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Life Extension Magazine January 2012

Brain Trauma

Traumatic brain injury and hypopituitarism.

Results of recent and ongoing studies have made it clear that brain injuries like traumatic brain injury (TBI) pose substantial risk to pituitary function, perhaps even greater risk than previously believed. Patients with TBI should be screened both prospectively and retrospectively for isolated, multiple and even total pituitary deficits. It is well known that, patients with “classical” hypopituitarism (due to primary hypothalamic-pituitary pathologies) do benefit from hormonal replacement therapy. It has been suggested that patients with TBI-induced hypopituitarism may benefit with appropriate hormonal replacement receiving replacement therapy such as anti-diuretic hormone (ADH), glucocorticoid and thyroid hormones when needed. Gonadal and recombinant human growth hormone (rhGH) replacement therapy should also be introduced if there are deficiencies demonstrated and even reconfirmed in a second step. The signs and symptoms of post-TBI hypopituitarism may be masked by what has been assumed to be merely the post-traumatic syndrome. By increasing awareness among physicians of the risks of brain injuries-induced endocrinopathies and the need for appropriate endocrinological testing, it may be possible to improve the quality of life and enhance the rehabilitation prospects for these patients. In most instances, these patients are first seen and treated by trauma surgeons and neurosurgeons, and subsequently by rehabilitation physicians; they must be knowledgeable about the risks of hypopituitarism so that they can determine which patients are candidates for screening for hypopituitarism. In addition, endocrinologists and internists must be educated about TBI-induced hypopituitarism and encouraged to actively share their expertise with other physicians.

ScientificWorldJournal. 2005 Sep 15;5:777-81

Traumatic brain injury in children and adolescents: surveillance for pituitary dysfunction.

BACKGROUND: Children who sustain traumatic brain injury (TBI) are at risk for developing hypopituitarism, of which growth hormone deficiency (GHD) is the most common manifestation. OBJECTIVE: To determine the prevalence of GHD and associated features following TBI among children and adolescents. STUDY DESIGN: A total of 32 children and adolescents were recruited from a pediatric TBI clinic. Participants were diagnosed with GHD based on insufficient growth hormone release during both spontaneous overnight testing and following arginine/glucagon administration. RESULTS: GHD was diagnosed in 5/32 participants (16%). Those with GHD exhibited more rapid weight gain following injury than those without GHD and had lower levels of free thyroxine and follicle-stimulating hormone. Males with GHD had lower testosterone levels. CONCLUSIONS: GHD following TBI is common in children and adolescents, underscoring the importance of assessing.

Clin Pediatr (Phila). 2010 Nov;49(11):1044-9

Traumatic brain injury causes long-term reduction in serum growth hormone and persistent astrocytosis in the cortico-hypothalamo-pituitary axis of adult male rats.

In humans, traumatic brain injury (TBI) causes pathological changes in the hypothalamus (HT) and the pituitary. One consequence of TBI is hypopituitarism, with deficiency of single or multiple hormones of the anterior pituitary (AP), including growth hormone (GH). At present no animal model of TBI with ensuing hypopituitarism has been demonstrated. The main objective of this study was to investigate whether cortical contusion injury (CCI) could induce long-term reduction of serum GH in rats. We also tested the hypothesis that TBI to the medial frontal cortex (MFC) would induce inflammatory changes in the HT and AP. METHODS: Nine young adult male rats were given sham surgery (n = 4) or controlled impact contusions (n = 5) of the MFC. Two months post-injury they were killed, trunk blood collected and their brains and AP harvested. GH was measured in serum and AP using ELISA and Western blot respectively. Interleukin-1beta (IL-1beta) and glial fibrillary acidic protein (GFAP) were measured in the cortex (Cx), HT, and AP by Western blot. RESULTS: Lesion rats had significantly (p < 0.05) lower levels of GH in the AP and serum, unaltered serum IGF-1, and significantly (p < 0.05) higher levels of IL-1beta in the Cx and HT and GFAP in the Cx, HT, and AP compared to that of shams. CONCLUSION: CCI leads to a long-term depletion of serum GH in male rats. This chronic change in GH post-TBI is probably the result of systemic and persistent inflammatory changes observed at the level of HT and AP, the mechanism of which is not yet known.

J Neurotrauma. 2009 Aug;26(8):1315-24

GH deficiency as the most common pituitary defect after TBI: clinical implications.

Recent studies have demonstrated that hypopituitarism, and in particular growth hormone deficiency (GHD), is common among survivors of traumatic brain injury (TBI) tested several months or years following head trauma. In addition, it has been shown that post-traumatic neuroendocrine abnormalities occur early and with high frequency. These findings may have significant implications for the recovery and rehabilitation of patients with TBI. The subjects at risk are those who have suffered moderate-to severe head trauma although mild intensity trauma may precede hypopituitarism also. Particular attention should be paid to this problem in children and adolescents. GH deficiency is very common in TBI, particularly isolated GHD. For the assessment of the GH-IGF axis in TBI patients, plasma IGF-I concentrations plus GH response to a provocative test is mandatory. Growth retardation secondary to GHD is a predominant feature of GHD after TBI in children. Clinical features of adult GHD are variable and in most obesity is present. Neuropsychological examinations of patients with TBI show that a significant portion of variables like attention, concentration, learning, memory, conceptual thinking, problem solving and language are impaired in patients with TBI. In the few case reports described, hormone replacement therapy in hormone deficient head-injured patients resulted in major neurobehavioral improvements. Improvements in mental-well being and cognitive function with GH replacement therapy in GHD adults have been reported. The effect of GH replacement in posttraumatic GHD needs to be examined in randomized controlled studies.

Pituitary. 2005;8(3-4):239-43

Effect of growth hormone replacement therapy on cognition after traumatic brain injury.

Traumatic brain injury (TBI) is a major public health issue, and yet medical science has little to offer for the persistent symptoms that prevent many of these individuals from fully re-entering society. Post-traumatic hypopituitarism, and specifically growth hormone deficiency (GHD), has been found in a large percentage of individuals with chronic moderate to severe TBI. Presently, there are no published treatment studies of hormone replacement in this population. In this study, 83 subjects with chronic TBI were screened for hypopituitarism. Forty-two subjects were found to have either GHD or GH insufficiency (GHI), of which 23 agreed to be randomized to either a year of GH replacement or placebo. All subjects completed the study with no untoward side effects from treatment. A battery of neuropsychological tests and functional measures were administered before and after treatment. Improvement was seen on the following tests: Dominant Hand Finger Tapping Test, Wechsler Adult Intelligence Scale III-Information Processing Speed Index, California Verbal Learning Test II, and the Wisconsin Card Sorting Test (executive functioning). The findings of this pilot study provide preliminary evidence suggesting that some of the cognitive impairments observed in persons who are GHD/GHI after TBI may be partially reversible with appropriate GH replacement therapy.

J Neurotrauma. 2010 Sep;27(9):1565-75

Acute and long-term pituitary insufficiency in traumatic brain injury: a prospective single-centre study.

OBJECTIVE: To assess the prevalence of hypopituitarism following traumatic brain injury (TBI), describe the time-course and assess the association with trauma-related parameters and early post-traumatic hormone alterations. DESIGN: A 12-month prospective study. PATIENTS: Forty-six consecutive patients with TBI (mild: N = 22; moderate: N = 9; severe: N = 15). MEASUREMENTS: Baseline and stimulated hormone concentrations were assessed in the early phase (0-12 days post-traumatically), and at 3, 6 and 12 months postinjury. Pituitary tests included the Synacthen-test (acute +6 months) and the insulin tolerance test (ITT) or the GHRH + arginine test if the ITT was contraindicated (3 + 12 months). Insufficiencies were confirmed by retesting. RESULTS: Early post-traumatic hormone alterations mimicking central hypogonadism or hypothyroidism were present in 35 of the 46 (76%) patients. Three months post-traumatically, 6 of the 46 patients failed anterior pituitary testing. At 12 months, one patient had recovered, whereas none developed new insufficiencies. All insufficient patients had GH deficiency (5 out of 46), followed by ACTH- (3 out of 46), TSH- (1 out of 46), LH/FSH- (1 out of 46) and ADH deficiency (1 out of 46). Hypopituitary patients had more frequently been exposed to severe TBI (4 out of 15) than to mild or moderate TBI (1 out of 31) (P = 0.02). Early endocrine alterations including lowered thyroid and gonadal hormones, and increased total cortisol, free cortisol and copeptin were positively associated to TBI severity (P < 0.05), but not to long-term development of hypopituitarism (P > 0.1), although it was indicative in some. CONCLUSION: Long-term hypopituitarism was frequent only in severe TBI. During the 3-12 months follow-up, recovery but no new insufficiencies were recorded, indicating manifest hypothalamic or pituitary damage already a few months postinjury. Very early hormone alterations were not associated to long-term post-traumatic hypopituitarism. Clinicians should, nonetheless, be aware of potential ACTH deficiency in the early post-traumatic period.

Clin Endocrinol (Oxf). 2007 Oct;67(4):598-606

Neuroendocrine dysfunction in the acute phase of traumatic brain injury.

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 [initial Glasgow Coma Scale (GCS) score 3-13], and 31 matched healthy control volunteers were studied. METHODS: The glucagon stimulation test (GST) was performed at a median of 12 days (range 7-20) following TBI. Baseline thyroid function, PRL, IGF-1, gonadotrophins, testosterone or oestradiol, plasma sodium, plasma and urine osmolalities or the standard observed water deprivation test were performed. The control subjects underwent the GST for GH and cortisol responses; other parameters were compared to locally derived reference ranges. RESULTS: Control data indicated that peak serum GH of > 5 ng/ml and cortisol > 450 nmol/l following glucagon stimulation should be taken as normal. Nine TBI patients (18%) had GH response < 5 ng/ml (12 mU/l). Eight patients (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 (P < 0.05). GH and cortisol deficiencies were unrelated to patient age, BMI, initial GCS or IGF-1 values (P > 0.05). Forty patients (80%) had gonadotrophin deficiency, with low sex steroid concentrations, which was unrelated to the presence of hyperprolactinaemia. In males there was a positive correlation between serum testosterone concentration and GCS (r = 0.32, P = 0.04). One patient had TSH deficiency. Hyperprolactinaemia was present in 26 patients (52%) and serum PRL levels correlated negatively with the GCS score (r =-0.36, P = 0.011). Thirteen patients (26%) had cranial diabetes insipidus (DI) and seven (14%) had syndrome of inappropriate ADH secretion. 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.

Clin Endocrinol (Oxf). 2004 May;60(5):584-91