|Year : 2015 | Volume
| Issue : 6 | Page : 753-763
Pituitary and/or hypothalamic dysfunction following moderate to severe traumatic brain injury: Current perspectives
Zeeshan Javed1, Unaiza Qamar2, Thozhukat Sathyapalan1
1 Department of Academic Endocrinology, Diabetes and Metabolism, Hull York Medical School, University of Hull, Hull and East Yorkshire NHS Trust, Hull, UK
2 The Children's Hospital and Institute of Child Health, Department of Clinical Pathology, Punjab Health Department, Lahore, Pakistan
|Date of Web Publication||20-Oct-2015|
Department of Academic Endocrinology, Diabetes and Metabolism, Hull York Medical School, University of Hull, Hull and East Yorkshire NHS Trust, Hull
Source of Support: None, Conflict of Interest: None
| Abstract|| |
There is an increasing deliberation regarding hypopituitarism following traumatic brain injury (TBI) and recent data have suggested that pituitary dysfunction is very common among survivors of patients having moderate-severe TBI which may evolve or resolve over time. Due to high prevalence of pituitary dysfunction after moderate-severe TBI and its association with increased morbidity and poor recovery and the fact that it can be easily treated with hormone replacement, it has been suggested that early detection and treatment is necessary to prevent long-term neurological consequences. The cause of pituitary dysfunction after TBI is still not well understood, but evidence suggests few possible primary and secondary causes. Results of recent studies focusing on the incidence of hypopituitarism in the acute and chronic phases after TBI are varied in terms of severity and time of occurrence. Although the literature available does not show consistent values and there is difference in study parameters and diagnostic tests used, it is clear that pituitary dysfunction is very common after moderate to severe TBI and patients should be carefully monitored. The exact timing of development cannot be predicted but has suggested regular assessment of pituitary function up to 1 year after TBI. In this narrative review, we aim to explore the current evidence available regarding the incidence of pituitary dysfunction in acute and chronic phase post-TBI and recommendations for screening and follow-up in these patients. We will also focus light over areas in this field worthy of further investigation.
Keywords: Follow-up, Future perspectives, incidence, pituitary dysfunction, traumatic brain injury
|How to cite this article:|
Javed Z, Qamar U, Sathyapalan T. Pituitary and/or hypothalamic dysfunction following moderate to severe traumatic brain injury: Current perspectives. Indian J Endocr Metab 2015;19:753-63
|How to cite this URL:|
Javed Z, Qamar U, Sathyapalan T. Pituitary and/or hypothalamic dysfunction following moderate to severe traumatic brain injury: Current perspectives. Indian J Endocr Metab [serial online] 2015 [cited 2018 Mar 21];19:753-63. Available from: http://www.ijem.in/text.asp?2015/19/6/753/167561
| Introduction|| |
Traumatic brain injury (TBI) has been mentioned as a principal cause of disability and death in young adults., The consequences after TBI not only include physical disabilities but also lead to seizure disorders, long-term psychological, behavioral, and cognitive dysfunction., It has been suggested that 66–100% permanent neurological disability can develop in subjects after moderate to severe TBI [Table 1] explains severity and phases of TBI],, which has made it a major public health problem. Therefore, it has been suggested that prevention is of paramount importance given the high toll of long-term complications.
There is an increasing awareness regarding hypopituitarism following TBI which is defined as a documented biochemical deficiency in at least one endocrine axis which might be caused by either an inability of the gland itself to produce hormones or an insufficient supply of hypothalamic-releasing hormones., Recent data have suggested that pituitary dysfunction is very common among survivors of moderate to severe TBI, which may evolve or resolve over time.,, There are some studies that have suggested lower prevalence of hypopituitarism after TBI and explained that the prevalence is affected by use of distinct dynamic tests and cut-off values.,
Previously, the neurological sequel after TBI was attributed to postconcussion syndrome because of close resemblance to features of pituitary dysfunction which might have been overlooked and could be a reason for long-term morbidity in these patients. Due to high prevalence of pituitary dysfunction and its association with increased morbidity and poor recovery in subjects after moderate to severe TBI and the fact that it can be easily treated with hormone replacement, it has been suggested that early detection and treatment is necessary to prevent long-term neurological consequences.,,,,
In this narrative review, we aim to explore the current evidence available regarding the incidence of pituitary dysfunction in the acute and chronic phase post-TBI and recommendations for screening and follow-up in these patients. We will also focus light over areas in this field worthy of further investigation.
| Possible Underlying Pathological Mechanisms|| |
The pituitary gland lies within a bony enclosure called the sella turcica supplied mainly by long hypophyseal vessels. The inferior hypophyseal artery supplies a small part of anterior pituitary gland and entire poterior pituitary gland.,, The cause of pituitary dysfunction after TBI is still not well understood, but evidence suggests few possible mechanisms:
- Primary injury
- Secondary injury by events like hypoxia, brain swelling, hypotension, anemia
- Stress of critical illness and possible effects of medications.
The pituitary gland is at risk of damage at time of injury because of its position within the sella turcica. Basal skull fractures and subsequent fracture of sella can directly damage pituitary gland, infundibulum and hypothalamus especially by rotational and shearing impact during injury. Hemorrhage in sella turcica and within gland due to fractures can further damage the glands., One recent study found 43% showed acute infarcts of varying size and postulated that direct injury through axonal shearing stress can lead to pituitary and hypothalamic damage.
Secondary insults such as hypotension, hypoxia, increased intracranial pressure, changes in cerebral blood flow, and metabolism often accompany major injury, which may lead to ischemic damage to pituitary gland., The blood supply to anterior-pituitary is at increased risk of damage because it is supplied mainly by long hypophyseal vessels and portal capillaries in pituitary stalk and blood supply to posterior gland is less susceptible to damage as it is supplied by short hypophyseal vessels. It is evidenced by fact that anterior-pituitary dysfunction is more common than posterior-pituitary dysfunction in survivors of TBI., This concept is further supported by studies using magnetic resonance imaging (MRI) to look at the pathological changes in pituitary gland of patients admitted after TBI and found that in acute phase the pituitary gland is enlarged as compared to healthy control subjects with associated pathologies such as infarction, hemorrhage, signal problems, and pituitary stalk transection.,, In another study looking at morphological changes of the sella region in TBI patients using MRI or CT Scan found 80% of patients who later developed hypopituitarism had sella abnormalities with most common findings were reduced pituitary volume or empty sella followed by defects of pituitary perfusion and abnormal pituitary signaling. Other studies found that different patterns of hormonal insufficiency with deficiency have been seen mainly in growth hormone (GH) and gonadotropin levels because somatotropic and gonadotrophic cells are located in lateral parts of pituitary which are more susceptible to ischemic damage after head trauma as these areas are supplied by long hypophyseal vessels that are at increased risk of damage after TBI. The corticotrophs and thyrotrophs are located mainly in the central parts of pituitary gland and, therefore, less susceptible to damage because mainly short hypophyseal vessels supply them.
Few studies have also looked into the impact of acute stress changes and medication on pituitary function and recovery of patients. One of the studies found that almost 50% of the patients had acute secondary adrenal-insufficiency after moderate-severe head injury and suggested that excessive use of medications (opioids, phenobarbital, high dose heparins, and etomidate) commonly used in Intensive Care Unit is one of the reasons for aggravating clinical picture and can alter efficacy of endocrine testing, therefore special attention should be given to monitoring of cortisol levels to prevent prolonged damage due to hypotension and resulting ischemia.,,
Autoimmunity could also play a role in pituitary dysfunction after TBI. It has been investigated and shown in few studies that pituitary dysfunction was more severe in those patients who were positive for anti-pituitary antibodies (APA) and anti-hypothalamic antibodies (AHA)., Recently, a 5-year prospective study has also shown that pituitary dysfunction was remarkably higher in patients with positive AHA and APA antibodies.
Genetic predisposition has also been postulated as one of underlying mechanisms for pituitary dysfunction after TBI., Apolipoprotein E (ApoE) is a vital protein required for cell membrane repair, which also spreads neuritis following injury. ApoE genetic polymorphism has been studied in TBI patients that revealed poor outcome if they were positive for ApoE4 but better outcome has been seen in patients who had ApoE3 genotype.,,,
| Incidence of Pituitary Dysfunction in Acute Phase Following Traumatic Brain Injury|| |
Current evidence suggests that results of recent studies focusing on incidence of hypopituitarism after TBI ,, are varied and possible reasons could be difference in patient selection, severity of injury, methods used, study design and timing of assessment.
Few studies showed that serum cortisol increase in acute-phase and then back to normal after several days., Cernak et al., found low cortisol on days 1–3 but rose to high levels 5–7 days after injury. Another study  found high cortisol level indicated abnormal activation of hypothalamic-pituitary-adrenal (HPA)-axis that failed to suppress by high dose dexamethasone administration. Recent studies also found adrenal insufficiency in acute postinjury phase but degree of insufficiency was not consistent as one study  found 16%, other  found 53% and third one found  9.8%.
The data related to GH in acute phase of TBI are inconsistent and have shown both low ,, and high basal levels of GH. Few studies have demonstrated reduced GH pulsatile release and blunted response to arginine stimulation 24–48 h after severe TBI, which was associated with poor outcome.,, Other studies revealed progressive increase in GH response after 48 h of initial poor response and paradoxical rise in GH levels after intravenous glucose administration in patients with severe injury., In contrast, Bondanelli et al. studied GH/insulin-like growth factor-1 (IGF-1) axis using basal and dynamic tests in patients during acute phase after severe TBI and found no significant difference in GH secretion as compared to healthy controls, indicating normal GH axis in acute phase of TBI. Only one patient had subnormal response to GHRH plus arginine stimulation. Recently, severe growth hormone deficiency (GHD) has been demonstrated in 18% of patients during acute phase using basal plus glucagon stimulation test and in 20.4% patients using basal GH levels within 24 h of TBI.,
Similarly, many studies found low testosterone in acute-phase indicating suppression of hypothalamic-pituitary-gonadal (HPG) axis that has been related to severity of head injury.,, Another study found suppressed gonadal axis in 32% of subjects and suggested it an adaptive response of body in such patients to decrease use of energy and metabolic substrates by less vital organs.
Evidence related to thyroid and prolactin levels in acute phase are also very inconsistent with some studies have shown elevated levels ,, while others have found reduced levels ,, and few have shown no change in their levels.
In summary, some of the acute changes in pituitary function after TBI, such as hypogonadism and hyperprolactinemia reflect adaptive response of body in such situation. However, adrenal insufficiency has been associated with serious consequences which need particular attention to reduce long-term morbidity and improve recovery.,,,
| Incidence of Pituitary Dysfunction during Recovery Phase Following Traumatic Brain Injury|| |
The evidence related to the prevalence of pituitary dysfunction in recovery phase is also varied. One of the studies on 22 patients assessed pituitary functions 26 months postinjury and showed 18% had impaired GH response, one patient had impaired cortisol response, one female patient had gonadotropin deficiency, and one had thyroid-stimulating hormone (TSH) deficiency. Some degree of hypopituitarism occurred in 40% of patients with GHD being most common.
Another study  enrolled 70 patients and assessed pituitary function 49 ± 8 months after TBI. Results revealed GHD in 14.6%. Free-T4 and TSH were low in 21.7% with impaired cortisol response in 7.1%. Hyperprolactinemia and hypogonadism were rare.
In 2004, another study  assessed patients 19 months after TBI using two stimulation tests, revealed 28% had at least one pituitary hormone deficiency with 11% GHD, 12% gonadotropin deficiency, 1% TSH deficiency, 13% hyperprolactinemia, and 1% had panhypopituitarism.
Similarly, many other studies ,,,,,,,,,, revealed figures close enough to above-mentioned studies [Table 2]. However, one recent study  selected 170 patients a year after severe TBI and found 24.7% had any form of pituitary deficiency with gonadotropin deficiency was most prevalent. GH, TSH and ACTH deficiency was near to 6%. Several studies have also reported sports-related TBI induced pituitary dysfunction especially those including collision and/or contact as well as high-velocity sports such as soccer, boxing, rugby, football, ice hockey, martial arts, roller skating, motor racing, cycling, skiing, and equestrian sports.,, The degree of dysfunction was more if the duration of sports engagement was prolonged and in those who had more head injury episodes. GHD was most common in these patients.,,,, Few other studies  showed that diabetes insipidus was present in 7% patients after head injury and SIADH in around 2.3–36% post-TBI that was mainly transient. Recently, Klose et al. assessed the prevalence of GHD 2.5 years after TBI in 439 patients and 124 healthy controls using insulin tolerance test (ITT), pyridostigmine (PD)-GHRH or GHRH-arginine test, local versus guideline cut-off values, single versus repetitive testing, and using different GH assays. They found that the prevalence of GHD was less using local than by guideline cut-off values (12% vs. 19% [PD-GHRH/GHRH-arginine]; 4.5% vs. 5% [ITT, P = 0.9]), and by ITT than by PD-GHRH/GHRH-arginine (P = 0.006 [local cut-offs]; P < 0.001 [guideline cut-offs]). Only 1% had GHD according to 2 tests and GH assessment by the Immulite or iSYS assay caused no significant diagnostic differences. They also observed significant number of false positive results in the control group. However, this study had few limitations; most importantly, the majority of patients involved in this study had mild TBI, second PD-GHRH stimulation is not a well-standardized test and is not used commonly for the diagnosis of GHD  and is not pertinent to confirm results acquired from ITT which is more sensitive. Third, GHRH-arginine test was used only for those patients who had contraindications to other tests though it has been more commonly used test and is also more widely available. Recently, a systematic review has been published in which authors compared either the prevalence of abnormal endocrine tests was higher in TBI patients as compared to controls or not and included only those studies that applied at least one endocrine test in a matched control group. They found that pooled prevalence of GHD was 7.7% and 1.4% in patients and controls respectively (P < 0.001) according to the results obtained from ITT using local cut-offs values by Klose et al. and standard cut-offs used by other studies. The pooled prevalence of GHD according to the combined tests was 11.1% and 1.3% in patients and controls respectively (P < 0.001).
|Table 2: Prevalence of pituitary dysfunction in postacute phase of TBI,,,,,,,,,,,,,,,,,|
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Although the literature available does not show consistent values and there are differences in study parameters and diagnostic tests used, it is clear that pituitary dysfunction is very common after moderate to severe TBI ,,,,,,,,, and patients should be carefully monitored in order to reduce long-term morbidity and mortality.,,,,,,,
Recommended investigations of assessing pituitary function in acute phase following traumatic brain injury: Caveats and pitfalls
Current evidence suggests that patients having moderate-severe TBI should be assessed for anterior and posterior-pituitary dysfunction in acute phase after TBI (generallyfirst 10–14 days after TBI, [Table 1]) to diagnose and prevent life-threatening endocrine complications. Those who are at increased risk of developing short and long term endocrine complications, must undergo serial pituitary-function assessments, but it is important to exclude those patients who are not going to get any benefit from hormone replacement therapy such as patients with severe disability or in vegetative state.,
It is not pertinent and practical to perform dynamic tests in acute phase after TBI, and there is no international consensus on diagnostic cut-off values. Current data related to assessment of pituitary dysfunction in the acute phase demonstrate that changes in levels of GH, Follicle-stimulating hormone/luteinizing hormone (FSH/LH) and TSH are transient and usually recover within 3–12 months after TBI.,,,,, Furthermore, the evidence regarding the beneficial effects of FSH/LH, GH, and TSH replacement during acute phase in TBI patients is also not transparent and suggests no benefits.,, However, in the acute phase after TBI, it is very important not to miss acute hypoadrenalism, because it can be life-threatening.,, It has been recommended, that during acute phase, the prime focus should be adrenal insufficiency that has been shown to be associated with severe hyponatremia, hypoglycemia, excessive need for vasoactive drugs, refractory hypotension, hemodynamic instability, and poor neurological outcome.,,, As the dynamic tests to assess cortisol deficiency are not practical under such situations, the authors recommend basal cortisol <200 nmol/l (7.25 µg/dl) in the acute-stage suggestive of ACTH-deficiency and treatment with glucocorticoids is recommended until after acute-stage when full assessment can be performed., If basal cortisol is between 200 and 400 nmol/l (7.25–14.5 µg/dl), treatment should only be commenced if the patient is having signs of adrenal-insufficiency. It is important to remember that cortisol levels can be affected by many factors under this clinical setting such as medications, sepsis and low cortisol-binding-globulin which should also be considered while measuring cortisol levels.
It has also been recommended that rapid diagnosis and treatment of diabetes-insipidus in acute-phase of TBI is required as it is associated with increased mortality due to associated hypernatremia. Although hyponatremia due to SIADH is transient in acute-phase, it should still be looked for, as if undiagnosed can lead to profound hyponatremia that could be fatal.
Recommendations regarding follow-up for pituitary dysfunction in postacute phase following traumatic brain injury
Current evidence shows that there is high risk of hypopituitarism after TBI.,,,, The exact timing of development cannot be predicted but has suggested regular assessment of pituitary function at least up to 1 year after TBI.,,,,,,, Several prospective studies have looked into the development of pituitary dysfunction 3 and 12 months after TBI ,,,,, and found that, although pituitary dysfunction develops in the postacute phase that may normalize over a period of 12 months, but new onset pituitary abnormalities may also develop after postacute phase of TBI. The pituitary dysfunction at the end of 12 months varied from 13% to 50% and the most common pituitary-axis affected was somatotropic (GH-axis).
As it is difficult to predict the exact timing of pituitary dysfunction development, current evidence suggests a plan for follow-up of patients after TBI as shown in [Figure 1]. However, signs and symptoms can be misleading in these patients, it has been suggested that universal screening is performed. This would include baseline hormonal work-up and dynamic tests if indicated.,
|Figure 1: Suggested algorithm for the assessment of patients after traumatic brain injury,|
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Diagnostic tests for evaluating traumatic brain injury induced pituitary dysfunction
Gonadotropin secretion in premenopausal women who have had a TBI is assessed by checking oestradiol levels on two or more occasions. In females with central hypogonadism low oestradiol levels will be associated with the absence of elevated FSH. The GnRH-test used to diagnose central hypogonadism lacks both sensitivity and specificity and rarely adds helpful information to basal endocrine levels.,, It is recommended that basal levels of oestradiol and gonadotropins associated with appropriate clinical context are sufficient to make diagnosis of central hypogonadism. However, GnRH test can be helpful in cases where patients have normal sex steroid levels but reduced LH/FSH response indicating the patients may be at risk of hypogonadism in future and need regular follow-up. In men, central hypogonadism can best be diagnosed by repeated low levels of morning serum testosterone associated with low/normal LH.,,
Also, before confirming diagnosis of central hypogonadism, it is important to exclude hyperprolactinemia as it has been seen to be associated with hypogonadism in some cases that might be due to lesions of pituitary stalk or hypothalamus or drug interference.,
Somatotroph (growth hormone-insulin-like growth factor-1) axis
It has been recommended, if required, to confirm GHD by a dynamic test unless patients have other pituitary hormone deficiencies associated with low levels of IGF-1, as the chances of GHD increase in TBI patients if there are additional pituitary axis deficiencies. Although none of the dynamic tests are completely reliable in diagnosing GHD, GHRH + arginine and ITT have been recommended in current literature as tests of choice having similar accuracy in evaluating TBI induced GHD. The recommended cut-off values for diagnosing GHD in GHRH + arginine test and ITT are 9 µg/dl and 3 µg/dl, respectively in case of lean adults ,,, while for children are 20 µg/dl and 8–10 µg/dl, respectively because GH secretory capacity in children is high. Additionally, for patients in transition phase between early adulthood and puberty, cut-off values of 5 µg/dl and 6.1 µg/dl have been suggested in case if ITT is used., However, use of these cut-off values in obese and overweight patients can lead to high false positive results because GH secretory response to dynamic tests decreases with increasing BMI in adults that need special consideration when making diagnosis in this particular population.,,,
Another test that has been substantially studied and validated in TBI patients is GHRH + GHRP6 (GH-releasing peptide-6) test. It also holds significant accuracy in defining patients with severe GHD and has BMI-dependent cut-off values of 15 µg/dl and 5 µg/dl for lean and obese patients, respectively.,
Finally, glucagon stimulation test (GST) is also recommended as a good alternative if ITT or GHRH + arginine tests are unavailable or contraindicated. GST has also been suggested to possess a sensitivity and specificity of 100% if a cut-off value of 3 µg/dl is used. However, it is time-consuming and also age and BMI-dependent like other stimulation tests.,
In order to assess HPA axis, morning serum cortisol levels are checked on 2 or more occasions. Levels below <3 µg/dl (83–100 nmol/l) are considered diagnostic and levels > µg/dl (500 nmol/l) are considered normal and excludes adrenal insufficiency.,,, Levels between 3 and 18 µg/dl require stimulation test. Various dynamic tests can be used to assess HPA axis including ITT, corticotrophin-releasing hormone test and ACTH test (using either 250 µg or 1 µg (low dose) of corticotrophin).
Some authors have recommended confirming diagnosis only if patients fail two provocative tests. Current evidence suggests that definition of normal or impaired corticotrophin secretion in head injury patients is still under debate, and it is very important to assess the whole scenario of each patient in borderline cases.
Thyrotropin releasing hormone-thyroid stimulating hormone-thyroid axis
The diagnosis of central hypothyroidism in TBI patients is easily made when low serum free T4 is associated with normal or low serum TSH values. Although some studies have used TRH stimulation test to diagnose TSH deficiency in patients having TBI, current evidence suggests serial measurements of free T4 and TSH only as dynamic testing does not add to diagnostic reliability.,,
Evidence related to beneficial effects of treatment after traumatic brain injury
To date, there is no comprehensible evidence that the replacement of FSH/LH, TSH and GH during the acute phase post-TBI is beneficial. Studies have shown that TSH deficiency generally recuperates during or after acute phase and thyroid hormone replacement in critically ill patients has not shown any improvement., Similarly, changes in gonadotropins in the acute phase after TBI are transient and reflect an adaptive response.
Studies related to GH therapy in the acute phase after TBI are conflicting as one prospective, placebo-controlled study  showed significant improvements in nutritional and metabolic markers after IGF-1 and GH (0.05 mg/kg/day) therapy while another study revealed increased mortality in critically ill patients. Experimental studies, on the other hand, have shown that GH and IGF-1 play a vital role in neuronal recovery mechanisms after TBI.,,, It has been proposed that further placebo-controlled human studies are required to resolve this conflict and currently GH therapy has not been suggested in acute phase after TBI. However, during acute phase, diagnosis and treatment of cortisol deficiency should be done promptly as it can be life threatening.,,
Currently, no studies have been published, assessing the long-term effects of FSH/LH, TSH, and ACTH treatment in TBI patients having pituitary dysfunction.
Recent studies have clearly indicated significant morbidity in TBI patients having GHD including impaired metabolic parameters, increased cardiovascular risk, impaired quality of life (QOL) and cognitive functions, decreased muscle force and aerobic capacity.,, To date, few clinical studies and case reports have been published assessing the effects of GH replacement therapy in TBI patients. The results demonstrated significant improvements with GH therapy in patients with moderate to severe TBI in terms of improvement in QOL, cognition, memory, information processing speed, vocabulary, executive functioning, and verbal learning.,,,,, Furthermore, the data also suggest that deficits due to GHD in TBI patients are amenable to treatment and GH therapy seems to be as beneficial as in those patients having GHD due to other causes.
| Conclusion|| |
Current evidence suggests high prevalence of pituitary dysfunction after moderate to severe TBI, though the values are varied. The exact timing of occurrence cannot be predicted and a follow-up of at least 1 year with regular pituitary assessment has been suggested regardless of clinical evidence for pituitary dysfunction.
| Future Research Perspectives|| |
All previous studies show varied results in postacute phase and can be attributed to lack of one specific dynamic test. Because of this lack of uniformity, it is difficult to select which dynamic test is preferable to assess pituitary function in postacute phase, as pituitary response is very unpredictable after TBI. Hence, further longitudinal studies are required to compare different stimulation tests to standardize the diagnostic strategy. Second, levels of pituitary hormones fluctuate in postacute phase and cannot be correlated with normal ranges. Future directions in this field should be an emphasis in determining approximate levels of hormones at various points in postacute phase to determine the critical values to guide early and timely treatment. Some other areas in this field worthy of further investigation include: What is the normal neurohormonal response to head injury? Are there any gender and age disparities? How to predict TBI induced hypopituitarism and who should be screened? Is it possible to predict recovery of pituitary function? What is the link between hypopituitarism and mortality post-TBI? Does the treatment of chronic hypopituitarism improve the eventual outcome from TBI?
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Salazar AM, Warden DL, Schwab K, Spector J, Braverman S, Walter J, et al.
Cognitive rehabilitation for traumatic brain injury: A randomized trial. Defense and Veterans Head Injury Program (DVHIP) Study Group. JAMA 2000;283:3075-81.
Agha A, Thompson CJ. Anterior pituitary dysfunction following traumatic brain injury (TBI). Clin Endocrinol (Oxf) 2006;64:481-8.
Bondanelli M, Ambrosio MR, Zatelli MC, De Marinis L, degli Uberti EC. Hypopituitarism after traumatic brain injury. Eur J Endocrinol 2005;152:679-91.
Beghi E. Overview of studies to prevent posttraumatic epilepsy. Epilepsia 2003;44 Suppl 10:21-6.
Tanriverdi F, Schneider HJ, Aimaretti G, Masel BE, Casanueva FF, Kelestimur F. Pituitary dysfunction after traumatic brain injury: A clinical and pathophysiological approach. Endocr Rev 2015;36:305-42.
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:81-4.
Consensus conference. Rehabilitation of persons with traumatic brain injury. NIH consensus development panel on rehabilitation of persons with traumatic brain injury. JAMA 1999;282:974-83.
Menon DK, Schwab K, Wright DW, Maas AI; Demographics and Clinical Assessment Working Group of the International and Interagency Initiative toward Common Data Elements for Research on Traumatic Brain Injury and Psychological Health. Position statement: Definition of traumatic brain injury. Arch Phys Med Rehabil 2010;91:1637-40.
Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, Stalla GK, Ghigo E. Hypopituitarism. Lancet 2007;369:1461-70.
Nemes O, Kovacs N, Czeiter E, Kenyeres P, Tarjanyi Z, Bajnok L, et al.
Predictors of post-traumatic pituitary failure during long-term follow-up. Hormones (Athens) 2014;[In Press].
Richmond E, Rogol AD. Traumatic brain injury: Endocrine consequences in children and adults. Endocrine 2014;45:3-8.
Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, Stalla GK, Agha A. Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: A systematic review. JAMA 2007;298:1429-38.
Kokshoorn NE, Wassenaar MJ, Biermasz NR, Roelfsema F, Smit JW, Romijn JA, et al.
Hypopituitarism following traumatic brain injury: Prevalence is affected by the use of different dynamic tests and different normal values. Eur J Endocrinol 2010;162:11-8.
Bavisetty S, Bavisetty S, McArthur DL, Dusick JR, Wang C, Cohan P, et al.
Chronic hypopituitarism after traumatic brain injury: Risk assessment and relationship to outcome. Neurosurgery 2008;62:1080-93.
Prasanna KL, Mittal RS, Gandhi A. Neuroendocrine dysfunction in acute phase of moderate-to-severe traumatic brain injury: A prospective study. Brain Inj 2015;29:336-42.
Schneider HJ, Schneider M, Saller B, Petersenn S, Uhr M, Husemann B, et al.
Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury. Eur J Endocrinol 2006;154:259-65.
Wachter D, Gündling K, Oertel MF, Stracke H, Böker DK. Pituitary insufficiency after traumatic brain injury. J Clin Neurosci 2009;16:202-8.
Elovic EP, Glenn MB. Anterior pituitary dysfunction after traumatic brain injury, part II. J Head Trauma Rehabil 2004;19:184-7.
Daniel PM. The pituitary gland and its blood supply. Sci Basis Med Annu Rev 1963:83-98.
Gorczyca W, Hardy J. Arterial supply of the human anterior pituitary gland. Neurosurgery 1987;20:369-78.
Dusick JR, Wang C, Cohan P, Swerdloff R, Kelly DF. Pathophysiology of hypopituitarism in the setting of brain injury. Pituitary 2012;15:2-9.
Kornblum RN, Fisher RS. Pituitary lesions in craniocerebral injuries. Arch Pathol 1969;88:242-8.
Salehi F, Kovacs K, Scheithauer BW, Pfeifer EA, Cusimano M. Histologic study of the human pituitary gland in acute traumatic brain injury. Brain Inj 2007;21:651-6.
Benvenga S, Campenní A, Ruggeri RM, Trimarchi F. Clinical review 113: Hypopituitarism secondary to head trauma. J Clin Endocrinol Metab 2000;85:1353-61.
Maiya B, Newcombe V, Nortje J, Bradley P, Bernard F, Chatfield D, et al.
Magnetic resonance imaging changes in the pituitary gland following acute traumatic brain injury. Intensive Care Med 2008;34:468-75.
Kibayashi K, Shimada R, Nakao K, Ro A. Analysis of pituitary lesions in fatal closed head injury. Am J Forensic Med Pathol 2012;33:206-10.
Schneider HJ, Sämann PG, Schneider M, Croce CG, Corneli G, Sievers C, et al.
Pituitary imaging abnormalities in patients with and without hypopituitarism after traumatic brain injury. J Endocrinol Invest 2007;30:RC9-12.
Cohan P, Wang C, McArthur DL, Cook SW, Dusick JR, Armin B, et al.
Acute secondary adrenal insufficiency after traumatic brain injury: A prospective study. Crit Care Med 2005;33:2358-66.
Thomas Z, Bandali F, McCowen K, Malhotra A. Drug-induced endocrine disorders in the intensive care unit. Crit Care Med 2010;38 6 Suppl: S219-30.
Vuong C, Van Uum SH, O'Dell LE, Lutfy K, Friedman TC. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev 2010;31:98-132.
Tanriverdi F, De Bellis A, Bizzarro A, Sinisi AA, Bellastella G, Pane E, et al.
Antipituitary antibodies after traumatic brain injury: Is head trauma-induced pituitary dysfunction associated with autoimmunity? Eur J Endocrinol 2008;159:7-13.
Tanriverdi F, De Bellis A, Battaglia M, Bellastella G, Bizzarro A, Sinisi AA, et al.
Investigation of antihypothalamus and antipituitary antibodies in amateur boxers: Is chronic repetitive head trauma-induced pituitary dysfunction associated with autoimmunity? Eur J Endocrinol 2010;162:861-7.
Tanriverdi F, De Bellis A, Ulutabanca H, Bizzarro A, Sinisi AA, Bellastella G, et al.
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 2013;30:1426-33.
Waters RJ, Nicoll JA. Genetic influences on outcome following acute neurological insults. Curr Opin Crit Care 2005;11:105-10.
Welsh-Bohmer KA, Gearing M, Saunders AM, Roses AD, Mirra S. Apolipoprotein E genotypes in a neuropathological series from the Consortium to Establish a Registry for Alzheimer's Disease. Ann Neurol 1997;42:319-25.
Tanriverdi F, Taheri S, Ulutabanca H, Caglayan AO, Ozkul Y, Dundar M, et al.
Apolipoprotein E3/E3 genotype decreases the risk of pituitary dysfunction after traumatic brain injury due to various causes: Preliminary data. J Neurotrauma 2008;25:1071-7.
Liaquat I, Dunn LT, Nicoll JA, Teasdale GM, Norrie JD. Effect of apolipoprotein E genotype on hematoma volume after trauma. J Neurosurg 2002;96:90-6.
Crawford FC, Vanderploeg RD, Freeman MJ, Singh S, Waisman M, Michaels L, et al.
APOE genotype influences acquisition and recall following traumatic brain injury. Neurology 2002;58:1115-8.
Diaz-Arrastia R, Gong Y, Fair S, Scott KD, Garcia MC, Carlile MC, et al.
Increased risk of late posttraumatic seizures associated with inheritance of APOE epsilon4 allele. Arch Neurol 2003;60:818-22.
Behan LA, Phillips J, Thompson CJ, Agha A. Neuroendocrine disorders after traumatic brain injury. J Neurol Neurosurg Psychiatry 2008;79:753-9.
Cernak I, Savic VJ, Lazarov A, Joksimovic M, Markovic S. Neuroendocrine responses following graded traumatic brain injury in male adults. Brain Inj 1999;13:1005-15.
Hackl JM, Gottardis M, Wieser C, Rumpl E, Stadler C, Schwarz S, et al.
Endocrine abnormalities in severe traumatic brain injury – A cue to prognosis in severe craniocerebral trauma? Intensive Care Med 1991;17:25-9.
Feibel J, Kelly M, Lee L, Woolf P. Loss of adrenocortical suppression after acute brain injury: Role of increased intracranial pressure and brain stem function. J Clin Endocrinol Metab 1983;57:1245-50.
Agha A, Rogers B, Mylotte D, Taleb F, Tormey W, Phillips J, et al.
Neuroendocrine dysfunction in the acute phase of traumatic brain injury. Clin Endocrinol (Oxf) 2004;60:584-91.
Tanriverdi F, Senyurek H, Unluhizarci K, Selcuklu A, Casanueva FF, Kelestimur F. 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 2006;91:2105-11.
Jeevanandam M, Holaday NJ, Petersen SR. Plasma levels of insulin-like growth factor binding protein-3 in acute trauma patients. Metabolism 1995;44:1205-8.
Petersen SR, Jeevanandam M, Harrington T. Is the metabolic response to injury different with or without severe head injury? Significance of plasma glutamine levels. J Trauma 1993;34:653-60.
De Marinis L, Mancini A, Valle D, Bianchi A, Gentilella R, Liberale I, et al.
Hypothalamic derangement in traumatized patients: Growth hormone (GH) and prolactin response to thyrotrophin-releasing hormone and GH-releasing hormone. Clin Endocrinol (Oxf) 1999;50:741-7.
Melarvie S, Jeevanandam M, Holaday NJ, Petersen SR. Pulsatile nature of growth hormone levels in critically ill trauma victims. Surgery 1995;117:402-8.
Della Corte F, Mancini A, Valle D, Gallizzi F, Carducci P, Mignani V, et al.
Provocative hypothalamopituitary axis tests in severe head injury: Correlations with severity and prognosis. Crit Care Med 1998;26:1419-26.
King LR, Knowles HC Jr, McLaurin RL, Brielmaier J, Perisutti G, Piziak VK. Pituitary hormone response to head injury. Neurosurgery 1981;9:229-35.
Bondanelli M, Ambrosio MR, Margutti A, Boldrini P, Basaglia N, Franceschetti P, et al.
Evidence for integrity of the growth hormone/insulin-like growth factor-1 axis in patients with severe head trauma during rehabilitation. Metabolism 2002;51:1363-9.
Agha A, Rogers B, Sherlock M, O'Kelly P, Tormey W, Phillips J, et al.
Anterior pituitary dysfunction in survivors of traumatic brain injury. J Clin Endocrinol Metab 2004;89:4929-36.
Krysiak R, Szkróbka W, Okopien B. Secondary hypogonadism after traumatic brain injury: A case report. Przegl Lek 2014;71:352-4.
Ulutabanca H, Hatipoglu N, Tanriverdi F, Gökoglu A, Keskin M, Selcuklu A, et al.
Prospective investigation of anterior pituitary function in the acute phase and 12 months after pediatric traumatic brain injury. Childs Nerv Syst 2014;30:1021-8.
Hannon MJ, Crowley RK, Behan LA, O'Sullivan EP, O'Brien MM, Sherlock M, et al.
Acute glucocorticoid deficiency and diabetes insipidus are common after acute traumatic brain injury and predict mortality. J Clin Endocrinol Metab 2013;98:3229-37.
Olivecrona Z, Dahlqvist P, Koskinen LO. Acute neuro-endocrine profile and prediction of outcome after severe brain injury. Scand J Trauma Resusc Emerg Med 2013;21:33.
Hannon MJ, Sherlock M, Thompson CJ. Pituitary dysfunction following traumatic brain injury or subarachnoid haemorrhage – In "Endocrine Management in the Intensive Care Unit". Best Pract Res Clin Endocrinol Metab 2011;25:783-98.
Kelly DF, Gonzalo IT, Cohan P, Berman N, Swerdloff R, Wang C. Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: A preliminary report. J Neurosurg 2000;93:743-52.
Lieberman SA, Oberoi AL, Gilkison CR, Masel BE, Urban RJ. Prevalence of neuroendocrine dysfunction in patients recovering from traumatic brain injury. J Clin Endocrinol Metab 2001;86:2752-6.
Bondanelli M, De Marinis L, Ambrosio MR, Monesi M, Valle D, Zatelli MC, et al.
Occurrence of pituitary dysfunction following traumatic brain injury. J Neurotrauma 2004;21:685-96.
Aimaretti G, Ambrosio MR, Di Somma C, Fusco A, Cannavò S, Gasperi M, et al.
Traumatic brain injury and subarachnoid haemorrhage are conditions at high risk for hypopituitarism: Screening study at 3 months after the brain injury. Clin Endocrinol (Oxf) 2004;61:320-6.
Ioachimescu AG, Hampstead BM, Moore A, Burgess E, Phillips LS. Growth hormone deficiency after mild combat-related traumatic brain injury. Pituitary 2015;18:535-41.
Popovic V, Pekic S, Pavlovic D, Maric N, Jasovic-Gasic M, Djurovic B, et al.
Hypopituitarism as a consequence of traumatic brain injury (TBI) and its possible relation with cognitive disabilities and mental distress. J Endocrinol Invest 2004;27:1048-54.
Herrmann BL, Rehder J, Kahlke S, Wiedemayer H, Doerfler A, Ischebeck W, et al.
Hypopituitarism following severe traumatic brain injury. Exp Clin Endocrinol Diabetes 2006;114:316-21.
Klose M, Juul A, Poulsgaard L, Kosteljanetz M, Brennum J, Feldt-Rasmussen U. Prevalence and predictive factors of post-traumatic hypopituitarism. Clin Endocrinol (Oxf) 2007;67:193-201.
Bushnik T, Englander J, Katznelson L. Fatigue after TBI: Association with neuroendocrine abnormalities. Brain Inj 2007;21:559-66.
Srinivasan L, Roberts B, Bushnik T, Englander J, Spain DA, Steinberg GK, et al.
The impact of hypopituitarism on function and performance in subjects with recent history of traumatic brain injury and aneurysmal subarachnoid haemorrhage. Brain Inj 2009;23:639-48.
van der Eerden AW, Twickler MT, Sweep FC, Beems T, Hendricks HT, Hermus AR, et al.
Should anterior pituitary function be tested during follow-up of all patients presenting at the emergency department because of traumatic brain injury? Eur J Endocrinol 2010;162:19-28.
Berg C, Oeffner A, Schumm-Draeger PM, Badorrek F, Brabant G, Gerbert B, et al.
Prevalence of anterior pituitary dysfunction in patients following traumatic brain injury in a German multi-centre screening program. Exp Clin Endocrinol Diabetes 2010;118:139-44.
Kokshoorn NE, Smit JW, Nieuwlaat WA, Tiemensma J, Bisschop PH, Groote Veldman R, et al.
Low prevalence of hypopituitarism after traumatic brain injury: A multicenter study. Eur J Endocrinol 2011;165:225-31.
Leal-Cerro A, Flores JM, Rincon M, Murillo F, Pujol M, Garcia-Pesquera F, et al.
Prevalence of hypopituitarism and growth hormone deficiency in adults long-term after severe traumatic brain injury. Clin Endocrinol (Oxf) 2005;62:525-32.
Auer M, Stalla GK, Athanasoulia AP. Isolated gonadotropic deficiency after multiple concussions in a professional soccer player. Dtsch Med Wochenschr 2013;138:831-3.
Foley CM, Wang DH. Central diabetes insipidus following a sports-related concussion: A case report. Sports Health 2012;4:139-41.
Tanriverdi F, Unluhizarci K, Coksevim B, Selcuklu A, Casanueva FF, Kelestimur F. Kickboxing sport as a new cause of traumatic brain injury-mediated hypopituitarism. Clin Endocrinol (Oxf) 2007;66:360-6.
Tanriverdi F, Unluhizarci K, Kocyigit I, Tuna IS, Karaca Z, Durak AC, et al.
Brief communication: Pituitary volume and function in competing and retired male boxers. Ann Intern Med 2008;148:827-31.
Ives JC, Alderman M, Stred SE. Hypopituitarism after multiple concussions: A retrospective case study in an adolescent male. J Athl Train 2007;42:431-9.
Kelestimur F, Tanriverdi F, Atmaca H, Unluhizarci K, Selcuklu A, Casanueva FF. Boxing as a sport activity associated with isolated GH deficiency. J Endocrinol Invest 2004;27:RC28-32.
Kelly DF, Chaloner C, Evans D, Mathews A, Cohan P, Wang C, et al.
Prevalence of pituitary hormone dysfunction, metabolic syndrome, and impaired quality of life in retired professional football players: A prospective study. J Neurotrauma 2014;31:1161-71.
Klose M, Stochholm K, Janukonyté J, Lehman Christensen L, Frystyk J, Andersen M, et al.
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 2014;99:101-10.
Hazem A, Elamin MB, Malaga G, Bancos I, Prevost Y, Zeballos-Palacios C, et al.
The accuracy of diagnostic tests for GH deficiency in adults: A systematic review and meta-analysis. Eur J Endocrinol 2011;165:841-9.
Kleindienst A, Brabant G, Bock C, Maser-Gluth C, Buchfelder M. Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: A prospective longitudinal evaluation. J Neurotrauma 2009;26:1435-46.
Agha A, Phillips J, O'Kelly P, Tormey W, Thompson CJ. The natural history of post-traumatic hypopituitarism: Implications for assessment and treatment. Am J Med 2005;118:1416.
Aimaretti G, Ambrosio MR, Di Somma C, Gasperi M, Cannavò S, Scaroni C, et al.
Residual pituitary function after brain injury-induced hypopituitarism: A prospective 12-month study. J Clin Endocrinol Metab 2005;90:6085-92.
Masel BE, Urban R. Chronic endocrinopathies in traumatic brain injury disease. J Neurotrauma 2015. [In press].
Fernandez-Rodriguez E, Bernabeu I, Castro AI, Casanueva FF. Hypopituitarism after traumatic brain injury. Endocrinol Metab Clin North Am 2015;44:151-9.
Zheng P, He B, Tong W. Dynamic pituitary hormones change after traumatic brain injury. Neurol India 2014;62:280-4.
Wamstad JB, Norwood KW, Rogol AD, Gurka MJ, Deboer MD, Blackman JA, et al.
Neuropsychological recovery and quality-of-life in children and adolescents with growth hormone deficiency following TBI: A preliminary study. Brain Inj 2013;27:200-8.
Renner C, Hummelsheim H, Kopczak A, Steube D, Schneider HJ, Schneider M, et al.
The influence of gender on the injury severity, course and outcome of traumatic brain injury. Brain Inj 2012;26:1360-71.
Ciancia S. Pituitary insufficiency after traumatic brain injury: Consequences? Screening? Ann Fr Anesth Reanim 2012;31:e117-24.
Heather NL, Derraik JG, Brennan C, Jefferies C, Hofman PL, Kelly P, et al.
Cortisol response to synacthen stimulation is attenuated following abusive head trauma. Clin Endocrinol (Oxf) 2012;77:357-62.
Gasco V, Prodam F, Pagano L, Grottoli S, Belcastro S, Marzullo P, et al.
Hypopituitarism following brain injury: When does it occur and how best to test? Pituitary 2012;15:20-4.
Schneider HJ, Schneider M, Kreitschmann-Andermahr I, Tuschy U, Wallaschofski H, Fleck S, et al.
Structured assessment of hypopituitarism after traumatic brain injury and aneurysmal subarachnoid hemorrhage in 1242 patients: The German interdisciplinary database. J Neurotrauma 2011;28:1693-8.
Tanriverdi F, Agha A, Aimaretti G, Casanueva FF, Kelestimur F, Klose M, et al.
Manifesto for the current understanding and management of traumatic brain injury-induced hypopituitarism. J Endocrinol Invest 2011;34:541-3.
Gaddam SS, Buell T, Robertson CS. Systemic manifestations of traumatic brain injury. Handb Clin Neurol 2015;127:205-18.
Vespa PM. Hormonal dysfunction in neurocritical patients. Curr Opin Crit Care 2013;19:107-12.
Rosario ER, Aqeel R, Brown MA, Sanchez G, Moore C, Patterson D. Hypothalamic-pituitary dysfunction following traumatic brain injury affects functional improvement during acute inpatient rehabilitation. J Head Trauma Rehabil 2013;28:390-6.
Malekpour B, Mehrafshan A, Saki F, Malekmohammadi Z, Saki N. Effect of posttraumatic serum thyroid hormone levels on severity and mortality of patients with severe traumatic brain injury. Acta Med Iran 2012;50:113-6.
Wilkinson CW, Pagulayan KF, Petrie EC, Mayer CL, Colasurdo EA, Shofer JB, et al.
High prevalence of chronic pituitary and target-organ hormone abnormalities after blast-related mild traumatic brain injury. Front Neurol 2012;3:11.
Beca SG, High WM Jr, Masel BE, Mossberg KA, Urban RJ. What are critical outcome measures for patients receiving pituitary replacement following brain injury? Pituitary 2012;15:10-9.
Dupuis C, Thomas S, Faure P, Gayot A, Desrumaux A, Wroblewski I, et al.
Secondary adrenal insufficiency in the acute phase of pediatric traumatic brain injury. Intensive Care Med 2010;36:1906-13.
Sanoussi S, Ali A, Laouali H, Assoumane I, Chaibou Maman S, Baoua M. Traumatic brain injury and anterior pituitary dysfunction. Regarding 33 cases: Evolution profile over a six-month period. Neurochirurgie 2013;59:178-82.
Ghigo E, Masel B, Aimaretti G, Léon-Carrión J, Casanueva FF, Dominguez-Morales MR, et al.
Consensus guidelines on screening for hypopituitarism following traumatic brain injury. Brain Inj 2005;19:711-24.
Klose M, Juul A, Struck J, Morgenthaler NG, Kosteljanetz M, Feldt-Rasmussen U. Acute and long-term pituitary insufficiency in traumatic brain injury: A prospective single-centre study. Clin Endocrinol (Oxf) 2007;67:598-606.
Krahulik D, Zapletalova J, Frysak Z, Vaverka M. Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults. J Neurosurg 2010;113:581-4.
Glynn N, Agha A. Which patient requires neuroendocrine assessment following traumatic brain injury, when and how? Clin Endocrinol (Oxf) 2013;78:17-20.
Cooper MS, Stewart PM. Adrenal insufficiency in critical illness. J Intensive Care Med 2007;22:348-62.
Agha A, Sherlock M, Thompson CJ. Post-traumatic hyponatraemia due to acute hypopituitarism. QJM 2005;98:463-4.
Auble BA, Bollepalli S, Makoroff K, Weis T, Khoury J, Colliers T, et al.
Hypopituitarism in pediatric survivors of inflicted traumatic brain injury. J Neurotrauma 2014;31:321-6.
Sundaram NK, Geer EB, Greenwald BD. The impact of traumatic brain injury on pituitary function. Endocrinol Metab Clin North Am 2013;42:565-83.
Munoz A, Urban R. Neuroendocrine consequences of traumatic brain injury. Curr Opin Endocrinol Diabetes Obes 2013;20:354-8.
Baxter D, Sharp DJ, Feeney C, Papadopoulou D, Ham TE, Jilka S, et al.
Pituitary dysfunction after blast traumatic brain injury: The UK BIOSAP study. Ann Neurol 2013;74:527-36.
Norwood KW, Deboer MD, Gurka MJ, Kuperminc MN, Rogol AD, Blackman JA, et al.
Traumatic brain injury in children and adolescents: Surveillance for pituitary dysfunction. Clin Pediatr (Phila) 2010;49:1044-9.
Personnier C, Crosnier H, Meyer P, Chevignard M, Flechtner I, Boddaert N, et al.
Prevalence of pituitary dysfunction after severe traumatic brain injury in children and adolescents: A large prospective study. J Clin Endocrinol Metab 2014;99:2052-60.
West TA, Sharp S. Neuroendocrine dysfunction following mild TBI: when to screen for it. J Fam Pract 2014;63:11-6.
Casano-Sancho P, Suárez L, Ibáñez L, García-Fructuoso G, Medina J, Febrer A. Pituitary dysfunction after traumatic brain injury in children: Is there a need for ongoing endocrine assessment? Clin Endocrinol (Oxf) 2013;79:853-8.
Bellone S, Einaudi S, Caputo M, Prodam F, Busti A, Belcastro S, et al.
Measurement of height velocity is an useful marker for monitoring pituitary function in patients who had traumatic brain injury. Pituitary 2013;16:499-506.
Rose SR, Auble BA. Endocrine changes after pediatric traumatic brain injury. Pituitary 2012;15:267-75.
Rosén T, Burman P, Dahlqvist P, Dahm P, Edén-Engström B, Ekman B, et al.
Traumatic brain injury can cause pituitary deficiency. Suggestions for guidelines for assessment of pituitary function. Lakartidningen 2012;109:629-32.
Abadi MR, Ghodsi M, Merazin M, Roozbeh H. Pituitary function impairment after moderate traumatic brain injury. Acta Med Iran 2011;49:438-41.
Agrawal A, Reddy PA, Prasad NR. Endocrine manifestations of traumatic brain injury. Indian J Neurotrauma 2012;9:123-8.
Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML; Endocrine Society. Evaluation and treatment of adult growth hormone deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1587-609.
Aimaretti G, Corneli G, Razzore P, Bellone S, Baffoni C, Arvat E, et al.
Comparison between insulin-induced hypoglycemia and growth hormone (GH)-releasing hormone+arginine as provocative tests for the diagnosis of GH deficiency in adults. J Clin Endocrinol Metab 1998;83:1615-8.
Ghigo E, Aimaretti G, Gianotti L, Bellone J, Arvat E, Camanni F. New approach to the diagnosis of growth hormone deficiency in adults. Eur J Endocrinol 1996;134:352-6.
Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: Summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab 2000;85:3990-3.
Maghnie M, Aimaretti G, Bellone S, Bona G, Bellone J, Baldelli R, et al.
Diagnosis of GH deficiency in the transition period: Accuracy of insulin tolerance test and insulin-like growth factor-I measurement. Eur J Endocrinol 2005;152:589-96.
Clayton PE, Cuneo RC, Juul A, Monson JP, Shalet SM, Tauber M; European Society of Paediatric Endocrinology. Consensus statement on the management of the GH-treated adolescent in the transition to adult care. Eur J Endocrinol 2005;152:165-70.
Bonert VS, Elashoff JD, Barnett P, Melmed S. Body mass index determines evoked growth hormone (GH) responsiveness in normal healthy male subjects: Diagnostic caveat for adult GH deficiency. J Clin Endocrinol Metab 2004;89:3397-401.
Qu XD, Gaw Gonzalo IT, Al Sayed MY, Cohan P, Christenson PD, Swerdloff RS, et al.
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 2005;90:1563-9.
Biller BM, Samuels MH, Zagar A, Cook DM, Arafah BM, Bonert V, et al.
Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab 2002;87:2067-79.
Kelestimur F, Popovic V, Leal A, Van Dam PS, Torres E, Perez Mendez LF, et al.
Effect of obesity and morbid obesity on the growth hormone (GH) secretion elicited by the combined GHRH+GHRP-6 test. Clin Endocrinol (Oxf) 2006;64:667-71.
Popovic V, Leal A, Micic D, Koppeschaar HP, Torres E, Paramo C, et al.
GH-releasing hormone and GH-releasing peptide-6 for diagnostic testing in GH-deficient adults. Lancet 2000;356:1137-42.
Gómez JM, Espadero RM, Escobar-Jiménez F, Hawkins F, Picó A, Herrera-Pombo JL, et al.
Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults. Clin Endocrinol (Oxf) 2002;56:329-34.
Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003;361:1881-93.
Ferretti E, Persani L, Jaffrain-Rea ML, Giambona S, Tamburrano G, Beck-Peccoz P. Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J Clin Endocrinol Metab 1999;84:924-9.
Hartoft-Nielsen ML, Lange M, Rasmussen AK, Scherer S, Zimmermann-Belsing T, Feldt-Rasmussen U. Thyrotropin-releasing hormone stimulation test in patients with pituitary pathology. Horm Res 2004;61:53-7.
Mehta A, Hindmarsh PC, Stanhope RG, Brain CE, Preece MA, Dattani MT. Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children. J Clin Endocrinol Metab 2003;88:5696-703.
Vanhorebeek I, Van den Berghe G. Hormonal and metabolic strategies to attenuate catabolism in critically ill patients. Curr Opin Pharmacol 2004;4:621-8.
Hatton J, Kryscio R, Ryan M, Ott L, Young B. Systemic metabolic effects of combined insulin-like growth factor-I and growth hormone therapy in patients who have sustained acute traumatic brain injury. J Neurosurg 2006;105:843-52.
Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, et al.
Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999;341:785-92.
Aberg ND, Brywe KG, Isgaard J. Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain. ScientificWorldJournal 2006;6:53-80.
Hua K, Forbes ME, Lichtenwalner RJ, Sonntag WE, Riddle DR. Adult-onset deficiency in growth hormone and insulin-like growth factor-I alters oligodendrocyte turnover in the corpus callosum. Glia 2009;57:1062-71.
Molina DP, Ariwodola OJ, Linville C, Sonntag WE, Weiner JL, Brunso-Bechtold JK, et al.
Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats. Neurobiol Aging 2012;33:1938-49.
Ramsey MM, Weiner JL, Moore TP, Carter CS, Sonntag WE. Growth hormone treatment attenuates age-related changes in hippocampal short-term plasticity and spatial learning. Neuroscience 2004;129:119-27.
High WM Jr, Briones-Galang M, Clark JA, Gilkison C, Mossberg KA, Zgaljardic DJ, et al.
Effect of growth hormone replacement therapy on cognition after traumatic brain injury. J Neurotrauma 2010;27:1565-75.
Kreitschmann-Andermahr I, Poll EM, Reineke A, Gilsbach JM, Brabant G, Buchfelder M, et al.
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 2008;18:472-8.
Maric NP, Doknic M, Pavlovic D, Pekic S, Stojanovic M, Jasovic-Gasic M, et al.
Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy. J Endocrinol Invest 2010;33:770-5.
Tanriverdi F, Unluhizarci K, Karaca Z, Casanueva FF, Kelestimur F. Hypopituitarism due to sports related head trauma and the effects of growth hormone replacement in retired amateur boxers. Pituitary 2010;13:111-4.
Reimunde P, Quintana A, Castañón B, Casteleiro N, Vilarnovo Z, Otero A, et al.
Effects of growth hormone (GH) replacement and cognitive rehabilitation in patients with cognitive disorders after traumatic brain injury. Brain Inj 2011;25:65-73.
Moreau OK, Cortet-Rudelli C, Yollin E, Merlen E, Daveluy W, Rousseaux M. Growth hormone replacement therapy in patients with traumatic brain injury. J Neurotrauma 2013;30:998-1006.
[Table 1], [Table 2]