Traumatic Brain Injury (TBI) is defined as any injury caused by an external force that disrupts the normal function of the brain. The U.S. Center for Disease Control (CDC) estimates that TBI is responsible for 2.5 million hospitalizations and emergency department visits in the United States each year, with approximately 52,000 patient deaths [1]. This number does not include U.S. Veterans Affairs hospitals, persons who did not seek or receive care, nor patients who received treatment through outpatient clinics [1]. Within the military, TBI is one of the most prevalent injuries diagnosed in active-duty service members that served in Operations Iraqi Freedom, Enduring Freedom, and New Dawn, affecting 15 - 23% of combat soldiers [2], [3], [4] and 4.2% of all service members [5]. The age distribution of TBI is wide. According to the 2015 CDC report, adults aged 75 years and older are the most at risk for TBI related emergency department (ED) visits or hospitalizations [6] while patients younger than 19 years old account for 70% of all sports related TBIs [7]. Despite the prevalence of TBI, many cases are not recognized and therefore excluded from official data, partially due to variability in the definition of TBI, thus giving credence to the notion that TBI is simultaneously a “critical public health crisis” and a “silent epidemic” [8], [9].

TBI is commonly divided into four phases: the immediate phase (0-7 days post-injury), acute phase (1-6 weeks post-injury), the post-acute (7-12 weeks post-injury), and the chronic phase (>12 weeks post initial injury) [10]. TBI severity is categorized by the Glasgow Coma Scale (GCS) and the duration of loss of consciousness (LOC) and posttraumatic amnesia (PTA) [11]. The most common severity of TBI, mild TBI (mTBI) [6], is defined by several institutions including the American Congress of Rehabilitation Medicine (ACRM) and the World Health Organization (WHO) as a GCS score of 13-15 in the Emergency Department, LOC for <30 minutes when present, and PTA <24 hours [12], [13]. While similar to mTBI in definition, complicated mTBI (cmTBI) is additionally characterized by hospitalization for more than 24 hours or documented intracranial bleeding, brain swelling or skull fracture [14]. However, the U.S. Department of Veterans Affairs (VA) and Mayo Clinic define mild TBI utilizing neuroimaging to assist with classification of injury [15], [16], specifically using more sensitive and advanced neuroimaging modalities in place of computerized tomography which, historically, has been less sensitive in detecting cerebral injury [17]. Among active-duty military members, a 2010 study found that 80% of over 30,000 US military personnel diagnosed with TBI were deemed mild [18]. Survivors of TBI experience cognitive, physical, and emotional deficits [19], [20]. These symptoms can resolve after the acute stage, but some individuals suffer persistent symptoms in the chronic stage [19], [20]. Up to 30% of patients in one 2017 study exhibited symptoms greater than 3 months post-initial injury, which were referred to as persistent post concussive symptoms [14], [21].

TBI-induced hypopituitarism or post-traumatic hypopituitarism (PTHP), defined as a deficiency in one or more anterior pituitary hormones following TBI, historically has been considered rare, particularly in patients with a history of mTBI and therefore underdiagnosed overall due to lack of awareness among providers and lack of clinical consensus [5], [20], [22]. Incidence of post-traumatic hypopituitarism is estimated to be 100-350 per 100,000 in the general population [8]. Studies in the last two decades indicate a higher prevalence rate of hypopituitarism, with estimates of pituitary deficiencies post TBI occurring in 25% of patients with some estimates ranging as high as 56% in the acute stage of TBI and 36% at one year following injury [19], [23]. Among patients with a history of mTBI, more recent studies have shown prevalence ranging from 36% in patients with mTBI 3 -12 months following injury [14], though 46% of this cohort included patients with a history of multiple head injuries [14]. Further, in a study of patients with a history of cmTBI, 35% of patients were found to have confirmed AGHD one year post-injury and 48% of patients were found to have confirmed AGHD five years post-injury [24]. Forty-two percent of participants in one study of military personnel with blast TBI were found to have one or more abnormal pituitary hormone levels [18]. Discrepancies in the prevalence of PTHP is likely due to the heterogeneity in the study populations, and differences in methodologies, mTBI definition, temporal relationship with the traumatic event, and different PTHP criteria [11]. Growth hormone deficiency (GHD) is one of the most common endocrine dysfunctions of the anterior pituitary gland in the chronic phase of TBI, with studies indicating a prevalence of up to 40% [25], [26]. While most GHD occur in moderate to severe TBI, GHD has been documented in mTBI as well [25], *[27]. A review on mTBI found that GHD occurred in 45% of professional boxers and 27.3% of amateur kickboxers [28]. One 2021 study by Mercier and colleagues showed that 23% of civilian mTBI patients exhibited severe GHD and 40% exhibited GH insufficiency [14]. Among Veterans and active-duty service members, the prevalence of GHD was 21-50% of patients screened for PTHP [29], [30], [31]. Taken together and given the uncertainty on the true prevalence of AGHD in mTBI, more studies are needed to develop evidence-based guidelines on screening, diagnosis, and treatment of mTBI-induced GHD [25], [26].

There is some discrepancy in the reported causes of TBI. One review among civilians estimates that nearly 50% are caused by falls and about 25% by motor vehicle accidents [25] while another source reports 54-79% are caused by falls, 15% by a blunt object and 15% by motor vehicle collisions [30]. A population-based study found that 21% of all TBIs were caused by sports-related injury including those related to playing American football, hockey, boxing, kickboxing, and soccer *[7], [28]. A common mechanism of mTBI in the military population occurs via explosive blast TBI (bTBI), common to soldiers deployed to Iraq and Afghanistan, with roughly 10-20% of returnees diagnosed with at least one blast concussion [18]. Of non-blast mechanisms of mTBI of military members, 32.6% were caused by blunt objects, 25.6% by sports and recreation, 23.3% by falls and 18.6% by motor vehicle accident [3].

PTHP was first reported in the early 20th century *[7], [32], [33] primarily through post-mortem studies. However, it has been considered rare historically, particularly in patients with a history of mTBI, with approximately 16.8% of mTBI patients diagnosed with AGHD compared to 10.9% and 35.3% in patients with moderate and severe TBI respectively [27], and therefore underdiagnosed overall due to lack of awareness among providers, and lack of clinical consensus on its screening, diagnosis and the efficacy and safety of replacement [34]. The lack of or delay in diagnosis and treatment may be related to the fact that symptoms of hypopituitarism overlap with those of TBI itself [34] and patients with mTBI are less likely to seek or be offered assessment compared to moderate or severe TBI patients [25]. Research over the last two decades indicates that PTHP is a common complication of TBI, including mTBI [11]. Autopsies performed on severe TBI victims show lesions in 23% to 59% on the anterior lobe of the pituitary gland and pituitary stalk including hemorrhage, necrosis, and fibrosis [27]. Hypothalamic lesions were correlated with fractures of the middle cranial fossa and ischemic necrosis. Further, 68% of these severe TBI victims displayed microhemorrhages at autopsy indicative of possible structural damage caused by TBI [27]. It is hypothesized that the TBI injures the hypothalamus and adjacent third ventricle leading to disrupted communication between the hypothalamus and the pituitary gland [35]. Others hypothesize that the TBI causes physical jarring to the pituitary leading to swelling and increased intracranial pressure surrounding the pituitary gland. This can interrupt blood flow to the pituitary gland and contribute to hypotension, hypoxia, and subsequent anterior lobe infarction, leading to hypopituitarism in the acute phase. During the chronic phase, the swelling in the pituitary gland may resolve allowing for normal pituitary hormone function [27]. In some cases, the above-described inflammation and related sequelae may result in pituitary cell death resulting in PHDs including GHD [25]. Unfortunately, most studies do not differentiate between the pathophysiology of PTHP in mild and moderate/severe TBI.