TBI considered most at risk for Hypopituitarism with the goal of attaining beneficial effects in terms of morbidity and quality of life.   MAIN OUTCOMES AND RESULTS: Studies by Kelly DF, Gaw Gonzalo IT, Cohan P, et al. Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: A preliminary report. Journal of Neurosurgery 2000;93:743-751, Lieberman SA, Oberoi AL, Gilkison CR, et al. Prevalence of neuroendocrine dysfunction in patients recovering from traumatic brain injury. Journal of Clinical Endocrinology and Metabolism 2001;86:2752-2756 and Aimaretti G, Ambrosio MR, Di Somma C, et al. Traumatic brain injury and subarachnoid haemorrhage are conditions at high risk for hypopituitarism. Screening study at 3 months after the brain injury, In press., found that about one-half to one-third of patients with TBI had anterior pituitary hormone deficiencies, including growth hormone (GH) deficiency in 15-21%, and subtle deficiencies in thyroid, adrenal and gonadal axes. One or more hormonal deficiencies produce diverse physical and psychological symptoms that may mimic symptoms attributed to brain trauma and may impair rehabilitation. A more general concern is the fact that hypopituitarism increases the risk of significant morbidity (e.g. ischemic heart disease) and mortality (shortened life span).  CONCLUSIONS: To attain maximal improvement in mental and physical functioning as well as in quality of life for victims of TBI, it is crucial that anterior pituitary hormonal function be assessed. Appropriate hormone replacement therapy for those patients with both TBI and TBI-induced pituitary function impairment could, for the first time, allow treatment and correction of underlying causes of TBI sequelae rather than merely symptomatic treatment. Growth hormone in the brain: characteristics of specific brain targets for the hormone and their functional significance. Front Neuroendocrinol 2000 Oct;21(4):330-48. Nyberg F  Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. During the past decade studies have shown that growth hormone (GH) exerts profound effects on the central nervous system (CNS). For instance, GH replacement therapy was found to improve the psychological capabilities in adult GH deficient (GHD) patients. Furthermore, beneficial effects of the hormone on certain functions, including memory, mental alertness, motivation, and working capacity, have been reported. Likewise, GH treatment of GHD children has been observed to produce significant improvement in many behavioral problems seen in these individuals. Studies also indicated that GH therapy affects the cerebrospinal fluid levels of various hormones and neurotransmitters. Further support that the CNS is a target for GH emerges from observations indicating that the hormone may cross the blood-brain barrier (BBB) and from studies confirming the presence of GH receptors in the brain. Neuroendocrine dysfunction in the acute phase of traumatic brain injury. Clin Endocrinol (Oxf).  2004; 60(5):584-9. Agha A; Rogers B; Mylotte D; Taleb F; Tormey W; Phillips J; Thompson CJ. Academic Department of Endocrinology, Beaumount Hospital, Dublin, Ireland.  BACKGROUND: Pituitary hormone abnormalities have been reported in up to 50% of survivors of traumatic brain injury (TBI) who were investigated several months or longer following the event. The frequency of pituitary dysfunction in the early post-TBI period is unknown. AIM: To evaluate the prevalence of anterior and posterior pituitary dysfunction in the early phase following TBI. SUBJECTS: Fifty consecutive patients admitted to the neurosurgical unit with severe or moderate TBI. RESULTS:  18% had GH response 16% had peak cortisol responses < 450 nmol/l. Compared to controls, basal cortisol values were significantly lower in patients with subnormal cortisol responses to glucagon and significantly higher in patients with normal cortisol responses. GH and cortisol deficiencies were unrelated to patient age, BMI, initial GCS or IGF-1. 80% had gonadotrophin deficiency(testosterone). CONCLUSION: Our data show that post-traumatic neuroendocrine abnormalities occur early and with high frequency, which may have significant implications for recovery and rehabilitation of TBI patients. Hypopituitarism as a consequence of traumatic brain injury (TBI) and its possible relation with cognitive disabilities and mental distress. J Endocrinol Invest.  2004; 27(11):1048-54. Popovic V; et al. Institute of Endocrinology, University Clinical Center, Belgrade, Union of Serbia and Montenegro. Recent studies have demonstrated that hypopituitarism, in particular GH deficiency, is common among survivors of traumatic brain injury (TBI) tested several months or years following head trauma. We present the results of endocrine, neurological, neuropsychological and psychiatric evaluation in a group of 67 patients who suffered TBI at least one yr ago. Our study shows that decreased endocrine function is either restricted to one or more anterior pituitary hormones and is present in 34% of patients with any pituitary hormone deficit, while multiple pituitary hormone deficiencies are found in 10% of patients. Severe GHD is the most frequent deficiency present in 15% of TBI patients. Gonadotrophin deficiency was present in 9% of patients with TBI, while thyrotrophic and corticotrophic function seemed more refractory to impairment. Patients with moderate-to-severe trauma are not necessarily more likely to have hypopituitarism than those with mild injury. Neuropsychological testing revealed a significant positive correlation of peak GH levels with verbal learning and verbal short term memory. Verbal and visual memory was significantly lower, vasoconstriction abilities were significantly lower, Visual memory (free recall of complex figure after 30 min) significantly correlated with lower IGF-I levels. Gonadotrophins and testosterone correlated significantly with vasoconstriction abilities. Simple and complex conceptual tracking was significantly more impaired in older TBI patients and with longer time from trauma. The psychiatric evaluation by using two different scales showed depression, phobic anxiety and psychoticism to be more prominent in the TBI group. Paranoid ideation and somatization correlated with low GH responses to GHRH+GHRP-6 test. Depression scale showed that nearly half of patients suffered from mild to moderate depression. The benefits of hormone replacement therapy on cognitive functioning and mental distress in TBI patients can only be improved upon with the appropriate correction of the underlying hormonal deficiencies. Effect of Growth Hormone Replacement on Cerebral Metabolism in Adults with Growth Hormone Deficiency. Growth Hormone and IGF Research, 1998, 8, 317, 318, 349. IC Cranston, et al., . Dept of Medicine; Clinical PET Centre, UMDS St Thomas Hospital, London, UK. The beneficial effects of growth hormone (GH) replacement in GH-deficient adults on both quality of life, mood and cognitive functioning have been previously described. It is however unclear if these effects represent a direct central action of GH (perhaps via IGFI), or are secondary to the well-described peripheral effects of GH and the resulting improvements in systemic well-being. In order to determine this, we have studied 15 GH-deficient adults before and 3 months after growth hormone replacement  or placebo (randomized, double-blind) using quantitative, dynamic cerebral positron emission tomography (PET). Regional cerebral metabolic rate for glucose (RCMRglu) was determined by comparison of arterial tracer disappearance with brain tracer uptake by the PET scanner over 1h  after intravenous bolus of the positron emitter 18-Fluoro-Deoxyglucose (18FDG) as a glucose tracer.  In both GHD groups, the baseline whole-brain CMRglu was lower than that for previous non-GHD subjects after placebo this fell still further. In contrast, those receiving Growth Hormone sustained a significant rise in whole-brain CMRglu up-take. This effect was similar across all brain regions, with the exception of brainstem, where the effect of GH on CMRglu was negligible. In summary, resting cerebral metabolic rate in GHD adults is low, replacement with GH at physiological doses increases this towards normal, suggesting a direct effect of GH replacement on the central nervous system. Early predictors of postconcussive syndrome in a population of trauma patients with mild traumatic brain injury(MTBI). J Trauma.  2009; 66(2):289-96; discussion 296-7. PC; Ryb;GE; Kufera JA; Auman KM. National Study Center for Trauma and EMS, The University of Maryland School of Medicine, Baltimore, Maryland, USA. PURPOSE: The purpose of this analysis was to determine which of the initial symptoms after mild traumatic brain injury (MTBI) can best predict the development of persistent postconcussive syndrome (PCS). METHODS: One hundred eighty (180) MTBI patients admitted to a level I trauma center were enrolled in a prospective study and 110 followed for 3 months. MTBI was defined as a Glasgow Coma Score of 13 to 15 with a transient loss of consciousness or report of being dazed or confused. PCS was defined as the persistence of four or more symptoms long term. Patients were screened at admission and at 3 days to 10 days and 3 months. Symptom checklists were administered to ascertain the presence of symptoms (cognitive, emotional, and physical) after concussion. For a subset of patients that were physically able, balance tests were also conducted. Stepwise logistic regression was used to identify which symptoms best predicted PCS. RESULTS: The mean age of the subjects was 35 years, and 65% were men. Physical symptoms were the most prevalent in the 3 days to 10 days postinjury with most declining thereafter to baseline levels. Emotional and cognitive symptoms were less prevalent but more likely to remain elevated at 3 months; 41.8% of subjects reported PCS at 3 months. In multivariate regressions including age, gender, and early symptoms, only anxiety, NS and gender remained significant in the prediction of PCS. Interactions revealed that the effect of anxiety was seen primarily among women.  CONCLUSIONS: The strongest individual symptoms that predicted long-term PCS included anxiety, noise sensitivity (NS), and trouble thinking; reported by 49%, 27%, and 31% of the subjects at 3 days to 10 days, respectively x The cardiovascular risk of adult GH deficiency (GHD) improved after GH replacement and worsened in untreated GHD: a 12-month prospective study. J Clin Endocrinol Metab. 2002 Mar;87(3):1088-93.Colao A, et al. Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, 80131 Naples, Italy. Increased cardiovascular morbidity and mortality were reported in GH deficiency (GHD), and GH replacement can ameliorate cardiac abnormalities of adult GHD patients. To test the potential progression of untreated GHD on the cardiovascular risk and cardiac function, cardiovascular risk factors, cardiac size, and performance were prospectively evaluated in 15 GHD patients (age, 18-56 yr) who were treated with recombinant GH at the dose of 0.15-1.0 mg/d, 15 GHD patients (age, 18-56 yr) who refused GH replacement, and 30 healthy subjects (age, 18-53 yr). Electrocardiogram, systolic and diastolic blood pressure, and heart rate measurement, serum IGF-I, total cholesterol, low- and high-density lipoprotein (LDL, HDL) cholesterol, triglycerides, and fibrinogen level assay, echocardiography, and equilibrium radionuclide angiography were performed basally and after 12 months. At study entry, low IGF-I levels, unfavorable lipid profile, and inadequate cardiac and physical performance were found in GHD patients compared with controls. After 12 months of GH treatment, IGF-I levels normalized; HDL-cholesterol levels, left ventricular (LV) mass index (LVMi), left ventricular ejection fraction (LVEF) at peak exercise, peak filling rate, exercise duration and capacity significantly increased; total- and LDL-cholesterol levels significantly decreased. After 12 months in GH-untreated GHD patients, IGF-I levels remained stable, and HDL-cholesterol levels, LVEF both at rest and at peak exercise, and exercise capacity were further reduced; total- and LDL-cholesterol levels increased slightly. LVEF at rest and its response at peak exercise normalized in 60 and 53.3%, respectively, of GH-treated patients and in none of the GH-untreated patients.  In conclusion, 12 months of GH replacement normalized IGF-I and improved lipid profile and cardiac performance in adult GHD patients. A similar period of GH deprivation induced a further impairment of lipid profile and cardiac performance. This finding strongly supports the need of GH replacement in adult GHD patients. xx xx The Clinical Significance of Major Depression Following Mild Traumatic Brain Injury Psychosomatics 44:31-37, February 2003. Mark J. Rapoport, M.D., F.R.C.P.C., Scott McCullagh, M.D., F.R.C.P.C., David Streiner, Ph.D., C.Psych., and Anthony Feinstein, Ph.D., F.R.C.P.C. Presented in part at the 13th annual meeting of the American Neuropsychiatric Association, La Jolla, Calif., March 10–12, 2002. from Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Ave., Toronto, Ont. M4N 3M5, Canada. OBJECTIVE: The authors assessed the association of major depression with behavioral outcome following mild traumatic brain injury. RESULTS: Major depression was seen in 15.3% of the subjects after traumatic brain injury, and these individuals showed subjective and objective evidence of poorer outcome. CONCLUSIONS: Major depression is associated with poor outcome across multiple domains. This study highlights the need for the early diagnosis and prompt treatment of major depression following mild traumatic brain injury. Consensus guidelines on screening for hypopituitarism following traumatic brain injury.  Brain Inj. ;2005; 19(9):711-24 Ghigo;E. et al. Department of Internal Medicine, University of Turin, Turin, Italy.  PRIMARY OBJECTIVE: The goal of this consensus statement is to increase awareness among endocrinologists and physicians treating patients with traumatic brain injury (TBI) of the incidence and risks of hypopituitarism among patients with TBI. RATIONALE: TBI poses significant risk to the pituitary gland, leading to elevated risks of diabetes, hypopituitarism and other endocrinopathies. Signs and symptoms associated with hypopituitarism often mimic the sequela of TBI, although the severity of symptoms is not necessarily related to the severity of the injury. Patients with TBI-induced hypopituitarism may benefit both physically and psychologically from appropriate hormone replacement therapy (HRT). Participants at this unique consensus meeting attempted to define and spearhead an approach to increase awareness of the risks of TBI-induced endocrinopathies, in particular growth hormone deficiency (GHD), and to outline necessary and practical objectives for managing this condition. RECOMMENDATIONS: Systematic screening of pituitary function is recommended for all patients with moderate-to-severe TBI at risk of developing pituitary deficits. Patients with hypopituitarism benefit from appropriate hormonal replacement and prospects for rehabilitation of patients with TBI-induced hypopituitarism may be enhanced by appropriate HRT. Further exploration of this possibility requires: (1) active collaboration between divisions of endocrinology and rehabilitation at the local level to perform a screening of pituitary function in patients after TBI, (2) creation of a consultancy service by endocrine societies for use by rehabilitation centers, (3) development of continuing medical education (CME) programmes that can be offered as crossover training to the physicians who manage the care of patients with TBIs, (4) targeting of patient organizations with educational information for dissemination to patients and their families, (5) continued efforts to more clearly define the population at greatest risk of TBI-induced hypopituitarism and (6) monitor results of efficacy studies as they become available to evaluate whether and how much replacement therapy can improve the symptoms of individuals with TBI-induced hypopituitarism.