Anterior pituitary dysfunction following traumatic brain injury (TBI)

Transcription

1 Clinical Endocrinology (2006) 64, doi: /j x CLINICAL PRACTICE UPDATE Blackwell Publishing Ltd Anterior pituitary dysfunction following traumatic brain injury (TBI) Amar Agha and Christopher J. Thompson Division of Endocrinology and Diabetes, Beaumont Hospital and the RCSI Medical School, Dublin, Ireland Summary Traumatic brain injury (TBI) is the commonest cause of death and disability in young adults living in industrialized countries. Several recent studies have convincingly shown that anterior hypopituitarism is a common complication of head trauma with a prevalence of at least 25% among long-term survivors. This is a much higher frequency than previously thought and suggests that most cases of post-traumatic hypopituitarism (PTHP) remain undiagnosed and untreated. These findings raise important questions about the potential contribution of PTHP to the high physical and neuropsychiatric morbidity seen in this group of patients. In this review, we examine the published reports on the neuroendocrine abnormalities in TBI patients and highlight new data that give novel insights into the natural history of this disorder. We discuss the potential contribution of PTHP to recovery and rehabilitation after injury and the need for the identification and the appropriate and timely management of hormone deficiencies to optimize patient recovery from head trauma, improve quality of life and avoid the long-term adverse consequences of untreated hypopituitarism. (Received 4 January 2006; returned for revision 26 January 2006; finally revised 1 February 2006; accepted 2 February 2006) Introduction Traumatic brain injury (TBI) is increasingly common; persons per per year die or are hospitalized in industrialized countries as a result. 1 It is the leading cause of death and disability among young adults. 2 4 The population at greatest risk is young adult males under the age of 35 years, although it appears that the number of females sustaining TBI is rising steadily. 5 A significant proportion of survivors of TBI will continue to demonstrate persistent cognitive, physical and emotional deficits that will prevent functioning at preinjury level. 1,4,5 In the USA, it is estimated that five million persons are living with sequelae of TBI at a lifetime cost of $ to $1 9 million per person, 5 although reliable data on the comparative cost in the UK or Europe are not available. 6 Much of the cognitive and neuropsychiatric complications of TBI have traditionally been attributed to the post-concussional Correspondence: Dr Amar Agha, Department of Endocrinology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland. amaragha@yahoo.com syndrome. However, these morbid sequalae show close resemblance to the features seen in patients with anterior hypopituitarism. Therefore, it has been postulated that in some patients undiagnosed hypopituitarism may be responsible for some of the cognitive and neuropsychiatric dysfunction typical of TBI but is masked or overlooked because of the underlying primary diagnosis. As hypopituitarism has the potential to adversely affect recovery from and rehabilitation after TBI but is easily treatable with hormone replacement, much attention has recently focused on defining the true frequency of pituitary dysfunction following TBI. In this review, we examine the accumulating evidence that suggests a high prevalence of anterior hypopituitarism after TBI, the natural history of post-traumatic hypopituitarism (PTHP) and the potential implications of such findings for the care of head trauma patients. Historical perspective PTHP has been recognized for almost 90 years. 7 Escumilla and Lisser 8 reported TBI to account for hypopituitarism in only four of 595 hypopituitary patients (0 7%). Hence, the conventional view has held that PTHP is rare, despite autopsy results showing pituitary gland necrosis in up to one-third of patients who suffered fatal head injury. 9,10 Over the years, many case reports of PTHP appeared in the medical literature. Edwards and Clark 11 compiled a series of 53 cases of PTHP. In that series, the typical patient was a young male with significant head trauma and a history of transient or permanent diabetes insipidus. The usual presenting symptoms were those of hypogonadism with lethargy, anorexia and weight loss as common accompaniments. 11,12 More recently, Benvenga et al. 12 reviewed 367 case reports of PTHP. In their patients with anterior hypopituitarism, the frequency of gonadotrophin, ACTH, TSH and GH deficiencies and hyperprolactinaemia was 100%, 52 8%, 44 3%, 23 7% and 47 7%, respectively. Because this was a case-series report, there was an inherent bias in the relative frequency of the anterior pituitary hormone deficiencies seen. For instance, as hypogonadism (especially in the typical young adult head injury victim) gives rise to specific symptoms prompting the patient to seek help, gonadotrophin deficiency was invariable. In other patients, pituitary assessment was initiated because of the incidental finding of abnormal thyroid function after routine evaluation, which probably explains the high frequency of diagnosed TSH deficiency. A history of coma of varying duration was noted in most patients (93%). In 15% of patients the diagnosis of hypopituitarism was made more than 5 years after the accident. The majority 2006 Blackwell Publishing Ltd 481

2 482 A. Agha and C. J. Thompson of the patients (94%) had closed head trauma, while penetrating skull injury accounted for only 6% of cases, including 4% of all cases that were due to bullet wounds. The authors advised that physicians should be alert to the risk of PTHP, but did not offer any specific advice about follow-up of patients after TBI. 12 Prevalence of anterior hypopituitarism in long-term survivors of TBI The first study to systematically assess the frequency of anterior hypopituitarism following TBI was that by Kelly et al. 13 of 22 patients with moderate or severe TBI assessed at a median of 26 months postinjury. Using the insulin tolerance test (ITT), four patients (18%) had subnormal GH response, but it was not reported how many, if any, had clinically significant deficiency (peak response < 3 µg/l). 14 One patient had blunted cortisol response to hypoglycaemia, one patient had TSH deficiency and only one female patient had convincing evidence of gonadotrophin deficiency. In this study, all patients with pituitary dysfunction had sustained hypotensive or hypoxic insults during the course of TBI, which may have been responsible for the pituitary injury. The results of a larger study were subsequently reported by Lieberman et al., 15 who enrolled 70 patients with TBI from a transitional learning community. GH reserves were assessed in 48 patients, using the glucagon stimulation test (GST). Seven patients (14 6%) had a GH response less than 3 µg/l, five of whom also had the L-dopa test, and all five failed the test. The authors found 45% of their subjects to have morning cortisol levels < 7 µg/dl (193 nmol/l), although only five had a 45-min cortisol response to the high-dose short Synacthen test (SST) below 500 nmol/l. The authors were surprised by this remarkably high frequency of low basal serum cortisol concentrations but advised caution about interpreting its significance. Only one female patient had gonadotrophin deficiency, 11% of patients had low free T4 without elevated TSH levels and another 10% had normal free T4 with low TSH levels. Hyperprolactinaemia was present in 10% of patients, some of whom were on medications known to cause elevated serum PRL. In 2004 we reported the study of 102 patients who had suffered severe or moderate TBI, defined by Glasgow Coma Scale (GCS) scores of 3/15 13/15, at a median of 19 months post-injury. 16 The somatotrophic and corticotrophic axes were assessed first using the GST and subnormal responses were then assessed by a second stimulation test. This was the ITT for patients who were seizure-free; alternatively, the arginine + GH-releasing hormone (GHRH) test was used to assess GH and the SST to assess cortisol reserves as confirmatory tests in patients with seizures. Patients were defined as GH or ACTH deficient if they failed both the glucagon and the second dynamic test. Eleven per cent of patients had GH deficiency (GHD), including 8% with severe deficiency, and 13% had ACTH deficiency. Gonadotrophin deficiency was present in 12%, TSH deficiency in 1% and hyperprolactinaemia in 13% of patients. Twenty-eight per cent had at least one pituitary hormone deficiency. Hypopituitary patients had mainly single or dual abnormalities, with one patient only (1%) having panhypopituitarism. Several other studies have confirmed the findings of these initial reports and their results are summarized in Table 1. In the study by Bondanelli et al. 17 of 50 patients with varying severity of TBI, months after the event, 54% has some degree of pituitary dysfunction with 28% of all patients showing blunted GH response to the arginine + GHRH test. Similarly, Aimaretti et al. 18 studied 100 TBI patients 3 months after injury and reported hypopituitarism in 35%, including severe GHD (diagnosed by the arginine + GHRH test) in 21% of all patients. Leal-Cerro et al. 20 have recently reported the results of a large cohort of 170 patients with severe TBI who were initially selected for the study. In contrast to the previous studies, not all patients received systematic neuroendocrine assessment as patients who were judged to be symptomatically well were excluded from further evaluation, leaving 99 patients to undergo biochemical assessment. The prevalence (as a percentage of the total cohort of 170 subjects) of gonadotrophin, ACTH and TSH deficiencies was 17%, 6 4% and 5 8%, respectively. Patients with serum IGF-1 concentrations within the normal reference range were not considered to be GH deficient and did not undergo dynamic testing, but among the 44 patients who received one or more of three dynamic tests (GHRH + GH-releasing peptide-6, ITT and glucagon), 10 had evidence of GHD. Unfortunately, because almost 50% of adult patients with GHD will have serum IGF-1 concentrations in the normal reference range, 21 it is possible that the authors of the last study may have underestimated the true prevalence of GHD in their patients. Although the overall frequency of anterior pituitary hormone dysfunction varied with patient selection, diagnostic methodology and definition of abnormalities, there was broad agreement that hypopituitarism is common following TBI. In reviewing the literature available, the influence of patient selection and diagnostic methodology on the relative frequency of pituitary abnormalities should be considered. For example, when ACTH deficiency was diagnosed on the basis on a single morning serum cortisol value, the reported frequency was highly variable, 15,17,18,20 whereas more consistency was seen when dynamic tests were used. 13,16 The factors that predict the likelihood of developing hypopituitarism following TBI remain poorly understood. Published studies used the GCS, 22,23 which is widely used in clinical practice, to assess the severity of injury. This is a 15-point scale: 1 4 points are given for eye opening, 1 5 points for best verbal response, and 1 6 points for best motor response. Severe head injury is defined by a postresuscitation GCS score of 8/15 or less, moderate injury by a GCS score of 9/15 13/15 and mild injury by a score of 14/15 15/15. Most studies found no association between the initial post-resuscitation and pre-intubation GCS scores and anterior pituitary dysfunction in survivors of TBI, although one study found patients with PTHP to have slightly lower GCS scores than unaffected survivors. 17 The GCS is, however, a rather crude tool with significant inter- and intraobserver variability, and responses may be affected by factors other than the severity of head injury, such as alcohol consumption. In our series, we did not find an association between anterior hypopituitarism and the initial GCS scores, computed tomography (CT) scan appearance or late neurological outcome as assessed by the Glasgow Outcome Scale (GOS). 16 We were also unable to show a difference in the frequency of hypopituitarism between patients who had motor vehicle accidents (high-speed injury) and other types of head injury such as falls. The vast majority of patients tested in

3 Table 1. Summary of available data on the prevalence of anterior hypopituitarism in survivors of traumatic brain injury Post-traumatic hypopituitarism 483 Anterior pituitary dysfunction (%) Authors GCS scores Injury to testing time (months) Total GHD (severe) ACTHD GnTD TSHD PRL Association with TBI severity Kelly et al Median Diffuse brain swelling n = 22 Lieberman et al. 15 N/A Median None n = 70 (14 6) Agha et al Median None n = 102 (7 8) Aimaretti et al None n = 100 (21) Bondanelli et al Range Lower GCS scores n = 50 (8) Popovic et al Median None n = 67 (8) Leal-Cerro et al. 20 < 8 > N/A None n = 170 (99 had biochemical testing) D denotes deficiency; GnT, gonadotrophins; GCS, Glasgow Coma Scale; TBI, traumatic brain injury. Patients also had hypoxic or hypotensive insults. ITT was used as provocative test. Forty-eight patients had the glucagon stimulation test (GST) to assess GH secretion. Based on estimation of basal serum cortisol concentrations. Based on blunted response to GnRH. Diagnosed by failing two separate stimulation tests (see text). GH secretion assessed by the arginine + GHRH test; GH secretion assessed by GHRH + GH-releasing peptide-6 (GHRP-6) test. Excluding partial GHD. the various published studies had closed head injury, so it is unclear whether penetrating brain trauma, such as that caused by gun shots, carries a different risk of hypopituitarism. Neuroendocrine dysfunction in the acute phase of TBI Most studies performed in the acute period post-tbi focused largely on metabolic derangements and the relationship between the neuroendocrine changes and the severity of the injury, in an attempt to define variables that may predict outcome. They relied principally on the measurement of basal or random pituitary or target organ hormones. Although the studies of early neuroendocrine dysfunction post-tbi showed significant metabolic changes, they were not designed to reliably assess, nor specifically reported, the prevalence of hypopituitarism in the acute phase of TBI. Serum cortisol concentration was found to increase immediately following head injury, with a subsequent gradual decline towards normality, 24,25 and several days after severe TBI serum cortisol values were reported to be similar to those of controls. 26 Abnormal cortisol dynamics were seen in comatose patients following acute brain injury associated with raised intracranial pressure (ICP) as serum cortisol failed to suppress despite treatment with high doses of dexamethasone, 27 indicating activation of the hypothalamic pituitary adrenal axis. Some authors found the plasma cortisol concentration to correlate with severity in mild or moderate TBI, 28 and that normalization of serum cortisol predicted a good outcome. 29 In contrast to the above reports, one study found patients with severe penetrating head injury to have low serum cortisol on days 1 3, but high levels on days 5 7 after trauma. 24 As with the cortisol response, several studies showed activation of the somatotrophic axis following head injury. Basal serum GH concentrations were found to increase following TBI. 30,31 A paradoxical rise in serum GH concentrations following glucose load was observed in one study, which reverted to normal in the recovery phase. 30 Exaggerated GH response to GHRH and a paradoxical GH response to TRH on day 1 post-tbi were found in patients with severe head injury and unfavourable outcome. 25 Although these data indicate an overall increase in GH response following TBI, it is unclear if this was a consistent finding in all patients or whether some patients show blunted responses that may suggest somatotroph injury. Only one study in intensive care TBI patients reported impaired GH response to arginine stimulation in a small group of patients with very severe TBI associated with almost 100% mortality. 26 Suppression of the hypothalamic pituitary gonadal axis has been observed frequently following head injury, 24,26,32 34 as in other conditions of acute and chronic critical illnesses. 35,36 Serum testosterone concentrations have been found to correlate with the severity of head injury in some studies, 24,32 but not in others. 37 It has been suggested that it may be appropriate to switch off the production of anabolic androgens in critical illness, in order to reduce the use of energy and metabolic substrates by the less vital organs. 38 Therefore, hypogonadism in this situation is likely to represent an adaptive response to injury in most patients.

4 484 A. Agha and C. J. Thompson Considerable inconsistencies in the reported alterations of the thyroid axis after TBI can be found in the literature. Some studies showed no significant change in serum T4 concentration following head injury, 24,25 while others showed reduced, 34 or even elevated, levels. 26 Serum T3 concentrations were found to be low, 24 or low-normal, 25 following acute TBI. Similarly, conflicting results about serum TSH concentrations were reported by different authors; serum TSH concentration was found to be low 24,31 or normal 25 following severe TBI, but increased on days 1 3 following mild head trauma. 24 The clinical significance of these changes remains uncertain. Some studies have demonstrated that low serum concentrations of thyroid hormones and TSH are associated with worse prognosis. 24,39 In another study in severe TBI patients, a flat TSH response to TRH stimulation was associated with very poor prognosis, with almost 100% mortality 26 By contrast, other authors found no correlation between TSH response to TRH and the severity of head trauma. 25 Serum PRL concentration was found to be elevated, 31,40 unchanged 25 or even low 26 in acute TBI patients. Some authors found PRL, as a stress hormone, to correlate positively with the severity of the head injury. 31,40 The wide variations in hormone responses to acute head injury reported in these studies reflect differences in patient selection, severity of the head injury and the timing of hormonal assessment. In an attempt to define the frequency of acute PTHP, we evaluated 50 unselected adult TBI patients at a median of 12 days posttrauma. 41 None of the patients were receiving medication, such as glucocorticoids, that could interfere with the hormone assessment. Subnormal GH and cortisol response to glucagon was demonstrated in 18% and 16% of patients, respectively. Although some of the abnormalities were subtle, one patient developed hypotension, hyponatraemia and hypoglycaemia due to severe ACTH deficiency. Eighty per cent of patients had biochemical evidence of secondary hypogonadism, and there was a significant positive correlation between serum testosterone concentration and admission GCS scores, which were used to assess the severity of TBI. TSH deficiency was present in 2% and hyperprolactinaemia in 50% of patients. 41 The natural history of PTHP It is well recognized that posterior pituitary abnormalities after head injury are transient in the majority of cases, 42,43 but until very recently, the natural history of anterior pituitary dysfunction in TBI patients was unknown except for a few case reports that have documented late recovery of anterior pituitary function in patients with documented PTHP More recently, we assessed anterior pituitary function prospectively for 1 year in 50 patients following severe or moderate TBI. 48 Our data show that anterior pituitary hormone abnormalities, which occur soon after TBI, 41 recover in some patients, and in the majority recovery had occurred by 6 months. Hyperprolactinaemia and gonadotrophin deficiencies were particularly likely to recover completely in most patients. Recovery of normal GH production in two-thirds and cortisol production in one-half of patients was demonstrated in the post-acute phase, and persistent deficiency in the two axes was associated with more severe acute-phase GH and cortisol hyposecretion (Fig. 1). Conversely, some patients judged to have normal responses in the acute phase Fig. 1 Early and late (a) GH and (b) cortisol deficiencies in 50 patients assessed prospectively after severe or moderate traumatic brain injury using the glucagon stimulation test (see text 48 ). developed late pituitary dysfunction, particularly ACTH deficiency, which was demonstrated at the 6 months assessment, although no new abnormalities were detected later than 6 months (Fig. 1). Aimaretti et al. 49 reported the results of 70 TBI patients who underwent pituitary assessment at 3 months and again at 12 months after injury. Panhypopituitarism, which was diagnosed at 3 months, remains unchanged at 12 months, but most of the isolated and multiple deficiencies recovered or improved. Conversely, 5 5% of patients without abnormalities at 3 months showed isolated deficiencies by 12 months, and 13 3% of isolated deficiencies at 3 months became multiple by 12 months. These data and ours illustrate that there is a timedependent, dynamic change in pituitary function, particularly in the first 6 months after head injury, and underscore the need for periodic endocrine evaluation and monitoring in patients with head trauma. Mechanisms of Injury The pituitary gland is located within the bony sella turcica, where it is lined superiorly by a dense layer of connective tissues, the diaphragma sellae. Most of the blood supply to the anterior lobe of the pituitary gland (80 90%) is derived from the long hypophyseal vessels, giving rise to the hypophyseal portal circulation that carries hypothalamic neuropeptides from the hypothalamic neurones to the adenohypophysis. Blood supply to a small part of the adenohypophysis adjacent to the posterior lobe and the entire neurohypophysis is derived directly from the inferior hypophyseal artery, which arises from the internal carotid artery just below the diaphragma sellae (Fig. 2). 13,50

5 Post-traumatic hypopituitarism 485 Fig. 2 The vascular anatomy of the pituitary gland; the long hypophyseal portal system in the stalk (box) is a common site of injury (reproduced with permission). Several mechanisms of injury leading to hypopituitarism have been proposed, including compression of the pituitary gland and/ or the hypothalamic nuclei due to oedema, skull fracture, haemorrhage, increased ICP, hypoxic insult, or by direct mechanical injury to the hypothalamus, pituitary stalk or the pituitary gland. 12,13,51 The long hypophysial vessels and the portal capillaries in the stalk are particularly vulnerable to traumatic injury, resulting in anterior lobe infarction. Anterior lobe infarction can also occur with direct injury to the gland. The resulting swelling is confined within the sella and the overlying diaphragma sellae, leading to the compression of the long hypophysial vessels between the stalk and the free edge of the diaphragma sella, resulting in anterior pituitary infarction Different autopsy series have reported injury to the hypothalamus, pituitary gland or pituitary stalk in 26 86% of patients who died from TBI. 9,10,52 54 The site of the injury varies according to the study but necrosis of the anterior lobe was more frequent in patients who died within 1 week of TBI. 12 Although the correlation between the autopsy and the biochemical results is unknown, the findings are sufficiently significant to justify systematic studies of pituitary function in patients with TBI. Clinical imaging Magnetic resonance imaging (MRI) is the imaging method of choice for studying the hypothalamic pituitary region. Very few systematic reviews of the pituitary appearance in patients with PTHP have been performed. In patients with closed head injury and PTHP, abnormal pituitary MRI or CT scans, usually showing vascular injuries, were reported in over 90% of cases reviewed by Benvenga et al. 12 However, an earlier series reported normal pituitary CT scans in 10 of 11 cases. 55 Clinical significance and public health implications The findings from the cross-sectional retrospective and prospective studies raise important questions about the clinical significance of PTHP; in particular, its contribution to the morbidity and possibly the mortality associated with TBI. Some of the hormone deficiencies identified were partial defects and would be of uncertain pathophysiological significance in otherwise fit and healthy individuals. However, they may have added importance in TBI patients who have a high burden of physical and neuropsychiatric disabilities, resulting in increased morbidity and impaired recovery. Severe glucocorticoid deficiency can be life-threatening and acute adrenal crises have been reported in critically ill TBI patients. 56 Even partial glucocorticoid deficiency may impair recovery and rehabilitation in the frail TBI patient due to lethargy, muscle fatigue and poor exercise capacity. GHD may also slow recovery because of the associated reduced lean body mass, 57,58 decreased exercise capacity, 59 impaired cardiac function 60,61 and reduced bone mineral density, which may be particularly relevant for immobilized TBI patients, especially when sex-steroid deficiency is also present. In addition, poor quality of life in GHD 65,66 may exacerbate any underlying cognitive and neuropsychiatric morbidity. Testosterone deficiency in males leads to reduced lean body mass, reduced bone mineral density and impaired well-being; oestrogen deficiency in females predisposes to premature osteoporosis. Deficiency in thyroid hormones leads to anergia, muscle weakness and neuropsychiatric manifestations. All these effects can have a significant potential to impair recovery and slow rehabilitation, and may contribute to the significant morbidity associated with TBI. Pituitary screening after TBI The persuasive evidence that hypopituitarism is common after TBI and the potential for replacement therapy to reduce the morbidity and improve outcome justify the establishment of integrated screening programmes for PTHP as part of standard clinical care for TBI patients. Such programmes need close collaboration between neurosurgery, endocrinology, rehabilitation medicine and other interested disciplines to ensure optimal delivery of care.

6 486 A. Agha and C. J. Thompson Who should be tested? Although most of the available data fail to show an association between PTHP and the severity of the head injury, most patients studied had significant head trauma that can be classified as severe or moderate injury (defined as those with GCS scores of 3 13 or CT evidence of brain injury). In addition, patients with severe or moderate TBI are much more likely to continue to suffer long-term morbidity than those with milder degrees of head trauma, and therefore the former group will benefit most from routine screening to identify and treat PTHP. Patients with milder head injury should be screened if clinically indicated. When and how should the assessment be performed? The prospective data 48,49 suggest that the early endocrine abnormalities can be transient while late abnormalities develop during rehabilitation. Therefore, patients with PTHP need periodic evaluation in the first year after TBI. Because of the large number of TBI cases and the complex and labour-intensive nature of the hypothalamic pituitary assessment, a rational practical approach is required. We propose the following plan for the follow-up of patients with TBI, which is summarized in the algorithm of Fig. 3. In the acute phase of TBI, the diagnosis of adrenal insufficiency should not be missed because it can be life-threatening. 56 A basal cortisol concentration of less than 200 nmol/l in the acute TBI setting suggests ACTH deficiency, and treatment with appropriate replacement doses of glucocorticoids is indicated pending full assessment in the post-acute phase. In patients with acute-phase basal cortisol > 200 nmol/l but < 400 nmol/l, clinical judgement should be exercised and replacement glucocorticoid therapy needs to be considered if the patient exhibits features that could be due to adrenal insufficiency such as hypotension, hyponatraemia or hypoglycaemia. 56 Assessment of the GH, gonadal and thyroid axes is not necessary in the acute phase because there is currently no evidence that acute phase replacement of these hormones in the deficient patient improves outcome. All patients with moderate or severe TBI should have anterior pituitary assessment performed in the post-acute phase, which will vary considerably between patients but is usually between 3 and 6 months after injury. The choice of the stimulation test(s) for GH and ACTH reserves will depend on the preference and experience of the unit and normal responses will need to be defined locally. At that point, if no abnormalities are found, no further assessment will be necessary. However, if hypopituitarism is detected, replacement therapy with glucocorticoids, sex steroids and T4 should be given, as appropriate. Although no study has yet examined the impact of GH treatment on rehabilitation in patients with post-traumatic GHD, a trial of GH replacement in such patients during the rehabilitation phase may be considered. In patients with documented anterior hypopituitarism at 3 6 months post-tbi, repeat anterior pituitary assessment at 1 year may be considered if the clinical or biochemical parameters raise the possibility of delayed recovery. Effect of hormone replacement on recovery and rehabilitation after TBI: future research Hormone replacement in patients with clear evidence of glucocorticoid, gonadal steroid and thyroid hormone deficiencies has proven benefits, and is an accepted component of standard clinical care regardless of the cause of hypopituitarism. The timing for replacement is suggested in the previous section. However, the benefit of routine replacement therapy in patients with borderline deficiency (for example, mild glucocorticoid deficiency under unstressed conditions) is debatable. There is a justification for a randomized controlled trial to examine the benefit of replacement therapy in mild (borderline) cases of PTHP during the rehabilitation phase. Adult GH replacement therapy is indicated for patients with severe GHD. 14 As GH replacement may potentially have an added benefit for rehabilitating TBI patients, the effect of GH replacement in both severe and partial post-traumatic GHD needs to be the subject of future research. Conclusion Traumatic brain injury is a major public health problem that exerts a high cost both for the individual victim and for society at large. The evidence available from recent studies suggests that hypopituitarism is a common but underdiagnosed complication with a significant potential to adversely affect outcome in TBI patients. Identification and appropriate and timely management of PTHP may significantly aid the recovery and improve the outcome of the victims of TBI. Acknowledgements Fig. 3 Suggested algorithm for the assessment of patients after traumatic brain injury (see text for details). 48 Figure 2 was adapted from the slides collection Management of endocrine sequelae in patients sustaining a traumatic brain injury or subarachnoid haemorrhage with kind permission of Pfizer EndocrineCare.

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