More than 2.5 million people in the United States alone experience a traumatic brain injury, or TBI, each year.
Some of these people are plagued by a seemingly unrelated cascade of health issues for years after their head injury, including fatigue, depression, anxiety, memory issues, and sleep disturbances.
A collaborative team, led by Dr. Randall Urban, The University of Texas Medical Branch at Galveston’s Chief Research Officer and Professor of Endocrinology, has spent the past 20 years investigating this post-TBI syndrome.
The team has learned more about how a TBI triggers a reduction in growth hormone secretion and why most TBI patients improve after growth hormone replacement treatment.
The studies led to the definition of the syndrome as brain injury associated fatigue and altered cognition, or BIAFAC, as recently described in a commentary published by Drs Urban and Brent Masel, UTMB Professor of Neurology, in the Journal of Neurotrauma. Detailed information on the team’s two most recent advances also in the Journal of Neurotrauma.
The team’s work on brain injuries began in the late 1990’s when Galveston philanthropist Robert Moody asked the team whether TBI caused dysfunction of the hormones made by the brain’s pituitary gland and funded research for the study.
His son, Russell, had suffered a serious TBI during a car accident and was seeking ways to improve the life of his son and others living with brain injuries.
The team has been building on the discovery that TBI triggers a long-term reduction in growth hormone, or GH, secretion that is linked with BIAFAC.
Most TBI patients experience dramatic symptom relief with GH replacement therapy, but the symptoms return if the treatment stops.
The researchers are trying to better understand BIAFAC and exactly how and why GH replacement works so well in order to develop new interventions.
“We already knew that even mild TBI triggers both short- and long-term changes to functional connections in the brain,” said Urban. “GH administration has been extensively linked with both protection and repair of the brain following damage or disease, however we didn’t know much about the particular mechanisms and pathways involved.”
They examined 18 people with a history of mild TBI and inadequate GH secretion. The subjects received GH replacement in a year-long, double-blind, placebo-controlled study and were assessed for changes in physical performance, resting metabolic rate, fatigue, sleep quality, and mood. Functional magnetic resonance imaging was also used throughout the year to assess changes in brain structure and functional connections.
The study showed that GH replacement was linked with increased lean body mass and decreased fat mass as well as reduced fatigue, anxiety, depression and sleep disturbance. It was also found, for the first time, that these improvements were associated with better communications among brain networks that have been previously associated with GH deficiency. They also noted increases in both grey and white matter in frontal brain regions, the “core communications center of the brain,” that could be related to cognitive improvements.
The team has learned more about how a TBI triggers a reduction in growth hormone secretion and why most TBI patients improve after growth hormone replacement treatment.
“We noticed that TBI patients had altered amino acid and hormonal profiles suggesting chronic intestinal inflammation, so we recently completed a trial to investigate the role of the gut-brain axis in the long-lasting effects of TBI,” said Urban.
“We compared the fecal microbes of 22 moderate/severe TBI patients residing in a long-term care facility with 18 healthy age-matched control subjects, identifying disruptions of intestinal metabolism and changes in nutrient utilization in TBI patients that could explain the reduced growth hormone function.”
The results suggest that the people with TBI-related fatigue and altered cognition also have different fecal bacterial communities than the control group. Urban said that the findings suggest that supplementing or replacing the dysbiotic intestinal communities may help to ease the symptoms experienced after TBI.
“These two studies further characterize BIAFAC and act as a springboard for new treatment options,” said Urban.
“We hope that the publications will focus the collective wisdom of the research community to better understand and treat this syndrome, providing hope for many. Because these symptoms can manifest months to years after the initial injury and as this cluster of symptoms hasn’t been previously grouped together, it often goes unidentified in the medical community.”
Funding: The work was supported by the Moody Endowment, the TIRR Foundation, Moody Neurorehabilitation Institute, the National Institutes of Health, Pfizer, the Centre for Neuroskills and the Baylor Alkek Center.
Traumatic brain injury (TBI) is defined as non-degenerative, non-congenital insult to the brain from an external mechanical force causing temporary or permanent neurological dysfunction, which may result in the impairment of cognitive, physical, and psychosocial functions . TBI can be classified according to the mechanism of injury (open versus closed). The clinical severity is commonly assessed according to the Glasgow Coma Scale (GCS) or injury severity score, and structurally by imaging and prognostic models .
Historically, GCS has evolved as the universal classification of TBI severity with GCS scores of 13 to 15 classified as mild, 9 to 12 as moderate, and 3 to 8 as severe TBI . A recent study found that the incidence of TBI was estimated to be 69 million (95% CI 64–74 million) worldwide . There exist differences in the incidence of TBI across the world with low- and middle-income countries experiencing nearly three times more cases of TBI proportionally than high income countries . Complications of TBI include increased mortality and morbidity.
Post traumatic hypopituitarism (PTHP), a recognized clinical entity for a century, is one contributor to morbidity in this cohort . This was previously thought to be rare, but in the last 15 years, it has received more recognition as a common complication of TBI.
Hypopituitarism is defined as a deficiency in the production of one, several, or all of the pituitary hormones, regardless of the cause. This is of clinical importance as unrecognized PTHP can impair rehabilitation and recovery .
PTHP is common, with the prevalence of PTHP for at least one pituitary hormone estimated at 28% . Severe TBI seems to confer the highest risk of PTHP . In this article, we reviewed growth hormone deficiency (GHD) following moderate/severe TBI.
The reported prevalence of GHD after TBI is highly variable (Table 1 and Table 2). This variability in prevalence is possibly due to a number of factors including the timing of the assessment, injury severity, age of onset, and the methods used to diagnose/confirm pituitary hormone dysfunction .
The prevalence of acute GHD, within one month of TBI, has been reported as between 2–30% [8,9,10] (Table 1). In the acute TBI setting, methods of assessment include basal IGF-1 and growth hormone measurement as well as glucagon stimulation test. Unfortunately, random GH and basal IGF-1 values are not a reliable measure of GHD.
In the majority of studies, GHD is the most common anterior pituitary hormone deficiency in the chronic phase of TBI and ranges between 10–63.6% [9,11,12,13,14,15,16,17,18,19] (Table 2). A lower incidence was reported when using a strict diagnostic criterion. The study that reported the highest incidence included both partial and severe GHD . This review will discuss GHD diagnosed in the chronic phase post TBI as this is deemed to be clinically relevant, especially in the rehabilitative period.
GH/IGF-1 and the Brain
Growth hormone (GH) is a peptide hormone synthesized by somatotropic cells of the anterior pituitary. Its release is regulated primarily by hypothalamic peptides and negative feedback. GH releasing hormone (GHRH) stimulates GH release, whereas somatostatin inhibits its release. GH acts via two independent mechanisms: directly via GH receptors (GHR) and by inducing the secretion of insulin growth factor 1 (IGF-1) in the liver.
GHR is a transmembrane receptor found on the cell surface of most cells. Centrally, GHR is expressed in high concentrations in the choroid plexus, hippocampus, hypothalamus, and the pituitary [20,21]. The choroid plexus, found in the ventricles of the brain, is made up of modified ependymal cells .
Its main function is to release cerebrospinal fluid (CSF) and also forms the blood–CSF barrier via tight junctions between adjacent epithelial cells. GH is thought to cross the blood brain barrier (BBB) via the receptor-mediated transport in the choroid plexus . The hippocampus is part of the limbic system and is involved in memory, learning, and emotions. Thus, the cognition and quality of life problems experienced by patients with GHD may be explained by the reduced expression of GH activity in these areas of the brain. Peripherally, GHR is found in many other tissues including the liver, muscle, bone, and adipose .
GH is a pleiotropic hormone and is one of the major players of the nervous system development. It also promotes cell growth and differentiation . GH has been shown to play an important role in neuroprotection and neuro-regeneration [26,27,28]. It has also been shown to be one of the key hormones involved in the regulation of appetite, cognitive function, energy, memory, mood, neuroprotection, sleep, and well-being . Peripherally, GH is an anabolic hormone, known to increase growth in skeletal and soft tissue . It also plays an important role in metabolism.
GH binding to the GHR in target tissue stimulates the production and secretion of IGF-1 from many tissues, particularly the liver . However, some IGF-1 is also produced locally by brain tissue. IGF-1 is a single polypeptide chain of 70 amino acids with 43% homology to proinsulin .
It exerts its physiologic activity by binding to the IGF-1 receptor (IGF-1R), a glycoprotein. Some IGF-1 is produced locally in the brain, but like GH, also crosses the BBB via transport mediated uptake . IGF-1 and its receptors have also been shown to be present in the adult brain and to be involved in the pathogenesis of several growth-related neurological disorders . Indeed, low IGF-1 levels have been linked to cognitive impairment .
The GH/IGF-1 axis is important for central nervous system tissue growth, development, myelination, and plasticity . In rat studies, GH has been shown to stimulate neuronal proliferation and differentiation and improve cognitive function [36,37].
It has been shown to be neuroprotective in hypoxic/ischemic injury partly via its anti-apoptotic effect . In rat studies, IGF-I seems to be emerging as a restorative molecule for increasing hippocampal neurogenesis and memory accuracy in aged individuals . It is known that impaired release of GH/IGF-1 such as that seen with advancing age leads to severe alterations in brain structures and functions .
Outside the CNS, the GH/IGF-1 axis is important for other functions. These include stimulating lipolysis, reducing hepatic triglyceride secretion, activating the nitric oxide system (and reducing vascular tone), increasing cardiac performance and exercise capacity, and promoting longitudinal skeletal growth .
Pathophysiology of GHD after TBI
Multiple theories have been described to explain the pathophysiology of GHD post TBI. The most widely accepted theory is that of ischemic injury to the pituitary [41,42]. Acute TBI is characterized by two injury phases: primary and secondary . In the primary phase, direct trauma to the brain at the time of the initial impact results in a series of biochemical processes that result in secondary brain injury .
Primary brain injury may lead to pituitary stalk traumatic transection, direct trauma to the hypothalamus and pituitary, or the compressive effect of increased intracranial pressure, resulting in ischemia and necrosis of the anterior pituitary and thus hypopituitarism [44,45]. The pituitary stalk that connects the hypothalamus to the pituitary gland is structurally fragile and vulnerable to the effects of TBI . The anterior pituitary does not have direct arterial blood-supply, but instead gets all of its blood supply via the hypophyseal portal vessels .
The long hypophyseal portal veins connect the hypothalamus to the anterior pituitary providing 70–90% of the anterior pituitary blood supply, whereas the shorter portal vessels originating in the lower part of the pituitary stalk and the posterior lobe provide the remaining 10–30% [42,48].
The somatotropic cells are located laterally in the pituitary with the majority of its vascular supply provided by the long portal veins that have an anterolateral distribution in the gland . GH releasing hormone (GHRH) neurons in the hypothalamus also seem to be vulnerable to ischemic injury due to their position .
Contributing to the initial brain injury, other factors associated with trauma such as hypotension and hypoxia may cause ischemic injury to the pituitary at this time. To support the theory of vascular injury/ ischemia as a cause of PTHP, magnetic resonance imaging (MRI) in the acute phase has shown swelling of the pituitary gland compared to healthy controls, whereas in the chronic phase, volume loss or empty sella has been described in patients who went on to develop PTHP [51,52].
Molecular Mechanisms of the Growth Hormone Deficiency after Traumatic Brain Injury
After the initial primary phase of TBI, the secondary phase is characterized by a combination of ischemic, cytotoxic, and inflammatory processes that further propagate the brain injury (Figure 1) . As described below, neuroinflammation is strongly implicated in the molecular pathophysiology of PTHP and thus
It is hypothesized that the initial hypoxic-ischemic insult that occurs at the time of trauma leads to subsequent oxidative stress and cytotoxicity leading to the death of neuronal cells by apoptosis or necrosis . Histological examination of patients post-TBI showed that the underlying pituitary pathology in patients dying after TBI were acute infarction of the pituitary, capsular hemorrhage around the pituitary, anterior lobe necrosis, and stalk necrosis [44,45,54].
Secondary ischemic brain injury, focal contusions, sustained high intracranial pressure, and poor outcome have been shown to be strongly associated with high excitatory amino acid levels (glutamate) in patients with TBI . At the time of the TBI, there is a release of excitotoxins such as glutamate and aspartate that act on the N-methyl-D-aspartate (NMDA) channel, altering cell wall permeability with an uncontrolled shift of sodium, potassium, calcium, and activation of calcineurin and calmodulin . This ultimately leads to severe cell swelling and cell death .
Cortical brain injury might induce pathological changes in structures distal to the cortical injury like the hypothalamus and pituitary gland by persistence and spread of inflammatory factors at the site of injury, resulting in secondary necrosis and apoptosis of distal brain tissue . Rat models have shown that pro inflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor (TNF), released as a result of TBI at the primary injury site of injury, may also contribute to the development of PTHP .
Rat models have also shown a significant increase in the expression of IL-1β and glial fibrillary acidic protein (GFAP) in the hypothalamus and pituitary post bilateral cortical brain injury . It is hypothesized that the inflammatory factors produced in the cortex diffuse to distant sites through the ventricles or by movement through extracellular fluid and spaces, activating further cytokine (IL-1) production downstream from the initial injury and activating a rolling cascade of inflammatory reactions [56,58].
Other Possible Mechanisms
There is also some evidence to suggest that autoimmunity is a contributor to pituitary hormonal deficits post TBI. Anti-pituitary antibodies (APA) have been detected in patients with TBI when compared to normal controls . Tanriverdi et al. found a positive correlation between APA positivity and PTHP, with close to 50% of the patients with positive antibodies developing hypopituitarism three years after TBI .
In the same study, the authors found that high APA titers were associated with a low GH response to the GH releasing hormone (GHRH) + GH related peptide (GHRP)-6 test. When these patients were followed up for a period of five years, those with pituitary dysfunction had significantly higher titers of both anti-hypothalamus antibodies (AHA) and APA . In another study by the same group, AHA and not APA was significantly correlated with the development of PTHP in a cohort of boxers . However, these autoantibodies were non-specific and have been detected in other forms of pituitary pathology such as Sheehan’s syndrome and sometimes in patients without any pituitary/hypothalamus pathology [62,63]. Thus, no causal relationship can be concluded between GHD and autoimmunity in the context of TBI.
Genetic predisposition to the development of PTHP has also been implicated. Apolipoprotein E (APOE) is the major apolipoprotein produced in the central nervous system. It is synthesized by astrocytes, microglia, and neurons under conditions of stress and has an inhibitory effect on the neuroinflammatory cascade following injury [53,64]. Predominantly, patients with the APOE ε3/ε3 genotype seem to have a lower risk of developing PTHP than patients with other genotypes .
Signs and Symptoms
In adults, the signs and symptoms of GHD can be subtle and are shown in Table 3. There is some overlap between the symptoms of GHD and those from TBI, which may contribute to delays in the diagnosis of GHD post TBI. GHD, regardless of cause, is associated with poor quality of life (QoL), diminished lean body mass (LBM), increased body fat, disrupted lipoprotein and carbohydrate metabolism, reduced bone mineral density, and impaired cardiac function [66,67]. These may be partially ameliorated by treatment with recombinant human GH (rhGH) replacement. The literature is more robust for growth hormone treatment improving cognition and QoL, and not for all the other parameters as discussed below.
Signs and symptoms of growth hormone deficiency.
|Decreased muscle mass|
Increased fat mass
Altered metabolic profile
Decreased exercise capacity
GH—Growth Hormone; QoL—Quality of Life; BMD—Body mineral density.