Pituitary Dysfunction After Traumatic Brain Injury: A Clinical and Pathophysiological Approach

CT and conventional MRI do not allow discrimination of DAI.

“CT and conventional magnetic resonance imaging (MRI) do not allow discrimination of DAI (107).”

• cites [107] Kim, 2011, Imaging for the diagnosis and management of traumatic brain injury, Neurotherapeutics sourceDisputed

  The “Traumatic axonal injury” section says CT can show characteristic findings in some patients and that MRI is far more sensitive, detecting both hemorrhagic and nonhemorrhagic lesions. Although the “Advanced MRI techniques” section notes that conventional CT or MR images can be normal despite injury, the paper does not say these methods cannot detect or distinguish axonal injury. (LLM, conf=0.87)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

In these studies, pituitary hormone evaluations were performed only at one time point during the acute phase of TBI.

“It is important to note that, in these studies, pituitary hormone evaluations were performed only at one time point during the acute phase of TBI (15, 149, 150).”

• cites [15] Tanriverdi, 2006, High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [149] Agha, 2005, The natural history of post-traumatic hypopituitarism: implications for assessment and treatment, Am J Med sourceDisputed

  The Abstract describes pituitary-function evaluations during the acute phase and again at 6 and 12 months after injury. Table 2 (section 1416.e6) reports results at all three time points, contrary to the claim that evaluations in this study occurred only once during the acute phase. (LLM, conf=0.91)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [150] Klose, 2007, Acute and long-term pituitary insufficiency in traumatic brain injury: a prospective single-centre study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

GH assessment by Immulite or Isys assay caused no significant diagnostic differences.

“GH assessment by Immulite or Isys assay caused no significant diagnostic differences.”

• cites [21] Klose, 2014, Prevalence of posttraumatic growth hormone deficiency is highly dependent on the diagnostic set-up: results from The Danish National Study on Posttraumatic Hypopituitarism, J Clin Endocrinol Metab sourceSupported

In TBI patients, the prevalence of GH deficiency was lower by ITT than by PD-GHRH/GHRH+ARG testing.

“and by ITT than by PD-GHRH/GHRHϩARG (P ϭ .006[local cutoffs]; P Ͻ .001[guideline cutoffs]).”

• cites [21] Klose, 2014, Prevalence of posttraumatic growth hormone deficiency is highly dependent on the diagnostic set-up: results from The Danish National Study on Posttraumatic Hypopituitarism, J Clin Endocrinol Metab sourceSupported

A substantial number of false-positive GH test results were found in the control group.

“Moreover, they showed that a substantial number of false-positive results were found in the control group.”

• cites [21] Klose, 2014, Prevalence of posttraumatic growth hormone deficiency is highly dependent on the diagnostic set-up: results from The Danish National Study on Posttraumatic Hypopituitarism, J Clin Endocrinol Metab sourceSupported

Only 1% of TBI patients had GH deficiency according to two tests.

“Only 1% of patients had GHD according to two tests.”

• cites [21] Klose, 2014, Prevalence of posttraumatic growth hormone deficiency is highly dependent on the diagnostic set-up: results from The Danish National Study on Posttraumatic Hypopituitarism, J Clin Endocrinol Metab sourceSupported

In TBI patients, the prevalence of GH deficiency was lower by local than by guideline cutoffs.

“The prevalence of GHD was found to be lower by local than by guideline cutoffs (12 vs 19% [PD-GHRH/GHRHϩARG, P Ͻ .001];4.5 vs 5% [ITT, P ϭ .9])”

• cites [21] Klose, 2014, Prevalence of posttraumatic growth hormone deficiency is highly dependent on the diagnostic set-up: results from The Danish National Study on Posttraumatic Hypopituitarism, J Clin Endocrinol Metab sourceSupported

Among individuals who have sustained TBI, those with lower testosterone levels appear to have an increased risk for Alzheimer's disease.

“Of the individuals who have sustained TBI, those with lower T levels also appear to have an increased risk for Alzheimer's disease, which makes the connection between sex hormones and brain injury even more intriguing (65).”

• cites [65] Jellinger, 2001, Traumatic brain injury as a risk factor for Alzheimer disease. Comparison of two retrospective autopsy cohorts with evaluation of ApoE genotype, BMC Neurol sourcePartly supported

  The Abstract Conclusions and Discussion report an association between TBI and Alzheimer disease. They do not address whether testosterone levels change that risk among people with TBI; searches for testosterone, lower T levels, and androgens found no such passage. No page numbers are available in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Testosterone supplementation in hypogonadal males, as well as in normal healthy males, has shown some improvement in some domains of memory.

“The results of T supplementation in hypogonadal males, as well as in normal healthy males, have shown some improvement in some domains of memory (61,62);”

• cites [61] Cherrier, 2003, Cognitive changes associated with supplementation of testosterone or dihydrotestosterone in mildly hypogonadal men: a preliminary report, J Androl sourceSupported
• cites [62] Cherrier, 2005, The role of aromatization in testosterone supplementation: effects on cognition in older men, Neurology sourceNot checked — no full text of the source

GHD (19.1%) and hypogonadism (8.8%) were the most common pituitary dysfunctions after repetitive sports-related concussion in football players.

“GHD (19.1%) and hypogonadism (8.8%) were found to be the most common pituitary dysfunction after repetitive sports-related concussion in football players (48).”

• cites [48] Kelly, 2014, Prevalence of pituitary hormone dysfunction, metabolic syndrome, and impaired quality of life in retired professional football players: a prospective study, J Neurotrauma sourceSupported

False-positive results after GH testing occurred in 2-8% of controls, depending on the tests and cutoffs used.

“Additionally, Klose et al (21) showed that false-positive results after GH testing occurred in 2-8% of controls, depending on the tests and cutoffs used.”

• cites [21] Klose, 2014, Prevalence of posttraumatic growth hormone deficiency is highly dependent on the diagnostic set-up: results from The Danish National Study on Posttraumatic Hypopituitarism, J Clin Endocrinol Metab sourcePartly supported

  The 'Impact of local vs guideline-derived cutoff values' section reports false-positive GH-deficiency results in healthy controls that varied by test and cutoff. But it gives 4% for ITT and up to 20% for combined tests under guideline cutoffs, so the claimed 2–8% range is not supported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Available evidence suggests GH as the principal player in the pathophysiological mechanism of diabetes and insulin resistance in patients with hypopituitarism due to its interaction with many other hormonal and/or peptidic systems.

“The pathophysiological mechanism of diabetes and insulin resistance in patients with hypopituitarism is not completely understood; however, available evidence suggests GH as the principal player due to its interaction with many other hormonal and/or peptidic systems (74,91).”

• cites [74] Luque, 2011, Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes, PLoS One sourcePartly supported

  The Discussion (section “AOiGHD improves whole body insulin sensitivity”; page not supplied) reports that isolated GH deficiency improved insulin sensitivity in mice and discusses anti-insulin effects of GH in clinical studies. It does not establish GH as the principal cause of diabetes and insulin resistance in patients with hypopituitarism, or attribute that role to interactions with many other hormonal or peptide systems; it says the mechanism by which GH reduces insulin sensitivity remains unclear. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [91] Mersebach, 2003, Comparisons of leptin, incretins and body composition in obese and lean patients with hypopituitarism and healthy individuals, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

It is feasible that TBI patients with neuroendocrine dysfunction may have metabolic alterations.

“Consequently, it is feasible that TBI patients with neuroendocrine dysfunction may have metabolic alterations; however, few studies have evaluated these issues, including changes in body composition and BMI, lipid profile, glucose metabolism, and hypertension (46,48,80,81).”

• cites [46] Tanriverdi, 2008, Brief communication: pituitary volume and function in competing and retired male boxers, Ann Intern Med sourceNot checked — no full text of the source
• cites [48] Kelly, 2014, Prevalence of pituitary hormone dysfunction, metabolic syndrome, and impaired quality of life in retired professional football players: a prospective study, J Neurotrauma sourceSupported
• cites [80] Klose, 2007, Posttraumatic hypopituitarism is associated with an unfavorable body composition and lipid profile, and decreased quality of life 12 months after injury, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [81] Prodam, 2013, Metabolic alterations in patients who develop traumatic brain injury (TBI)-induced hypopituitarism, Growth Horm IGF Res sourceNot checked — no full text of the source

Low HDL-cholesterol was shown in classical hypopituitarism subjects with respect to controls chosen in obese subjects without hypopituitarism.

“Low HDL-cholesterol was shown in classical hypopituitarism subjects with respect to controls chosen in obese subjects without hypopituitarism (75).”

• cites [75] Nyenwe, 2009, Nonalcoholic fatty liver disease and metabolic syndrome in hypopituitary patients, Am J Med Sci sourcePartly supported

  The Results section reports a significantly higher prevalence of low HDL cholesterol in hypopituitary patients than in controls. But the Methods say controls were matched for BMI, and the Results distinguish obese from non-obese controls; the comparison was not exclusively with obese subjects without hypopituitarism. Page numbers were not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

DAI is the primary neuropathology of TBI that is caused by the shearing of fragile axons by acceleration/deceleration forces from head trauma.

“DAI is the primary neuropathology of TBI that is caused by the shearing of fragile axons (disruption of axonal fibers and myelin sheaths) by acceleration/deceleration forces from the head trauma (105, 106).”

• cites [105] Johnson, 2013, Axonal pathology in traumatic brain injury, Exp Neurol sourcePartly supported

  The Introduction calls DAI one of the most common neuropathological consequences of TBI and links it to mechanical loading during rapid head acceleration; it does not call DAI the primary neuropathology. The section “Potential Primary Mechanical Damage due to Axonal Trauma” also says immediate shearing apart of axons is relatively rare and that disconnection usually develops secondarily after cytoskeletal damage, so the claim oversimplifies the mechanism. Page numbers were not available in our copy. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [106] Adams, 1989, Diffuse axonal injury in head injury: definition, diagnosis and grading, Histopathology sourceNot checked — no full text of the source

These processes induce adhesion molecules and mobilize immune and glial cells in a parallel and synergistic way.

“These processes induce adhesion molecules and, in order, mobilize immune and glial cells in a parallel and synergistic way (94, 126 -128).”

• cites [94] Frattalone, 2013, Moderate and severe traumatic brain injury: pathophysiology and management, Neurosurg Clin N Am sourceNot checked — no full text of the source
• cites [126] Fabricius, 2006, Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex, Brain sourceNot checked — no full text of the source
• cites [127] Lucas, 2006, The role of inflammation in CNS injury and disease, Br J Pharmacol sourceSupported
• cites [128] Potts, 2006, Traumatic injury to the immature brain: inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets, NeuroRx sourcePartly supported

  The “Inflammation and brain injury” section (pp. 2–3) describes integrated inflammatory activity, adhesion-molecule upregulation after traumatic brain injury, and leukocyte recruitment. It also identifies activated microglia as a feature of early inflammation, but does not say that these processes mobilize glial cells or that immune and glial cells act in a parallel, synergistic way. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

In Harper et al.'s investigation, all patients with large- or medium-sized pituitary infarctions had increased ICP at some point.

“In this investigation, all patients with large-or medium-sized pituitary infarctions had increased ICP at some point.”

• cites [141] Harper, 1986, Analysis of abnormalities in pituitary gland in non-missile head injury: study of 100 consecutive cases, J Clin Pathol sourceSupported

Antibodies may form after TBI due to disruption of the blood-brain barrier, allowing brain proteins to leak into the circulation and evoke an immune response.

“Antibodies may form after TBI due to the disruption of the blood-brain barrier, which allows brain proteins (especially the release of sequestered pituitary and hypothalamic antigens from injured/ necrotic tissue) to leak into the circulation, evoking an immune response (164, 165).”

• cites [164] Tanriverdi, 2010, Investigation of antihypothalamus and antipituitary antibodies in amateur boxers: is chronic repetitive head trauma-induced pituitary dysfunction associated with autoimmunity?, Eur J Endocrinol sourceNot checked — no full text of the source
• cites [165] Papa, 2012, Elevated levels of serum glial fibrillary acidic protein breakdown products in mild and moderate traumatic brain injury are associated with intracranial lesions and neurosurgical intervention, Ann Emerg Med sourcePartly supported

  The Results report that GFAP breakdown products appeared rapidly in serum after TBI, and the Discussion describes their release from injured glial cells. The paper does not attribute that appearance to blood–brain barrier disruption or discuss antibody formation, an immune response, or pituitary and hypothalamic antigens. No page numbers were provided for these passages. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

In Zhang et al.'s study, serum levels of glial fibrillary acidic protein autoantibodies increased up to 7 days after injury.

“In that study, the authors did not evaluate the effects of TBI on pituitary function, but they clearly demonstrated that serum levels of glial fibrillary acidic protein autoantibodies increased up to 7 days after the injury.”

• cites [166] Zhang, 2014, Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products, PLoS One sourceSupported

Based on prospective clinical studies, significant percentages of acute pituitary hormonal deficiencies are transient and recover after 3 to 12 months of injury.

“Based on the prospective clinical studies, significant percentages of the acute pituitary hormonal deficiencies are transient and recover after 3 to 12 months of injury (15, 25, 149 -151).”

• cites [15] Tanriverdi, 2006, High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [25] Kleindienst, 2009, Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: a prospective longitudinal evaluation, J Neurotrauma sourceNot checked — no full text of the source
• cites [149] Agha, 2005, The natural history of post-traumatic hypopituitarism: implications for assessment and treatment, Am J Med sourceSupported
• cites [150] Klose, 2007, Acute and long-term pituitary insufficiency in traumatic brain injury: a prospective single-centre study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [151] Krahulik, 2010, Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults, J Neurosurg sourceNot checked — no full text of the source

Kasturi and Stein reported that cortical contusion injury in young adult male rats leads to suppression of GH in serum and anterior pituitary 2 months after injury.

“Kasturi and Stein (176) reported that cortical contusion injury in young adult male rats leads to the suppression of GH in the serum and in the anterior pituitary 2 months after injury.”

• cites [176] Kasturi, 2009, Traumatic brain injury causes long-term reduction in serum growth hormone and persistent astrocytosis in the cortico-hypothalamo-pituitary axis of adult male rats, J Neurotrauma sourceSupported

The authors concluded that the chronic change seen in post-TBI GH level is probably the result of systemic and persistent inflammatory changes in the hypothalamus and anterior pituitary.

“Based on these findings, the authors concluded that the chronic change seen in the post-TBI GH level is probably the result of systemic and persistent inflammatory changes in the hypothalamus and anterior pituitary (176).”

• cites [176] Kasturi, 2009, Traumatic brain injury causes long-term reduction in serum growth hormone and persistent astrocytosis in the cortico-hypothalamo-pituitary axis of adult male rats, J Neurotrauma sourceSupported

Significant reductions in GH levels in both serum and anterior pituitary at 2 months after injury were observed.

“Significant reductions in the levels of GH in both serum and anterior pituitary at 2 months after injury were observed.”

• cites [176] Kasturi, 2009, Traumatic brain injury causes long-term reduction in serum growth hormone and persistent astrocytosis in the cortico-hypothalamo-pituitary axis of adult male rats, J Neurotrauma sourceSupported

They demonstrated up-regulation of IL-1b and glial fibrillary acidic protein levels in the cerebral cortex, hypothalamus, and anterior pituitary.

“Moreover, they demonstrated the up-regulation of IL-1b and glial fibrillary acidic protein levels in the cerebral cortex, hypothalamus, and anterior pituitary.”

• cites [176] Kasturi, 2009, Traumatic brain injury causes long-term reduction in serum growth hormone and persistent astrocytosis in the cortico-hypothalamo-pituitary axis of adult male rats, J Neurotrauma sourcePartly supported

  The sections on IL-1β production and astrocytosis report increased IL-1β in the cerebral cortex and hypothalamus, and increased GFAP in all three regions. But the IL-1β section explicitly says there was no alteration in the anterior pituitary, so the claim overstates where both markers were up-regulated. Page numbers were not provided in the supplied passages. (LLM, conf=0.94)

  Experimental — accuracy not yet measured

Experimental animal models are critical in understanding the links between clinical outcomes of TBI and cellular/molecular dysfunction resulting in neuroendocrine dysfunction.

“They are critical in understanding the links between the clinical outcomes of TBI and some cellular/ molecular dysfunction resulting in neuroendocrine dysfunction (193).”

• cites [193] Cernak, 2005, Animal models of head trauma, NeuroRx sourcePartly supported

  The Introduction and Conclusion describe animal TBI models as important for relating injury outcomes to cellular and molecular mechanisms. Neither passage establishes that those mechanisms result in neuroendocrine dysfunction; searches for neuroendocrine and endocrine terms did not find support for that part of the claim. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

To date, only four experimental model studies investigating the effects of head trauma on the hypothalamo-pituitary region and function have been published recently.

“To date, a significant number of different TBI experimental models have been defined to understand the pathophysiology of brain damage; however, only four experimental model studies investigating the effects of head trauma on the hypothalamo-pituitary region and function have been published recently (175-178).”

• cites [175] Greco, 2013, The effects of repeat traumatic brain injury on the pituitary in adolescent rats, J Neurotrauma sourceNot checked — no full text of the source
• cites [176] Kasturi, 2009, Traumatic brain injury causes long-term reduction in serum growth hormone and persistent astrocytosis in the cortico-hypothalamo-pituitary axis of adult male rats, J Neurotrauma sourceSupported
• cites [177] Osterstock, 2014, Sustained alterations of hypothalamic tanycytes during posttraumatic hypopituitarism in male mice, Endocrinology sourceNot checked — no full text of the source
• cites [178] Ozdemir, 2012, Relationship between circulating IGF-1 levels and traumatic brain injury-induced hippocampal damage and cognitive dysfunction in immature rats, Neurosci Lett sourceNot checked — no full text of the source

The GH response to GHRH+ARG and to all known GH provocative stimuli significantly declines with increasing BMI in adults.

“However, the GH response to GHRHϩARG, and to all known GH provocative stimuli, significantly declines with increasing BMI in adults (221, 222); thus, the use of a non-BMI-related cutoff in obese subjects causes a high percentage of false-positive results (203).”

• cites [221] Bonert, 2004, Body mass index determines evoked growth hormone (GH) responsiveness in normal healthy male subjects: diagnostic caveat for adult GH deficiency, J Clin Endocrinol Metab sourcePartly supported

  The Results (p. 2) report a significant inverse correlation between BMI and GH response to arginine-GHRH in 59 healthy men. The Discussion (p. 3) also says BMI relates inversely to responses to insulin tolerance testing, but the paper does not establish a decline for all known GH provocative stimuli or for adults generally. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [222] Qu, 2005, Influence of body mass index and gender on growth hormone (GH) responses to GH-releasing hormone plus arginine and insulin tolerance tests, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Differences in the reported frequency of TBI-induced hypopituitarism may be due to more stringent diagnostic criteria applied by some studies but not others.

“Differences in the reported frequency of TBI-induced hypopituitarism may be due to more stringent diagnostic criteria being applied by some studies but not by others (21,194).”

• cites [21] Klose, 2014, Prevalence of posttraumatic growth hormone deficiency is highly dependent on the diagnostic set-up: results from The Danish National Study on Posttraumatic Hypopituitarism, J Clin Endocrinol Metab sourceSupported
• cites [194] Schneider, 2007, Hypopituitarism, Lancet sourceNot checked — no full text of the source

In most studies, no significant associations between TBI severity according to postresuscitation GCS and hypopituitarism in the chronic phase have been reported.

“In most studies, no significant associations between TBI severity according to postresuscitation GCS and hypopituitarism in the chronic phase have been reported (15, 23, 24, 27, 29, 181, 231-233), whereas others have demonstrated that hypopituitarism was more frequent in patients with more severe TBI (18,30,154).”

• cites [15] Tanriverdi, 2006, High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [23] Herrmann, 2006, Hypopituitarism following severe traumatic brain injury, Exp Clin Endocrinol Diabetes sourceNot checked — no full text of the source
• cites [24] Leal-Cerro, 2005, Prevalence of hypopituitarism and growth hormone deficiency in adults long-term after severe traumatic brain injury, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [27] Schneider, 2006, Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury, Eur J Endocrinol sourceNot checked — no full text of the source
• cites [29] Agha, 2004, Anterior pituitary dysfunction in survivors of traumatic brain injury, J Clin Endocrinol Metab sourceSupported
• cites [181] Aimaretti, 2005, Residual pituitary function after brain injury-induced hypopituitarism: a prospective 12-month study, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [231] Kozlowski Moreau, 2012, Lasting pituitary hormone deficiency after traumatic brain injury, J Neurotrauma sourceNot checked — no full text of the source
• cites [232] Popovic, 2004, Hypopituitarism as a consequence of traumatic brain injury (TBI) and its possible relation with cognitive disabilities and mental distress, J Endocrinol Invest sourceNot checked — no full text of the source
• cites [233] Schneider, 2011, Structured assessment of hypopituitarism after traumatic brain injury and aneurysmal subarachnoid hemorrhage in 1242 patients: the German interdisciplinary database, J Neurotrauma sourceNot checked — no full text of the source

Glucocorticoid deficiency in the acute phase of TBI is life-threatening.

“However, in the acute phase of TBI, the diagnosis of glucocorticoid deficiency should not be missed because it is life-threatening (14, 238, 241, 257, 258).”

• Also stated in: § 1. Treatment of TSH, FSH/LH, and GH deficiencies in the acute phase · plain

  “However, in the acute phase of TBI, the diagnosis of glucocorticoid deficiency, due to central ACTH insufficiency, should not be missed because it is life-threatening (14, 238, 241, 257).”

• cites [14] Schneider, 2007, Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review, JAMA sourceNot checked — no full text of the source
• cites [238] Cohan, 2005, Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study, Crit Care Med sourceNot checked — no full text of the source
• cites [241] Hannon, 2013, Acute glucocorticoid deficiency and diabetes insipidus are common after acute traumatic brain injury and predict mortality, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [257] Cooper, 2007, Adrenal insufficiency in critical illness, J Intensive Care Med sourceNot checked — no full text of the source
• cites [258] Tanriverdi, 2013, Hypopituitarism due to head trauma: new insights into an old story, Erciyes Med J sourceSupported

Six major prospective studies have investigated pituitary function during the first 3 months of TBI and 12 months later.

“published investigating pituitary function during the first 3 months of TBI and 12 months later (15, 27, 149 -151, 181).”

• cites [15] Tanriverdi, 2006, High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [27] Schneider, 2006, Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury, Eur J Endocrinol sourceNot checked — no full text of the source
• cites [149] Agha, 2005, The natural history of post-traumatic hypopituitarism: implications for assessment and treatment, Am J Med sourceSupported
• cites [150] Klose, 2007, Acute and long-term pituitary insufficiency in traumatic brain injury: a prospective single-centre study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [151] Krahulik, 2010, Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults, J Neurosurg sourceNot checked — no full text of the source
• cites [181] Aimaretti, 2005, Residual pituitary function after brain injury-induced hypopituitarism: a prospective 12-month study, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Most pituitary hormonal changes (especially FSH/LH, GH, and TSH deficiencies) are transient and recover within 3 to 12 months after TBI.

“Based on the prospective studies evaluating pituitary function, most pituitary hormonal changes (especially FSH/LH, GH, and TSH deficiencies) are transient and recover within 3 to 12 months after injury (15, 25, 149 -151).”

• cites [15] Tanriverdi, 2006, High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [25] Kleindienst, 2009, Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: a prospective longitudinal evaluation, J Neurotrauma sourceNot checked — no full text of the source
• cites [149] Agha, 2005, The natural history of post-traumatic hypopituitarism: implications for assessment and treatment, Am J Med sourceSupported
• cites [150] Klose, 2007, Acute and long-term pituitary insufficiency in traumatic brain injury: a prospective single-centre study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [151] Krahulik, 2010, Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults, J Neurosurg sourceNot checked — no full text of the source

Prospective studies show dynamic properties of hypopituitarism in isolated and multiple pituitary deficiencies as well as in improvement (recovery) or worsening (new-onset hormonal deficiencies) of pituitary function.

“These prospective studies showed the dynamic properties of hypopituitarism in isolated and multiple pituitary deficiencies as well as in the improvement (recovery) or worsening (new-onset hormonal deficiencies) of pituitary function.”

• cites [15] Tanriverdi, 2006, High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [27] Schneider, 2006, Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury, Eur J Endocrinol sourceNot checked — no full text of the source
• cites [149] Agha, 2005, The natural history of post-traumatic hypopituitarism: implications for assessment and treatment, Am J Med sourceSupported
• cites [150] Klose, 2007, Acute and long-term pituitary insufficiency in traumatic brain injury: a prospective single-centre study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [151] Krahulik, 2010, Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults, J Neurosurg sourceNot checked — no full text of the source
• cites [181] Aimaretti, 2005, Residual pituitary function after brain injury-induced hypopituitarism: a prospective 12-month study, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Her hormonal profile was compatible with recovery from gonadotropin deficiency.

“Her hormonal profile was compatible with the recovery from gonadotropin deficiency.”

• cites [260] Ruggeri, 2010, Spontaneous recovery from isolated post-traumatic central hypogonadism in a woman, Hormones (Athens) sourceSupported

Pituitary function may recover as long as 12 years after head trauma.

“Although this is a single case report, the findings suggest that pituitary function may recover as long as 12 years after head trauma.”

• cites [260] Ruggeri, 2010, Spontaneous recovery from isolated post-traumatic central hypogonadism in a woman, Hormones (Athens) sourceSupported

Only five clinical studies and two case reports have been published on effects of GH replacement due to TBI.

“However, until now, only five clinical studies and two case reports have been published regarding the effects of GH replacement due to TBI (272-278).”

• cites [272] Bhagia, 2010, Effect of recombinant growth hormone replacement in a growth hormone deficient subject recovering from mild traumatic brain injury: a case report, Brain Inj sourceNot checked — no full text of the source
• cites [273] High, 2010, Effect of growth hormone replacement therapy on cognition after traumatic brain injury, J Neurotrauma sourcePartly supported

  The Methods describe this paper's randomized trial of GH replacement after TBI, so it is an example of a clinical study cited in the sentence. The Introduction calls the literature scant, and the Discussion mentions other studies and a case report, but neither section establishes the claimed total of five clinical studies and two case reports. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [274] Kreitschmann-Andermahr, 2008, Growth hormone deficient patients after traumatic brain injury–baseline characteristics and benefits after growth hormone replacement–an analysis of the German KIMS database, Growth Horm IGF Res sourceNot checked — no full text of the source
• cites [275] Maric, 2010, Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy, J Endocrinol Invest sourceNot checked — no full text of the source
• cites [276] Moreau, 2013, Growth hormone replacement therapy in patients with traumatic brain injury, J Neurotrauma sourceNot checked — no full text of the source
• cites [277] Reimunde, 2011, Effects of growth hormone (GH) replacement and cognitive rehabilitation in patients with cognitive disorders after traumatic brain injury, Brain Inj sourceNot checked — no full text of the source
• cites [278] Tanriverdi, 2010, Hypopituitarism due to sports related head trauma and the effects of growth hormone replacement in retired amateur boxers, Pituitary sourceNot checked — no full text of the source

GH replacement seems to have beneficial effects in TBI patients as in those with other causes of GHD in adults.

“Current data show that GH replacement seems to have beneficial effects in TBI patients as in those with other causes of GHD in adults.”

• cites [273] High, 2010, Effect of growth hormone replacement therapy on cognition after traumatic brain injury, J Neurotrauma sourceSupported
• cites [274] Kreitschmann-Andermahr, 2008, Growth hormone deficient patients after traumatic brain injury–baseline characteristics and benefits after growth hormone replacement–an analysis of the German KIMS database, Growth Horm IGF Res sourceNot checked — no full text of the source
• cites [275] Maric, 2010, Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy, J Endocrinol Invest sourceNot checked — no full text of the source
• cites [276] Moreau, 2013, Growth hormone replacement therapy in patients with traumatic brain injury, J Neurotrauma sourceNot checked — no full text of the source
• cites [277] Reimunde, 2011, Effects of growth hormone (GH) replacement and cognitive rehabilitation in patients with cognitive disorders after traumatic brain injury, Brain Inj sourceNot checked — no full text of the source

GH replacement literature suggests at least some of these deficits may be amenable to treatment.

“Furthermore, the GH replacement literature suggests that at least some of these deficits may be amenable to treatment.”

• cites [273] High, 2010, Effect of growth hormone replacement therapy on cognition after traumatic brain injury, J Neurotrauma sourceSupported
• cites [274] Kreitschmann-Andermahr, 2008, Growth hormone deficient patients after traumatic brain injury–baseline characteristics and benefits after growth hormone replacement–an analysis of the German KIMS database, Growth Horm IGF Res sourceNot checked — no full text of the source
• cites [275] Maric, 2010, Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy, J Endocrinol Invest sourceNot checked — no full text of the source
• cites [276] Moreau, 2013, Growth hormone replacement therapy in patients with traumatic brain injury, J Neurotrauma sourceNot checked — no full text of the source
• cites [277] Reimunde, 2011, Effects of growth hormone (GH) replacement and cognitive rehabilitation in patients with cognitive disorders after traumatic brain injury, Brain Inj sourceNot checked — no full text of the source

Findings from studies on GH replacement on neurocognitive/neuropsychological functions and quality of life provide promise as a treatment for cognitive impairment after brain injury.

“Although the gains are modest, the findings from studies on the effects of GH replacement on neurocogni-tive/neuropsychological functions and quality of life provide promise as a treatment for cognitive impairment after brain injury (273-277).”

• cites [273] High, 2010, Effect of growth hormone replacement therapy on cognition after traumatic brain injury, J Neurotrauma sourceSupported
• cites [274] Kreitschmann-Andermahr, 2008, Growth hormone deficient patients after traumatic brain injury–baseline characteristics and benefits after growth hormone replacement–an analysis of the German KIMS database, Growth Horm IGF Res sourceNot checked — no full text of the source
• cites [275] Maric, 2010, Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy, J Endocrinol Invest sourceNot checked — no full text of the source
• cites [276] Moreau, 2013, Growth hormone replacement therapy in patients with traumatic brain injury, J Neurotrauma sourceNot checked — no full text of the source
• cites [277] Reimunde, 2011, Effects of growth hormone (GH) replacement and cognitive rehabilitation in patients with cognitive disorders after traumatic brain injury, Brain Inj sourceNot checked — no full text of the source

In the systematic review, 1203 patients remained for analysis of chronic-phase prevalence.

“Thus, 1203 patients remained (Table 3).”

Most included studies used only one stimulation test for the GH and/or ACTH axes.

“Most studies used only one simulation test for the GH and/or ACTH axes;”

There was heterogeneity among the included studies regarding TBI severity.

“Within the 16 studies, there was heterogeneity regarding TBI severity.”

There was heterogeneity among the included studies regarding the tests used and preselection procedures for testing.

“There was also heterogeneity regarding the tests used and preselection procedures for testing.”

In six studies reporting response rate, 645 of 1563 eligible patients participated, a response rate of 41%.

“In these six studies, a total of 1563 eligible patients were invited to participate.From these eligible patients, 645 patients participated, representing a response rate of 41%.”

According to combined tests, the pooled prevalence of GHD was 11.1% in patients and 1.3% in controls.

“According to the combined tests, the pooled prevalence of GHD was 11.1 and 1.3% in patients and controls, respectively (P Ͻ .001).”

The pooled prevalence of abnormal results suggesting ACTH deficiency was 14.1% in patients and 6.6% in controls.

“The pooled prevalence of abnormal results suggesting ACTH deficiency was 14.1 and 6.6% in patients and controls, respectively (P ϭ .12).”

In very recent data from our clinic including 129 patients, using appropriate cutoff values, the reliability and efficacy of GST and ITT are similar.

“Moreover, in very recent data from our clinic including 129 patients, we have shown that by using appropriate cutoff values, the reliability and efficacy of GST and ITT are similar (229).”

• cites [229] Simsek, 2015, A comparison of low-dose ACTH, glucagon stimulation and insulin tolerance test in patients with pituitary disorders, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

Among 313 TBI patients at least 3 months post-injury in studies with confirmatory tests, 11.8% had GH deficiency based on pathological screening tests.

“| Total N | 313 | 37 | 21 | 34 | 4 | 62 | 12 |”

• Also stated in: § X. Summary and Future Directions · plain

  “| Total % | 100.0 | 11.8 | 6.7 | 10.9 | 1.3 | 19.8 | 3.8 |”

Among 1203 TBI patients in the chronic phase across studies, 27.8% had hypopituitarism.

“| Total TBI, n | 1203 | 156 | 123 | 142 | 51 | 315 | 70 | |”

• Also stated in: § X. Summary and Future Directions · plain

  “| Total TBI, % | 100.0% 13.0% 10.2% 11.8% 4.2% 27.8% | 6.2% | | | | | | |”

Among 1203 TBI patients in the chronic phase across studies, 13.0% had GH deficiency.

“| Total TBI, n | 1203 | 156 | 123 | 142 | 51 | 315 | 70 | |”

• Also stated in: § X. Summary and Future Directions · plain

  “| Total TBI, % | 100.0% 13.0% 10.2% 11.8% 4.2% 27.8% | 6.2% | | | | | | |”

Among 1203 TBI patients in the chronic phase across studies, 11.8% had ACTH deficiency.

“| Total TBI, n | 1203 | 156 | 123 | 142 | 51 | 315 | 70 | |”

• Also stated in: § X. Summary and Future Directions · plain

  “| Total TBI, % | 100.0% 13.0% 10.2% 11.8% 4.2% 27.8% | 6.2% | | | | | | |”

Among 313 TBI patients at least 3 months post-injury in studies with confirmatory tests, 14.7% had hypopituitarism based on pathological confirmatory tests.

“| Total N | 313 | 27 | 14 | 19 | 3 | 46 | 12 |”

• Also stated in: § X. Summary and Future Directions · plain

  “| Total % | 100.0 | 8.6 | 4.5 | 6.1 | 1.0 | 14.7 | 3.8 |”

Among 957 TBI patients with all GCS in the chronic phase across studies, 28.8% had hypopituitarism.

“| Total TBI all GCS, n | 957 | 144 | 81 | 129 | 39 | 255 | 50 | |”

• Also stated in: § X. Summary and Future Directions · plain

  “| Total TBI all GCS, % | 100.0% 15.0% 8.5% | 13.5% 4.1% 28.8% | 5.6% | | | | | |”

Among 313 TBI patients at least 3 months post-injury in studies with confirmatory tests, 19.8% had hypopituitarism based on pathological screening tests.

“| Total N | 313 | 37 | 21 | 34 | 4 | 62 | 12 |”

• Also stated in: § X. Summary and Future Directions · plain

  “| Total % | 100.0 | 11.8 | 6.7 | 10.9 | 1.3 | 19.8 | 3.8 |”

TBI patients without hypopituitarism had longer coma duration than those with hypopituitarism (14.0 vs 1.8 days, P<.003).

“| Days of coma | 14.0 Ϯ 2.7 | 1.8 Ϯ 0.8 | Ͻ.003 |”

TBI patients with hypopituitarism had a higher prevalence of dyslipidemia than those without hypopituitarism (46.7% vs 12.8%, P<.01).

“| Dyslipidemia, % (n) | 12.8 (6) | 46.7 (7) | Ͻ.01 |”

TBI patients with hypopituitarism had a higher prevalence of altered glucose than those without hypopituitarism (33.3% vs 2.6%, P<.005).

“| Altered glucose, % (n) | 2.6 (1) | 33.3 (5) | Ͻ.005 |”

TBI patients with hypopituitarism were older than those without hypopituitarism (46.4 vs 37.1 years, P<.02).

“| Age, y | 37.1 Ϯ 2.5 | 46.4 Ϯ 3.7 | Ͻ.02 |”

Among 246 TBI patients with GCS ≤8 in the chronic phase across studies, 24.4% had hypopituitarism.

“| Total TBI GCS Յ 8, n | 246 | 12 | 42 | 13 | 12 | 60 | 20 | |”

Among 313 TBI patients at least 3 months post-injury in studies with confirmatory tests, 8.6% had GH deficiency based on pathological confirmatory tests.

“| Total N | 313 | 27 | 14 | 19 | 3 | 46 | 12 |”

• Also stated in: § X. Summary and Future Directions · plain

  “| Total % | 100.0 | 8.6 | 4.5 | 6.1 | 1.0 | 14.7 | 3.8 |”

Among 1203 TBI patients in the chronic phase across studies, 10.2% had LH/FSH deficiency.

“| Total TBI, n | 1203 | 156 | 123 | 142 | 51 | 315 | 70 | |”

• Also stated in: § X. Summary and Future Directions · plain

  “| Total TBI, % | 100.0% 13.0% 10.2% 11.8% 4.2% 27.8% | 6.2% | | | | | | |”

TBI patients with hypopituitarism had a higher proportion of males than those without hypopituitarism (14/1 vs 24/15, P<.01).

“| Gender (M/F), n | 24/15 | 14/1 | Ͻ.01 |”

TBI patients without hypopituitarism had a higher prevalence of epilepsy than those with hypopituitarism (23.7% vs 6.7%, P<.03).

“| Epilepsy, % (n) | 23.7 (9) | 6.7 (1) | Ͻ.03 |”

TBI patients with hypopituitarism had higher HOMA-IR than those without hypopituitarism (4.8 vs 3.4, P<.02).

“| HOMA-IR | 3.4 Ϯ 0.2 | 4.8 Ϯ 0.8 | Ͻ.02 |”

TBI patients with hypopituitarism had higher triglycerides than those without hypopituitarism (161.3 vs 98.0 mg/dL, P<.05).

“| Triglycerides, mg/dL | 98.0 Ϯ 16.8 | 161.3 Ϯ 29.3 | Ͻ.05 |”

Two preliminary studies reported a high prevalence of hypopituitarism after TBI.

“In addition, two preliminary studies reported a high prevalence of hypopituitarism after TBI (13,18).”

• cites [13] Lieberman, 2001, Prevalence of neuroendocrine dysfunction in patients recovering from traumatic brain injury, J Clin Endocrinol MetabNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [18] Kelly, 2000, Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report, J Neurosurg sourceNot checked — no full text of the source

TBI was recognized as a potential cause of hypopituitarism after a review summarized 367 cases of posttraumatic hypopituitarism.

“TBI was recognized as a potential cause of hypopituitarism after a review summarized the literature on 367 cases of posttraumatic hypopituitarism (12).”

• cites [12] Benvenga, 2000, Clinical review 113: hypopituitarism secondary to head trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source

The frequency of hypopituitarism after TBI varies widely, with most studies reporting 15-50% of patients with TBI.

“The frequency of hypopituitarism after TBI varies widely among different studies (15-50% of the patients with TBI in most studies).”

• Also stated in: § I. Introduction · plain

  “Although the frequency of hypopituitarism after TBI varies widely in published reports, this finding at most reports a range of 15-50% of the patients with TBI (14,15).”

• cites [14] Schneider, 2007, Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review, JAMA sourceNot checked — no full text of the source
• cites [15] Tanriverdi, 2006, High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source

A 2007 systematic review suggested that neuroendocrine dysfunction was common after TBI.

“In 2007, a systematic review was performed to summarize the literature, suggesting that neuroendocrine dysfunction was common after TBI (14).”

• cites [14] Schneider, 2007, Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review, JAMA sourceNot checked — no full text of the source

Other studies reported a lower prevalence of hypopituitarism after brain damage, ranging from 5% to 30%.

“Other studies questioned these results by reporting a lower prevalence of hypopituitarism after brain damage (28 vs 5% [19] to 30% [20]).”

• cites [19] Kokshoorn, 2010, Hypopituitarism following traumatic brain injury: prevalence is affected by the use of different dynamic tests and different normal values, Eur J Endocrinol sourceNot checked — no full text of the source
• cites [20] Bavisetty, 2008, Chronic hypopituitarism after traumatic brain injury: risk assessment and relationship to outcome, Neurosurgery sourceNot checked — no full text of the source

Of the kickboxers, 27.3% had at least one anterior pituitary hormone deficiency.

“Of the patients, 27.3% had at least one anterior pituitary hormone deficiency.”

• cites [38] Tanriverdi, 2007, Kickboxing sport as a new cause of traumatic brain injury-mediated hypopituitarism, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

Blast injury may cause hypopituitarism at least 12 months after the event.

“These two studies suggest that blast injury may cause hypopituitarism at least 12 months after the event.”

In 104 TBI patients, there was a positive relationship between cortisol levels and GCS: less severe injuries were associated with higher cortisol levels.

“Tanriverdi et al (59) measured pituitary functions within 24 hours of trauma in a sample of 104 patients with TBI.They found that there was a positive relationship between cortisol levels and the GCS: the less severe injuries were associated with higher cortisol levels.”

• cites [59] Tanriverdi, 2007, Pituitary functions in the acute phase of traumatic brain injury: are they related to severity of the injury or mortality?, Brain Inj sourceNot checked — no full text of the source

Eight of 17 retired boxers (47%) had GHD.

“In other words, eight of the 17 retired boxers (47%) had GHD.”

• cites [46] Tanriverdi, 2008, Brief communication: pituitary volume and function in competing and retired male boxers, Ann Intern Med sourceNot checked — no full text of the source

Boxers and kickboxers are at risk of hypopituitarism.

“Therefore, boxers and kickboxers are at risk of hypopituitarism.”

Sustained increased levels of neuron-specific enolase in amateur boxers suggest subacute brain injury due to repetitive head blows.

“Sustained, increased levels of neuron-specific enolase in amateur boxers suggest subacute brain injury due to repetitive head blows.”

Body composition variables including fat ratio, fat mass, abdominal fat ratio, abdominal fat mass, BMI, and waist circumference were significantly higher in boxers with GHD compared with GH-normal boxers.

“Body composition variables, including fat ratio, fat mass, abdominal fat ratio, abdominal fat mass, body mass index (BMI), and waist circumference, were significantly higher in boxers with GHD when compared with GH-normal boxers.”

• cites [46] Tanriverdi, 2008, Brief communication: pituitary volume and function in competing and retired male boxers, Ann Intern Med sourceNot checked — no full text of the source

Boxing and kickboxing are novel causes of hypopituitarism.

“In summary, boxing and kickboxing are novel causes of hypopituitarism.”

Pituitary volume in GH-deficient boxers was significantly lower than pituitary volume in GH-normal boxers.

“Interestingly, pituitary volume in GH-deficient boxers was significantly lower than pituitary volume in GH-normal boxers.”

• cites [46] Tanriverdi, 2008, Brief communication: pituitary volume and function in competing and retired male boxers, Ann Intern Med sourceNot checked — no full text of the source

The issue of cognitive changes with sex hormone supplementation or replacement remains unresolved.

“Presently, the issue of cognitive changes with sex hormone supplementation or replacement remains unresolved (66).”

• cites [66] Moffat, 2005, Effects of testosterone on cognitive and brain aging in elderly men, Ann NY Acad Sci sourceNot checked — no full text of the source

Studies on cognitive improvement after estrogen supplementation in females have yielded conflicting results.

“however, studies on cognitive improvement after estrogen supplementation in females have yielded conflicting results (63,64).”

• cites [63] Genazzani, 2007, Estrogen, cognition and female ageing, Hum Reprod Update sourceNot checked — no full text of the source
• cites [64] Kampen, 1994, Estrogen use and verbal memory in healthy postmenopausal women, Obstet Gynecol sourceNot checked — no full text of the source

In a study by Zetterberg et al, neuron-specific enolase was significantly increased after boxing compared to normal controls.

“For example, in a study by Zetterberg et al (43), neuron-specific enolase (NSE), a glycolytic enzyme expressed selectively in neurons, was significantly increased after boxing when compared to normal controls.”

• cites [43] Zetterberg, 2009, Sustained release of neuron-specific enolase to serum in amateur boxers, Brain Inj sourceNot checked — no full text of the source

Hypothyroid patients typically demonstrate deficits seen after TBI, such as in executive functioning, speed of information processing, and aspects of memory, predominantly short-term memory.

“Hypothyroid patients typically demonstrate the types of deficits so commonly seen after TBI, such as in executive functioning, speed of information processing, and aspects of memory, predominantly short-term memory (55).”

• cites [55] Denicoff, 1990, Neuropsychiatric manifestations of altered thyroid state, Am J Psychiatry sourceNot checked — no full text of the source

Peak GH levels after GHRH+GHRP-6 stimulation correlated negatively with boxing duration and number of bouts.

“Similarly, peak GH levels after GHRHϩ GHRP-6 stimulation correlated negatively with boxing duration and number of bouts.”

• cites [37] Kelestimur, 2004, Boxing as a sport activity associated with isolated GH deficiency, J Endocrinol Invest sourceNot checked — no full text of the source

Factors associated with injury severity are antagonistic to an elevated cortisol response.

“Taken together, the results of these two studies suggest that factors associated with injury severity are antagonistic to an elevated cortisol response.”

The diagnosis and treatment of posttraumatic hypopituitarism may play a significant role in cognitive recovery from a brain injury.

“The diagnosis and treatment of posttraumatic hypopituitarism may, therefore, play a significant role in the cognitive recovery from a brain injury.”

Common cognitive symptoms after TBI are quite similar to the cognitive symptoms of hypothyroidism.

“Clearly, the common cognitive symptoms after a TBI are quite similar to the cognitive symptoms of hypothyroidism.”

There are no clear data regarding thyroid hormone replacement and cognitive outcomes in TBI patients.

“however, there are no clear data regarding thyroid hormone replacement and cognitive outcomes in TBI patients.”

In active and retired amateur boxers, IGF-1 levels were significantly lower in retired boxers than in actively competing young and adult competitors.

“IGF-1 levels were found to be significantly lower in retired boxers than in actively competing young and adult competitors.”

• cites [47] Tanriverdi, 2008, Body composition, serum IGF-1 and leptin level changes in amateur boxers: retired boxers have risk factors for cardiovascular disorders, Obes MetabNot checked yet

  Not checked in the free run.

Low IGF-1 levels, negatively correlated with body composition variables in retired boxers, could be responsible for abnormal anthropometric and body composition parameters.

“This study clearly shows that the low IGF-1 levels, which were negatively correlated with body composition variables in retired boxers, could be responsible for abnormal anthropometric and body composition parameters (47).”

• cites [47] Tanriverdi, 2008, Body composition, serum IGF-1 and leptin level changes in amateur boxers: retired boxers have risk factors for cardiovascular disorders, Obes MetabNot checked yet

  Not checked in the free run.

GH appears to affect cognitive functioning by enhancing excitatory synaptic transmission through the N-methyl-D-aspartate receptors in the hippocampus.

“GH appears to affect cognitive functioning by enhancing excitatory synaptic transmission through the N-methyl-D-aspartate receptors in the hippocampus (67).”

• cites [67] Le Grevès, 2006, Growth hormone replacement in hypophysectomized rats affects spatial performance and hippocampal levels of NMDA receptor subunit and PSD-95 gene transcript levels, Exp Brain Res sourceNot checked — no full text of the source

The results of León-Carrión et al. must be interpreted cautiously because there was no indication that injury severity was similar across groups.

“These results must be interpreted cautiously, however, because there was no indication that injury severity was similar across groups.”

• cites [73] León-Carrión, 2007, Cognitive deterioration due to GH deficiency in patients with traumatic brain injury: a preliminary report, Brain Inj sourceNot checked — no full text of the source

Greater cognitive dysfunction has been reported in patients with TBI who have GHD compared to those with normal GH levels.

“Greater cognitive dysfunction has been reported in patients with TBI who have GHD compared to those with normal GH levels (71).”

• cites [71] Kelly, 2006, Neurobehavioral and quality of life changes associated with growth hormone insufficiency after complicated mild, moderate, or severe traumatic brain injury, J Neurotrauma sourceNot checked — no full text of the source

GHD is the most common pituitary defect in TBI, either isolated or associated with other deficiencies.

“These data are supported by evidence that GHD is the most common pituitary defect in TBI, either isolated or associated with other deficiencies.”

GH modulates brain neurotransmitters.

“GH also modulates brain neurotransmitters (68) and may play a role in recovery from TBI.”

• cites [68] Burman, 1996, Growth hormone treatment affects brain neurotransmitters and thyroxine, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

There is a rapidly growing body of literature suggesting that hypopituitarism after TBI has a negative impact on cognition.

“In summary, there is a rapidly growing body of literature suggesting that hypopituitarism after TBI indeed has a negative impact on cognition.”

GHD has been demonstrated to interfere with cognitive functioning in individuals with nontraumatic conditions.

“In fact, GHD has been demonstrated to interfere with cognitive functioning in individuals with nontraumatic conditions (70).”

• cites [70] Falleti, 2006, The effects of growth hormone (GH) deficiency and GH replacement on cognitive performance in adults: a meta-analysis of the current literature, Psychoneuroendocrinology sourceNot checked — no full text of the source

Patients with hypopituitarism have a risk for premature cardiovascular death.

“In view of the risk for premature cardiovascular death in patients with hypopituitarism (77,88), major attention should be paid to those who encounter TBI because they suffer from the same comorbidities and may present other deterioration factors due to pharmacological treatments and restriction in participation in life activities and a healthy lifestyle.”

• cites [77] Tomlinson, 2001, Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group, Lancet sourceNot checked — no full text of the source
• cites [88] Rosén, 1990, Premature mortality due to cardiovascular disease in hypopituitarism, Lancet sourceNot checked — no full text of the source

The body of literature suggests that treatment of posttraumatic hypopituitarism has a positive effect on the cognitive problems associated with TBI.

“Although growing at a more moderate pace, the body of literature suggests that treatment of posttraumatic hypopituitarism has a positive effect on the cognitive problems associated with TBI.”

GH may play a role in recovery from TBI.

“GH also modulates brain neurotransmitters (68) and may play a role in recovery from TBI.”

• cites [68] Burman, 1996, Growth hormone treatment affects brain neurotransmitters and thyroxine, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

TBI patients who developed hypopituitarism had a worse metabolic profile than TBI patients who did not, particularly altered glucose levels, insulin resistance, and dyslipidemia, independent of BMI.

“More recently, Prodam et al (81), in a cross-sectional retrospective study in a tertiary care endocrinology center, confirmed that TBI patients who developed hypopituitarism had a worse metabolic profile than TBI patients who did not, particularly in terms of altered glucose levels, insulin resistance, and dyslipidemia, independent of the BMI of the patients (Table 6).”

• cites [81] Prodam, 2013, Metabolic alterations in patients who develop traumatic brain injury (TBI)-induced hypopituitarism, Growth Horm IGF Res sourceNot checked — no full text of the source

HDL cholesterol is mainly influenced by physical activity.

“It should be taken into account that HDL cholesterol is mainly influenced by physical activity (89), and physical limitations and prolonged recovery are specific for TBI patients.”

• cites [89] Barter, 2011, Raising HDL-C can be achieved by both lifestyle changes and pharmacological means. Introduction, Atheroscler Suppl sourceNot checked — no full text of the source

P300 amplitudes were significantly lower in GH-deficient boxers and kickboxers compared with GH-sufficient boxers and kickboxers and healthy controls.

“Consistent with impaired cognitive performance, P300 amplitudes were found to be significantly lower in GH-deficient boxers and kickboxers when compared with GH-sufficient boxers and kickboxers and healthy controls (72).”

• cites [72] Tanriverdi, 2013, Growth hormone deficiency due to sports-related head trauma is associated with impaired cognitive performance in amateur boxers and kickboxers as revealed by P300 auditory event-related potentials, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

TBI patients with hypopituitarism frequently present metabolic alterations, particularly altered glucose levels, insulin resistance, and hypertriglyceridemia.

“In summary, TBI patients with hypopituitarism frequently present metabolic alterations, particularly in terms of altered glucose levels, insulin resistance, and hypertriglyceridemia.”

There is a high prevalence of fasting or postchallenge glucose alterations in TBI patients with hypopituitarism.

“The second finding is the high prevalence of fasting or postchallenge glucose alterations.”

• cites [81] Prodam, 2013, Metabolic alterations in patients who develop traumatic brain injury (TBI)-induced hypopituitarism, Growth Horm IGF Res sourceNot checked — no full text of the source

The cardiovascular risk in patients with hypopituitarism without any GH treatment was the main reason that prompted researchers to propose substitutive therapy in adults.

“In fact, the cardiovascular risk in patients with hypopituitarism without any GH treatment was the main reason that prompted researchers also to propose this substitutive therapy in adults (88).”

• cites [88] Rosén, 1990, Premature mortality due to cardiovascular disease in hypopituitarism, Lancet sourceNot checked — no full text of the source

After an injury to the brain, IGF-1 increases progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus.

“After an injury to the brain, IGF-1 has also been found to increase progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus (69).”

• cites [69] Aberg, 2006, Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain, Scientific World J sourceNot checked — no full text of the source

The above-mentioned events lead to membrane degradation of cellular and vascular structures and eventually to necrosis or apoptosis of neurons.

“Furthermore, the above-mentioned events lead to membrane degradation of the cellular and vascular structures and eventually to necrosis or apoptosis of neurons (97,129,130).”

• cites [97] Werner, 2007, Pathophysiology of traumatic brain injury, Br J Anaesth sourceNot checked — no full text of the source
• cites [129] Nathoo, 2004, Influence of apoptosis on neurological outcome following traumatic cerebral contusion, J Neurosurg sourceNot checked — no full text of the source
• cites [130] Uzan, 2006, Evaluation of apoptosis in cerebrospinal fluid of patients with severe head injury, Acta Neurochir (Wien) sourceNot checked — no full text of the source

TBI induces inflammatory/immunological tissue responses similar to ischemic reperfusion injury.

“Moreover, TBI induces inflammatory/immunological tissue responses (neuroinflammation) similar to ischemic reperfusion injury.”

In another histopathological study of 42 patients who died after a motor vehicle accident, acute infarction was confirmed as the underlying adenohypophyseal pathology in those patients with TBI who did not die promptly after the trauma.

“In another histopathological study that included 42 patients who died after a motor vehicle accident, acute infarction was confirmed as the underlying adenohypophyseal pathology in those patients with TBI who did not die promptly after the trauma.”

• cites [144] Salehi, 2007, Histologic study of the human pituitary gland in acute traumatic brain injury, Brain Inj sourceNot checked — no full text of the source

Anterior pituitary necrosis is more frequent in patients who died within 1 week after head trauma.

“Several autopsy studies demonstrated that anterior pituitary necrosis is more frequent in patients who died within 1 week after head trauma (139, 142, 144).”

• cites [139] Ceballos, 1966, Pituitary changes in head trauma (analysis of 102 consecutive cases of head injury), Ala J Med SciNot checked — no full text of the source
• cites [142] Kornblum, 1969, Pituitary lesions in craniocerebral injuries, Arch PatholNot checked — no full text of the source
• cites [144] Salehi, 2007, Histologic study of the human pituitary gland in acute traumatic brain injury, Brain Inj sourceNot checked — no full text of the source

These histopathological findings suggest that in patients who survived for a couple of days after TBI, secondary insults including increased ICP and ischemic/hypoxic damage may account for a portion of pituitary and hypothalamic lesions.

“These histopathological findings suggest that in patients who survived for a couple of days after TBI, secondary insults, including increased ICP and ischemic/hypoxic damage may account for a portion of pituitary and hypothalamic lesions.”

Both primary and secondary insults may activate the release of proinflammatory mediators, prostaglandins, free radicals, and complement.

“Both primary and secondary insults may activate the release of proinflammatory mediators (cytokines or chemokines), prostaglandins, free radicals, and complement.”

Previous neuropathological studies including 638 cases after TBI have demonstrated a high frequency of 26 to 86% hypothalamo-pituitary damage in patients who died after head trauma.

“Previous neuropathological studies, including a total of 638 cases after TBI have demonstrated a high frequency of 26 to 86% hypothalamo-pituitary damage in patients who died after head trauma.”

The brain injury outcome of TBI is determined by two significantly different stages/pathophysiological mechanisms: primary insult and secondary insult.

“The brain injury outcome of TBI is determined by two significantly different stages/pathophysiological mechanisms.”

In the chronic phase after TBI, 80% of patients with TBI-induced hypopituitarism had at least one radiological anomaly, including decreased pituitary volume or empty sella, abnormal pituitary gland signal heterogeneity, and perfusion deficits.

“In the chronic phase after TBI, Schneider et al (159) demonstrated that 80% of patients with TBI-induced hypopituitarism had at least one radiological anomaly, including decreased pituitary volume or empty sella, abnormal pituitary gland signal heterogeneity, and perfusion deficits.”

• cites [159] Schneider, 2007, Pituitary imaging abnormalities in patients with and without hypopituitarism after traumatic brain injury, J Endocrinol Invest sourceNot checked — no full text of the source

Autoimmunity may explain the late appearance of pituitary dysfunction in some TBI patients who had normal pituitary function initially but developed dysfunction years after TBI.

“Autoimmunity may also explain the late appearance of pituitary dysfunction in some TBI patients in whom pituitary function was normal at the beginning but who developed pituitary dysfunction some years after TBI.”

Pituitary hormone levels were not reported in that early histopathological study.

“Nevertheless, pituitary hormone levels were not reported.”

In all patients who had persistent pituitary hormone deficiency from the third year to the fifth year, strong positivity of APA and/or AHA was present in the third year.

“Interestingly, in all patients who had persistent pituitary hormone deficiency from the third year to the fifth year, strong positivity of APA and/or AHA was present in the third year (16).”

• cites [16] Tanriverdi, 2013, A five year prospective investigation of anterior pituitary function after traumatic brain injury: is hypopituitarism long-term after head trauma associated with autoimmunity?, J Neurotrauma sourceNot checked — no full text of the source

In clinical studies of patients who survived TBI, acute radiological findings (DAI, basal skull fracture, diffuse brain swelling, evacuated intracerebral hematoma, or multiple contusions on cranial CT or MRI) were associated with hypopituitarism at least 6 months after head trauma.

“Moreover, in clinical studies including patients who survived after TBI, acute radiological findings (specifically DAI, basal skull fracture, diffuse brain swelling, evacuated intracerebral hematoma, or multiple contusions on cranial CT or MRI) were shown to be associated with hypopituitarism at least 6 months after the head trauma (18, 20, 154 -156).”

• cites [18] Kelly, 2000, Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report, J Neurosurg sourceNot checked — no full text of the source
• cites [20] Bavisetty, 2008, Chronic hypopituitarism after traumatic brain injury: risk assessment and relationship to outcome, Neurosurgery sourceNot checked — no full text of the source
• cites [154] Bondanelli, 2004, Occurrence of pituitary dysfunction following traumatic brain injury, J Neurotrauma sourceNot checked — no full text of the source
• cites [155] Jeong, 2010, Negative effect of hypopituitarism following brain trauma in patients with diffuse axonal injury, J Neurosurg sourceNot checked — no full text of the source
• cites [156] Schneider, 2008, Predictors of anterior pituitary insufficiency after traumatic brain injury, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

Despite abnormal pituitary functions in patients with TBI, MRI may fail to reveal any abnormalities.

“However, despite abnormal pituitary functions in patients with TBI, MRI may fail to reveal any abnormalities (157).”

• cites [157] Makulski, 2008, Neuroimaging in posttraumatic hypopituitarism, J Comput Assist Tomogr sourceNot checked — no full text of the source

The vascular hypothesis for TBI-induced chronic hypopituitarism is supported by some clinical and radiological studies.

“Regarding the pathophysiology of TBI-induced chronic hypopituitarism, the vascular hypothesis is supported by some clinical and radiological studies.”

Most acute phase pituitary hormonal changes, such as decreased gonadotropins and TSH but increased HPA axis activity, may simply represent adaptive physiological responses to critical illness.

“Most of the acute phase pituitary hormonal changes, such as decreased gonadotropins (FSH and/or LH) and TSH, but increased hypothalamic-pituitary-adrenal (HPA) axis activity, may simply represent adaptive physiological responses to critical illness.”

The second line of evidence that supports a vascular etiology for chronic hypopituitarism after TBI is related to the pattern of hormonal loss.

“The second line of evidence that supports a vascular etiology for chronic hypopituitarism after TBI is related to the pattern of hormonal loss.”

The relation between pathological findings and hormonal consequences was unknown in the autopsy studies.

“In addition, the relation between pathological findings and hormonal consequences was unknown.”

It is difficult to generalize about these histopathological findings for nonfatal TBI to explain chronic hypopituitarism in survivors.

“Therefore, it is difficult to generalize about these histopathological findings for nonfatal TBI to explain the chronic hypopituitarism in survivors.”

Recent radiological imaging studies of the hypothalamo-pituitary region after TBI have demonstrated several pathological changes consistent with vascular injury.

“First, recent radiological imaging studies of the hypothalamo-pituitary region after TBI have demonstrated several pathological changes consistent with vascular injury (136).”

• cites [136] Maiya, 2008, Magnetic resonance imaging changes in the pituitary gland following acute traumatic brain injury, Intensive Care Med sourceNot checked — no full text of the source

There were significant associations between the presence of strongly positive APA and/or AHA and hypopituitarism in the fifth year of TBI.

“There were significant associations between the presence of strongly positive APA and/or AHA and hypopituitarism in the fifth year of TBI.”

• cites [16] Tanriverdi, 2013, A five year prospective investigation of anterior pituitary function after traumatic brain injury: is hypopituitarism long-term after head trauma associated with autoimmunity?, J Neurotrauma sourceNot checked — no full text of the source

Higher APA titers were associated with lower GH response to the GHRH+GHRP-6 test.

“Additionally, higher APA titers were shown to be associated with lower GH response to the GHRHϩGHRP-6 test (161).”

• cites [161] Tanriverdi, 2008, Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

In an early histopathological study, injured portal vessels can regenerate and grow down into surviving areas of the anterior lobe.

“In an early histopathological study, it was demonstrated that the injured portal vessels can regenerate (mitotic figures among the surviving cells have been documented) and grow down into the surviving areas of the anterior lobe (132).”

• cites [132] Daniel, 1959, Traumatic infarction of the anterior lobe of the pituitary gland, Lancet sourceNot checked — no full text of the source

These studies favor a role of autoimmunity in the development of chronic hypopituitarism after TBI.

“These studies are in favor of the role of autoimmunity in the development of chronic hypopituitarism after TBI.”

Activation of the IGF-1 receptor antiapoptotic pathway by mild TBI could be part of a neuroprotective process for maintaining normal brain function.

“Activation of the IGF-1 receptor antiapoptotic pathway by mild TBI could be a part of a neuroprotective process for maintaining normal brain function (184).”

• cites [184] Rubovitch, 2010, The intricate involvement of the insulin-like growth factor receptor signaling in mild traumatic brain injury in mice, Neurobiol Dis sourceNot checked — no full text of the source

APO E has been shown to reduce the neuroinflammatory response in vitro and in vivo in an isoform-specific fashion.

“APO E has also been shown to reduce the neuroinflammatory response in vitro and in vivo in an isoform-specific fashion (171).”

• cites [171] Laskowitz, 1997, Apolipoprotein E suppresses glial cell secretion of TNF α, J Neuroimmunol sourceNot checked — no full text of the source

Microvascular and microstructural changes have been documented, especially in mild TBI.

“In addition, microvascular and microstructural changes have also been documented, especially in mild TBI.”

The APO E4 isoform is less effective than the APO E3 isoform in inhibiting inflammatory cytokines in the peripheral circulation and in the brain.

“The APO E4 isoform has been shown to be less effective than the APO E3 isoform in inhibiting inflammatory cytokines, both in the peripheral circulation and in the brain (172).”

• cites [172] Laskowitz, 2001, Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides, Exp Neurol sourceNot checked — no full text of the source

Recent clinical and experimental data indicate a possible role of autoimmunity and genetic predisposition in the development of TBI-induced hypopituitarism.

“Recent clinical and experimental data have indicated the possible role of autoimmunity and genetic predisposition in the development of TBI-induced hypopituitarism.”

After controlled cortical impacts in mice, barrier properties of tanycytes were compromised by disruption of tight junctions.

“Several pathological alterations were detected in the median eminence as follows: 1) the barrier properties of tanycytes were compromised by the disruption of tight junctions; 2) endogenous IgG was increased near the third ventricle; and 3) increased permeability of the third ventricle.”

• cites [177] Osterstock, 2014, Sustained alterations of hypothalamic tanycytes during posttraumatic hypopituitarism in male mice, Endocrinology sourceNot checked — no full text of the source

Due to anatomical localization, the pituitary gland, stalk, hypothalamus, and long hypophyseal portal vessels passing through the diaphragma sellae are particularly vulnerable to direct mechanical trauma, ischemic changes, and edema compression.

“In summary, due to the anatomical localization of the pituitary gland, stalk, and hypothalamus, and because the long hypophyseal portal vessels pass through the diaphragma sellae, they are particularly vulnerable to direct mechanical trauma, ischemic changes, and edema compression.”

An increase in Evans Blue dye extravasation in the pituitary gland was observed after repetitive mild TBI.

“An increase in Evans Blue dye extravasation in the pituitary gland was observed, which implies that a vascular event occurred, supporting the vascular hypothesis in the pathogenesis (175).”

• cites [175] Greco, 2013, The effects of repeat traumatic brain injury on the pituitary in adolescent rats, J Neurotrauma sourceNot checked — no full text of the source

Early pathological changes in cellular and microvascular structures of the brain may be detected by diffusion tensor imaging in boxers.

“Early pathological changes in the cellular and microvascular structures of the brain may be detected by diffusion tensor imaging in boxers (40).”

• cites [40] Zhang, 2003, Increased diffusion in the brain of professional boxers: a preclinical sign of traumatic brain injury?, AJNR Am J NeuroradiolNot checked — no full text of the source

Extensive experimental data in animal models indicate that repetitive minor head trauma with axonal damage increases the brain's vulnerability for additional concussive impacts.

“Extensive experimental data in animal models indicate that repetitive minor head trauma with axonal damage increases the brain's vulnerability for additional concussive impacts (173, 174).”

• cites [173] Barkhoudarian, 2011, The molecular pathophysiology of concussive brain injury, Clin Sports Med sourceNot checked — no full text of the source
• cites [174] Laurer, 2001, Mild head injury increasing the brain's vulnerability to a second concussive impact, J Neurosurg sourceNot checked — no full text of the source

Repeated closed mild head injury in adolescent rats causes significant acute and chronic suppression of GH and IGF-1 levels.

“This model of repetitive mild TBI documented significant acute and chronic suppression of GH and IGF-1 levels, suggesting that a cumulative effect may occur that results in the disruption of the GH/IGF-1 axis.”

The diagnosis of TBI-induced hypopituitarism is made similarly to the diagnosis of classical hypopituitarism because of hypothalamic or pituitary diseases.

“The diagnosis of TBI-induced hypopituitarism, defined as the deficient hormone secretion of one or more pituitary hormones because of TBI, is made similarly to the diagnosis of classical hypopituitarism because of hypothalamic or pituitary diseases.”

• cites [194] Schneider, 2007, Hypopituitarism, Lancet sourceNot checked — no full text of the source

GH and IGF-1 may play a crucial role in brain repair mechanisms or neuronal recovery after trauma by regulating neuronal plasticity, myelin formation, and vascular tone.

“Therefore, GH and IGF-1 may play a crucial role in brain repair mechanisms or neuronal recovery after trauma by regulating factors including neuronal plasticity, myelin formation, and vascular tone (69,(185)(186)(187)(188)(189).”

• cites 69,(185)(186)(187)(188)(189)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The ratio of pituitary dysfunction was significantly lower in subjects with APO E3/E3 (17.7%) than in subjects without the APO E3/E3 genotype (41.9%) (P=.01; OR=0.29).

“The ratio of pituitary dysfunction was significantly lower in subjects with APO E3/E3 (17.7%) than in subjects without the APO E3/E3 genotype (41.9%) (P ϭ .01;odds ratio ϭ 0.29) (163).”

• cites [163] Tanriverdi, 2008, Apolipoprotein E3/E3 genotype decreases the risk of pituitary dysfunction after traumatic brain injury due to various causes: preliminary data, J Neurotrauma sourceNot checked — no full text of the source

The vascular hypothesis is currently one of the strong hypotheses for the pathogenesis of chronic hypopituitarism after TBI.

“Therefore, the vascular hypothesis is currently one of the strong hypotheses for the pathogenesis of chronic hypopituitarism after TBI.”

In mice with controlled cortical impacts, GH levels were impaired at 1 month after head trauma.

“GH levels were impaired at 1 month after head trauma, suggesting a similarity between new-onset hormone deficiencies (delayed pituitary hormone deficiency long term after TBI) in human studies (16,161,181).”

• cites [177] Osterstock, 2014, Sustained alterations of hypothalamic tanycytes during posttraumatic hypopituitarism in male mice, Endocrinology sourceNot checked — no full text of the source

After controlled cortical impacts in mice, endogenous IgG was increased near the third ventricle.

“Several pathological alterations were detected in the median eminence as follows: 1) the barrier properties of tanycytes were compromised by the disruption of tight junctions; 2) endogenous IgG was increased near the third ventricle; and 3) increased permeability of the third ventricle.”

• cites [177] Osterstock, 2014, Sustained alterations of hypothalamic tanycytes during posttraumatic hypopituitarism in male mice, Endocrinology sourceNot checked — no full text of the source

In infant rats with contusion injury, IGF-1 levels were significantly decreased at both 7 days and 3 weeks after TBI.

“It was reported that the IGF-1 levels were significantly decreased at both 7 days and 3 weeks after TBI.”

• cites [178] Ozdemir, 2012, Relationship between circulating IGF-1 levels and traumatic brain injury-induced hippocampal damage and cognitive dysfunction in immature rats, Neurosci Lett sourceNot checked — no full text of the source

Despite exposure to similar severity of head trauma, some people develop pituitary dysfunction whereas others do not, suggesting individual susceptibility.

“Despite exposure to a similar severity of head trauma, some people develop pituitary dysfunction whereas others do not, suggesting individual susceptibility.”

This novel mechanism may partially explain development of autoantibodies after head trauma and TBI-induced hypopituitarism with normal pituitary gland and pituitary stalk.

“Therefore, this novel mechanism may partially explain the development of autoantibodies after head trauma and TBI-induced hypopituitarism with normal pituitary gland and pituitary stalk.”

Head trauma may trigger an ongoing cascade of vascular and histopathological alterations involving mediators of inflammation, particularly in individuals with a genetic predisposition.

“Head trauma may trigger an ongoing cascade of vascular and histopathological alterations involving mediators of inflammation (persistent neuroinflammation), particularly in individuals who have a genetic predisposition.”

After controlled cortical impacts in mice, permeability of the third ventricle was increased.

“Several pathological alterations were detected in the median eminence as follows: 1) the barrier properties of tanycytes were compromised by the disruption of tight junctions; 2) endogenous IgG was increased near the third ventricle; and 3) increased permeability of the third ventricle.”

• cites [177] Osterstock, 2014, Sustained alterations of hypothalamic tanycytes during posttraumatic hypopituitarism in male mice, Endocrinology sourceNot checked — no full text of the source

In a transgenic mouse model, somatotropes were considerably regenerated during the months after injury, suggesting recovery from stem/progenitor cells.

“The authors showed that the somatotropes were considerably regenerated during the months after injury, suggesting recovery of somatotropes from stem/progenitor cells (190).”

• cites [190] Fu, 2012, The adult pituitary shows stem/progenitor cell activation in response to injury and is capable of regeneration, Endocrinology sourceNot checked — no full text of the source

Dynamic hormonal changes during long-term prospective follow-up of TBI patients cannot be completely explained by the vascular hypothesis.

“However, the dynamic hormonal changes (new-onset hormonal deficiencies or recovery, especially in mild TBI) during the long-term prospective follow-up of TBI patients cannot be completely explained by the vascular hypothesis.”

In mild TBI and sports-related repetitive head trauma, concussion resulting in DAI due to rotational and shearing forces can affect hypothalamo-pituitary functions.

“In mild TBI and sports-related repetitive head trauma, concussion resulting in DAI, due to rotational and shearing forces, can also affect hypothalamo-pituitary functions.”

The GH impairment at 1 month in mice suggests similarity to new-onset hormone deficiencies in human studies.

“GH levels were impaired at 1 month after head trauma, suggesting a similarity between new-onset hormone deficiencies (delayed pituitary hormone deficiency long term after TBI) in human studies (16,161,181).”

• cites [16] Tanriverdi, 2013, A five year prospective investigation of anterior pituitary function after traumatic brain injury: is hypopituitarism long-term after head trauma associated with autoimmunity?, J Neurotrauma sourceNot checked — no full text of the source
• cites [161] Tanriverdi, 2008, Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [181] Aimaretti, 2005, Residual pituitary function after brain injury-induced hypopituitarism: a prospective 12-month study, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Decreased IGF-1 levels were closely associated with hippocampal neuronal loss and spatial memory deficits.

“Moreover, it was demonstrated that decreased IGF-1 levels were closely associated with hippocampal neuronal loss and spatial memory deficits (178).”

• cites [178] Ozdemir, 2012, Relationship between circulating IGF-1 levels and traumatic brain injury-induced hippocampal damage and cognitive dysfunction in immature rats, Neurosci Lett sourceNot checked — no full text of the source

In a recent meta-analysis including 27 studies, injury severity according to postresuscitation GCS was significantly associated with an increased risk of long-term hypopituitarism (>=12 mo after TBI).

“In a recent meta-analysis including 27 studies evaluating at least one potential predictor of TBI-induced hypopituitarism, the injury severity according to postresuscitation GCS was significantly associated with an increased risk of long-term hypopituitarism (Ն12 mo after TBI).”

• cites [234] Lauzier, 2014, Clinical outcomes, predictors, and prevalence of anterior pituitary disorders following traumatic brain injury: a systematic review, Crit Care Med sourceNot checked — no full text of the source

Acute phase radiological findings (specifically DAI, basal skull fracture, diffuse brain swelling, evacuated intracerebral hematoma, or multiple contusions on cranial CT or MRI) seem to be valuable for predicting hypopituitarism during the chronic phase of TBI.

“In conclusion, acute phase radiological findings (specifically DAI, basal skull fracture, diffuse brain swelling, evacuated intracerebral hematoma, or multiple contusions on cranial CT or MRI) seem to be valuable for predicting hypopituitarism during the chronic phase of TBI.”

No test, including the ITT, can classify all subjects correctly.

“It has to be borne in mind that no test, including the ITT, can classify all subjects correctly (194, 199, 206 -209).”

• cites [194] Schneider, 2007, Hypopituitarism, Lancet sourceNot checked — no full text of the source
• cites [199] Arlt, 2003, Adrenal insufficiency, Lancet sourceNot checked — no full text of the source
• cites [206] Mayenknecht, 1998, Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [207] Nye, 2001, Adrenocorticotropin stimulation tests in patients with hypothalamic-pituitary disease: low dose, standard high dose and 8-h infusion tests, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [208] Soule, 2000, The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [209] Suliman, 2002, The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

None of the tests for assessment of GHD are totally reliable.

“In conclusion, for the diagnosis of GHD in TBI patients, we need to consider that none of the tests for the assessment of GHD are totally reliable.”

Others have demonstrated that hypopituitarism was more frequent in patients with more severe TBI.

“In most studies, no significant associations between TBI severity according to postresuscitation GCS and hypopituitarism in the chronic phase have been reported (15, 23, 24, 27, 29, 181, 231-233), whereas others have demonstrated that hypopituitarism was more frequent in patients with more severe TBI (18,30,154).”

• cites [18] Kelly, 2000, Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report, J Neurosurg sourceNot checked — no full text of the source
• cites [30] Klose, 2007, Prevalence and predictive factors of post-traumatic hypopituitarism, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [154] Bondanelli, 2004, Occurrence of pituitary dysfunction following traumatic brain injury, J Neurotrauma sourceNot checked — no full text of the source

Use of a non-BMI-related cutoff in obese subjects causes a high percentage of false-positive results.

“However, the GH response to GHRHϩARG, and to all known GH provocative stimuli, significantly declines with increasing BMI in adults (221, 222); thus, the use of a non-BMI-related cutoff in obese subjects causes a high percentage of false-positive results (203).”

• cites [203] Schneider, 2006, Discrepant results in the diagnosis of GH deficiency with the insulin-tolerance test and the GHRH plus arginine test in patients with traumatic brain injury, Eur J Endocrinol sourceNot checked — no full text of the source

For the diagnosis of TBI-induced GHD, the ITT and the GHRH+ARG test are considered tests of choice with similar accuracy.

“For the diagnosis of TBI-induced GHD, the ITT and the GHRHϩARG test are now considered as the tests of choice with similar accuracy (194,215).”

• cites [194] Schneider, 2007, Hypopituitarism, Lancet sourceNot checked — no full text of the source
• cites [215] Molitch, 2011, Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab sourceNot checked — no full text of the source

In a small retrospective study, MRI or CT scans of 22 patients long term after TBI found abnormalities in the pituitary region in 80% of patients with TBI and hypopituitarism compared with only 29% of patients without hypopituitarism.

“In a small retrospective study, the MRI or CT scans of 22 patients were evaluated long term after TBI (mean time, nearly 17 Ϯ 15 y); abnormalities (the most common abnormality was loss of volume or empty sella) in the pituitary region were found in 80% of patients with TBI, and hypopituitarism compared with only 29% of patients without hypopituitarism (159).”

• cites [159] Schneider, 2007, Pituitary imaging abnormalities in patients with and without hypopituitarism after traumatic brain injury, J Endocrinol Invest sourceNot checked — no full text of the source

The glucagon stimulation test can differentiate between GH-deficient and healthy subjects with a sensitivity and specificity of 100% if a peak GH of 3 ug/L is considered.

“The glucagon stimulation test (GST) (1 mg glucagon im, GH measurements every 30 min until 240 min after administration) has been proposed as an alternative diagnostic because it is able to differentiate between GH-deficient and healthy subjects with a sensitivity and specificity of 100% if a peak GH of 3 g/L is considered (215, 226).”

• cites [215] Molitch, 2011, Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [226] Gómez, 2002, Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

MRI during the chronic phase of TBI may be normal despite abnormal pituitary functions in patients with TBI.

“In an article analyzing MRI as a neuroimaging method in posttraumatic pituitary region evaluation, the authors reported that despite abnormal pituitary functions in patients with TBI, MRI during the chronic phase of TBI may be normal (157).”

• cites [157] Makulski, 2008, Neuroimaging in posttraumatic hypopituitarism, J Comput Assist Tomogr sourceNot checked — no full text of the source

For the ITT, peak GH response levels lower than 3 ug/L indicate severe GHD in adults if hypoglycemia is adequately reached.

“For the ITT, peak GH response levels lower than 3 g/L indicate severe GHD in adults (if hypoglycemia is adequately reached) (194,215).”

• cites [194] Schneider, 2007, Hypopituitarism, Lancet sourceNot checked — no full text of the source
• cites [215] Molitch, 2011, Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Older age does not seem to be a strong predictor of hypopituitarism.

“Therefore, older age does not seem to be a strong predictor, and during daily clinical practice a patient cannot be excluded from pituitary testing based only on age.”

In a systematic review by Schneider et al including 1015 TBI patients, the pooled prevalence of hypopituitarism in the chronic phase was significantly higher in severe TBI patients compared with mild and moderate TBI patients.

“In a systematic review by Schneider et al (14) including 1015 TBI patients, the pooled prevalence of hypopituitarism in the chronic phase was significantly higher in severe TBI patients (according to postresuscitation GCS) when compared with mild and moderate TBI patients.”

• cites [14] Schneider, 2007, Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review, JAMA sourceNot checked — no full text of the source

The likelihood of GHD in TBI patients increases with additional pituitary axes deficiencies.

“The likelihood of GHD in TBI patients increases with additional pituitary axes deficiencies (230).”

• cites [230] Gasco, 2012, Hypopituitarism following brain injury: when does it occur and how best to test?, Pituitary sourceNot checked — no full text of the source

Normal radiological findings of the pituitary region at the chronic phase after TBI do not exclude the presence of posttraumatic hypopituitarism.

“However, at the chronic phase after TBI, normal radiological findings of the pituitary region do not exclude the presence of posttraumatic hypopituitarism.”

Panhypopituitarism in the acute phase may be a predictor of chronic hypopituitarism.

“However, panhypopituitarism in the acute phase may be a predictor of chronic hypopituitarism (181).”

• cites [181] Aimaretti, 2005, Residual pituitary function after brain injury-induced hypopituitarism: a prospective 12-month study, J Clin Endocrinol Metab sourceNot checked — no full text of the source

15 of 18 mild TBI patients (including the three patients with pituitary dysfunction) had abnormal initial CT findings (mainly epidural/subdural hematoma and cranial vault fractures).

“Moreover, 15 of 18 mild TBI patients (including the three patients with pituitary dysfunction) had abnormal initial CT findings (mainly epidural/subdural hematoma and cranial vault fractures), clearly showing that complicated mild TBI patients have a substantial risk of hypopituitarism (161).”

• cites [161] Tanriverdi, 2008, Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

The pooled prevalences of hypopituitarism in mild, moderate, and severe TBI were estimated as 16.8, 10.9, and 35.3%, respectively.

“The pooled prevalences of hypopituitarism in mild, moderate, and severe TBI were estimated as 16.8, 10.9, and 35.3%, respectively (14).”

• cites [14] Schneider, 2007, Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review, JAMA sourceNot checked — no full text of the source

Nearly 10-39% of patients with mild TBI have day-of-injury intracranial abnormalities (eg, edema, hematoma, or contusion) detected on CT.

“However, previous studies revealed that nearly 10 -39% of patients with mild TBI have day-ofinjury intracranial abnormalities (eg, edema, hematoma, or contusion) detected on CT (250 -252).”

• cites [250] Borg, 2004, Non-surgical intervention and cost for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury, J Rehabil Med sourceNot checked — no full text of the source
• cites [251] French, 1977, The value of computerized tomography in the management of 1000 consecutive head injuries, Surg NeurolNot checked — no full text of the source
• cites [252] Iverson, 2000, Prevalence of abnormal CT-scans following mild head injury, Brain Inj sourceNot checked — no full text of the source

Lower mean plasma cortisol during the first 10 days of TBI was significantly associated with the development of chronic hypopituitarism of any axis.

“The authors clearly demonstrated that lower mean plasma cortisol during the first 10 days of TBI was significantly associated with the development of chronic hypopituitarism of any axis.”

• cites [241] Hannon, 2013, Acute glucocorticoid deficiency and diabetes insipidus are common after acute traumatic brain injury and predict mortality, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Complicated mild TBI patients have a substantial risk of hypopituitarism.

“Moreover, 15 of 18 mild TBI patients (including the three patients with pituitary dysfunction) had abnormal initial CT findings (mainly epidural/subdural hematoma and cranial vault fractures), clearly showing that complicated mild TBI patients have a substantial risk of hypopituitarism (161).”

• cites [161] Tanriverdi, 2008, Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

There was a trend toward significant association for acute central DI to predict hypopituitarism other than GHD.

“There was also a trend toward significant association for acute central DI to predict hypopituitarism other than GHD (241).”

• cites [241] Hannon, 2013, Acute glucocorticoid deficiency and diabetes insipidus are common after acute traumatic brain injury and predict mortality, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Loss of consciousness and increased duration of coma were reported to be associated with chronic hypopituitarism.

“Moreover, in a retrospective clinical review, loss of consciousness and increased duration of coma were reported to be associated with chronic hypopituitarism (12).”

• cites [12] Benvenga, 2000, Clinical review 113: hypopituitarism secondary to head trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Neuropsychological functioning in complicated mild TBI is significantly worse than in uncomplicated TBI.

“In a previous study, it was clearly demonstrated that neuropsychological functioning in complicated mild TBI is significantly worse than in uncomplicated TBI (254).”

• cites [254] Lange, 2009, Neuropsychological functioning following complicated vs. uncomplicated mild traumatic brain injury, Brain Inj sourceNot checked — no full text of the source

In the acute phase, most pituitary hormonal changes, such as decreased gonadotropins and TSH and increased HPA axis activity, may simply represent adaptive physiological responses to critical illness.

“In the acute phase, most of the pituitary hormonal changes, such as decreased gonadotropins (FSH and/or LH) and TSH, and increased HPA axis activity may simply represent adaptive physiological responses to critical illness.”

Severity of head trauma is a strong predictor of hypopituitarism in patients with moderate and severe TBI.

“This approach seems logical and practical because the severity of head trauma is a strong predictor (Table 8) of hypopituitarism in patients with moderate and severe TBI.”

• cites Table 8Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Gender and BMI have not been uniformly identified as predictors.

“Gender and BMI, which have also been examined, have not been uniformly identified as predictors (15, 24, 30, 154, 232).”

• cites [15] Tanriverdi, 2006, High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [24] Leal-Cerro, 2005, Prevalence of hypopituitarism and growth hormone deficiency in adults long-term after severe traumatic brain injury, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [30] Klose, 2007, Prevalence and predictive factors of post-traumatic hypopituitarism, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [154] Bondanelli, 2004, Occurrence of pituitary dysfunction following traumatic brain injury, J Neurotrauma sourceNot checked — no full text of the source
• cites [232] Popovic, 2004, Hypopituitarism as a consequence of traumatic brain injury (TBI) and its possible relation with cognitive disabilities and mental distress, J Endocrinol Invest sourceNot checked — no full text of the source

In a meta-analysis including 1015 TBI patients, the pooled prevalence of anterior hypopituitarism was 27.5% (95% confidence interval, 22.8-28.9).

“However, in a meta-analysis including 1015 TBI patients, from 10 crosssectional and four prospective studies, the pooled prevalence of anterior hypopituitarism was reported as 27.5% (95% confidence interval, 22.8 -28.9).”

• cites [14] Schneider, 2007, Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review, JAMA sourceNot checked — no full text of the source

There is no clear evidence that replacement of GH, FSH/LH, and TSH deficiencies in critically ill TBI patients during the acute phase is beneficial.

“Currently, there is no clear evidence that the replacement of GH, FSH/LH, and TSH deficiencies in critically ill TBI patients during the acute phase is beneficial (14,244,256).”

• Also stated in: § 1. Treatment of TSH, FSH/LH, and GH deficiencies in the acute phase · plain

  “In summary, there is no clear evidence that the replacement of GH, FSH/LH, and TSH deficiencies in critically ill TBI patients during the acute phase is beneficial (14,244,256).”

• cites [14] Schneider, 2007, Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review, JAMA sourceNot checked — no full text of the source
• cites [244] Glynn, 2013, Which patient requires neuroendocrine assessment following traumatic brain injury, when and how?, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [256] Tanriverdi, 2013, Endocrinology of acute brain injuryNot checked yet

  Not checked in the free run.

Low cortisol levels were significantly associated with lower blood pressure and higher vasopressor use.

“Moreover, the low cortisol levels were significantly associated with lower blood pressure and higher vasopressor use (238).”

• cites [238] Cohan, 2005, Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study, Crit Care Med sourceNot checked — no full text of the source

There is no clear evidence that early GH replacement is beneficial for recovery of pituitary function or rehabilitation of TBI.

“Moreover, a 6-month period is generally too short to see the clinical features of GHD, and currently there is no clear evidence that early GH replacement could be beneficial for the recovery of pituitary function or for the rehabilitation of TBI; this is discussed in the pathophysiology and treatment sections in detail (Sections VI and IX).”

A 6-month period is generally too short to see clinical features of GHD.

“Moreover, a 6-month period is generally too short to see the clinical features of GHD, and currently there is no clear evidence that early GH replacement could be beneficial for the recovery of pituitary function or for the rehabilitation of TBI; this is discussed in the pathophysiology and treatment sections in detail (Sections VI and IX).”

In the first 2 weeks after TBI, reported incidence of ACTH deficiency ranges from 4% to 78% across 11 major studies.

“To date, there have been only 11 major studies evaluating pituitary function in the first 2 weeks after TBI; these have reported an incidence of ACTH deficiency of between 4 and 78% (15, 25, 59, 150, 151, 236 -241).”

• cites [15] Tanriverdi, 2006, High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [25] Kleindienst, 2009, Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: a prospective longitudinal evaluation, J Neurotrauma sourceNot checked — no full text of the source
• cites [59] Tanriverdi, 2007, Pituitary functions in the acute phase of traumatic brain injury: are they related to severity of the injury or mortality?, Brain Inj sourceNot checked — no full text of the source
• cites [150] Klose, 2007, Acute and long-term pituitary insufficiency in traumatic brain injury: a prospective single-centre study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [151] Krahulik, 2010, Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults, J Neurosurg sourceNot checked — no full text of the source
• cites [236] Agha, 2004, Neuroendocrine dysfunction in the acute phase of traumatic brain injury, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source
• cites [237] Cernak, 1999, Neuroendocrine responses following graded traumatic brain injury in male adults, Brain Inj sourceNot checked — no full text of the source
• cites [238] Cohan, 2005, Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study, Crit Care Med sourceNot checked — no full text of the source
• cites [239] Della Corte, 1998, Provocative hypothalamopituitary axis tests in severe head injury: correlations with severity and prognosis, Crit Care Med sourceNot checked — no full text of the source
• cites [240] Hackl, 1991, Endocrine abnormalities in severe traumatic brain injury–a cue to prognosis in severe craniocerebral trauma?, Intensive Care Med sourceNot checked — no full text of the source

Only three long-term prospective studies have reported screening pituitary functions for longer than 12 months.

“Only three long-term prospective studies have reported screening pituitary functions for longer than 12 months (16,25,161).”

• cites [16] Tanriverdi, 2013, A five year prospective investigation of anterior pituitary function after traumatic brain injury: is hypopituitarism long-term after head trauma associated with autoimmunity?, J Neurotrauma sourceNot checked — no full text of the source
• cites [25] Kleindienst, 2009, Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: a prospective longitudinal evaluation, J Neurotrauma sourceNot checked — no full text of the source
• cites [161] Tanriverdi, 2008, Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

Global pituitary screening of all TBI patients admitted to emergency units is not necessary due to the low risk of hypopituitarism.

“This study, which included mainly uncomplicated mild TBI patients, suggests that global pituitary screening of all TBI patients admitted to emergency units is not necessary due to the low risk of hypopituitarism.”

The main limitation of the three long-term studies is the low number of patients, especially in moderate and severe TBI groups.

“The main limitation of these three long-term studies (16,25,161) is the low number of patients, especially in the moderate and severe TBI groups.”

• cites [16] Tanriverdi, 2013, A five year prospective investigation of anterior pituitary function after traumatic brain injury: is hypopituitarism long-term after head trauma associated with autoimmunity?, J Neurotrauma sourceNot checked — no full text of the source
• cites [25] Kleindienst, 2009, Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: a prospective longitudinal evaluation, J Neurotrauma sourceNot checked — no full text of the source
• cites [161] Tanriverdi, 2008, Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

In Kleindienst et al study, all patients with TSH and FSH/LH deficiencies recovered completely in the chronic phase.

“All of the patients with TSH and FSH/LH deficiencies recovered completely in the chronic phase.”

• cites [25] Kleindienst, 2009, Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: a prospective longitudinal evaluation, J Neurotrauma sourceNot checked — no full text of the source

In Takala et al study, high-dose GH in critically ill patients (not TBI) doubled mortality.

“A large multicenter study by Takala et al (264) showed that the administration of high doses of GH (0.1 mg/kg/d) in critically ill patients (TBI patients were not included), instead of improving outcome, actually doubled mortality.”

• cites [264] Takala, 1999, Increased mortality associated with growth hormone treatment in critically ill adults, N Engl J Med sourceNot checked — no full text of the source

In critically ill burn or medical patients, acute thyroid hormone replacement therapy was not shown to produce short-term improvement.

“In critically ill burn or medical patients, acute thyroid hormone replacement therapy was not shown to produce short-term improvement (262).”

• cites [262] Vanhorebeek, 2004, Hormonal and metabolic strategies to attenuate catabolism in critically ill patients, Curr Opin Pharmacol sourceNot checked — no full text of the source

In Tanriverdi et al 3-year study, GHD decreased from 43.3% at 1 year to 23.3% at 3 years.

“Overall, the percentage of patients with GHD decreased from 43.3% at 1 year to 23.3% at 3 years.”

• cites [161] Tanriverdi, 2008, Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

TSH deficiency (central hypothyroidism) generally recovers during or after the acute phase.

“Prospective studies demonstrated that TSH deficiency (central hypothyroidism) generally recovers during or after the acute phase (14,261).”

• cites [14] Schneider, 2007, Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review, JAMA sourceNot checked — no full text of the source
• cites [261] Sundaram, 2013, The impact of traumatic brain injury on pituitary function, Endocrinol Metab Clin North Am sourceNot checked — no full text of the source

Adequate replacement with glucocorticoids, L-thyroxine, and sex steroids generally reverses symptoms and signs of relevant pituitary hormone deficiencies and normalizes associated risks.

“Adequate replacement with glucocorticoids, L-thyroxine, and sex steroids generally reverses the symptoms and signs of relevant pituitary hormone deficiencies and normalizes the risks associated with it (14).”

• cites [14] Schneider, 2007, Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review, JAMA sourceNot checked — no full text of the source

Experimental studies revealed GH and IGF-1 may play a crucial role in brain repair mechanisms or neuronal recovery after trauma by regulating neuronal plasticity, myelin formation, and vascular tone.

“As we discussed in the pathophysiology section (Section VI.B), experimental studies revealed that GH and IGF-1 may play a crucial role in brain repair mechanisms or neuronal recovery after trauma by regulating the factors including neuronal plasticity, myelin formation, and vascular tone (69,(185)(186)(187)(188)(189).”

• cites 69,(185)(186)(187)(188)(189)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

As another limitation of long-term prospective studies, the number of patients with TSH and gonadotropin deficiencies was significantly lower, causing difficulties in understanding natural history of these axes.

“As another limitation of the long-term prospective studies, the number of patients with TSH and gonadotropin deficiencies was significantly lower, causing difficulties in understanding the natural history of these axes (16,25,161).”

• cites [16] Tanriverdi, 2013, A five year prospective investigation of anterior pituitary function after traumatic brain injury: is hypopituitarism long-term after head trauma associated with autoimmunity?, J Neurotrauma sourceNot checked — no full text of the source
• cites [25] Kleindienst, 2009, Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: a prospective longitudinal evaluation, J Neurotrauma sourceNot checked — no full text of the source
• cites [161] Tanriverdi, 2008, Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

In Hatton et al study, the GH status of TBI patients was not defined.

“However, the GH status of TBI patients in this particular study was not defined.”