The true global incidence of traumatic brain injury (TBI) is difficult to fully ascertain; a recent meta-analysis suggested that the incidence is increasing and affects 134–618 persons per 100,000 per year with the highest incidence appearing in adult men (1). This makes TBI the most common cause of death and disability in young adults living in industrialized countries (2) and as such it presents a major public health concern.

However, the reported incidence of TBI varies wildly depending on numerous geographical and demographic factors. Most TBIs are mild and are not admitted to hospital (3). As a result, the vast majority of the literature on the subject relates to patients who required hospital admission, typically with moderate or severe TBI. The resultant underestimation of the true incidence of TBI has led to it being described as a “silent epidemic.”

Over the recent 15 years, numerous research studies have documented a high rate of pituitary gland dysfunction following moderate or severe TBI with evidence that post-traumatic hypopituitarism (PTHP) contributes significantly to the morbidity and possibly mortality in those patients (4). PTHP can masquerade as a post-concussional syndrome and can be overlooked leading to delayed recovery and impaired rehabilitation (5). Therefore, screening patients for PTHP should be an important part of the standard care provided following severe or moderate TBI.

This review will discuss the evidence supporting the need for screening of anterior pituitary function after TBI and our approach to the endocrine assessment and management of these patients.

Mechanisms of injury including vascular injury to the hypothalamus, stalk, or the pituitary gland resulting in infarction, direct traumatic injury to the pituitary from base of skull fractures or secondary insults from, hypoxia, hypotension, or raised intracranial pressure (19) have all been hypothesized. It is likely that a vascular injury is the commonest mechanism as autopsy studies have demonstrated pituitary infarction in up to 43% of cases of fatal TBI (20).

The relationship between the severity of the head injury and the risk of hypopituitarism remains controversial. Traditionally, the clinical severity of TBI is measured by the post-resuscitation and pre-intubation Glasgow Coma Scale (GCS) Score. A score of 3–8 indicates severe, 9–12 moderate, and 13–15 mild injury. In patients with moderate or severe TBI, the scores do not seem to predict the risk of PTHP (8) but it is important to emphasize that this scale is limited by significant inter-observer variability and that the GCS scores can fluctuate over time. Some authors have suggested that findings on computed tomography should be factored in to the initial assessment when determining severity of TBI. They have hypothesized that significant pathological findings like cerebral edema or hemorrhage on cranial imaging may infer a more severe TBI. The data on this is limited with one study demonstrating a correlation between diffuse brain swelling and PTHP (19) and another finding no such association (14).

The data for mild TBI and hypopituitarism are limited (3). While some studies showed a significant association (21), one excellent large study showed a very low incidence of PTHP in mild TBI cases (22).

In patients with TBI, acute-phase cortisol deficiency is potentially life threatening and a number of studies have shown an association between increased morbidity and mortality in acute post-traumatic hypoadrenalism (11, 23).

Long-term adult GH deficiency is associated with decreased quality of life (24), reduced lean body mass (25), reduced bone mineral density (26), and impaired cardiac function (27). The sequelae of sex steroids, ACTH, and TSH deficiencies are well known (Table 2). Recent data seem to confirm that anterior pituitary hormone deficiency has a negative impact on functional outcome at 6 months post TBI as assessed by mini-mental state exam and functional independence measure scores (4). Other studies have found a correlation between PTHP and unfavorable metabolic and body composition profiles with associated lower quality of life scores (28, 29) as well as decreased exercise capacity (30) and neuropsychiatric complications (31).

Screening every patient with a TBI for PTHP is clearly not feasible. This approach does not meet the criteria for an appropriate screening tool due to the high cost and the complexity of testing which often requires dynamic and sometimes repeat assessments. The most robust data with regard to incidence of PTHP are in those patients with moderate or severe TBI (14). We therefore do not routinely screen patients with mild TBI for pituitary dysfunction unless there are specific symptoms suggestive of hypopituitarism (21, 22). Features that seem to confer an increased risk of PTHP include diffuse axonal injury on brain imaging, prolonged admission to ICU, basal skull fracture, and increasing age (32).

Screening for mild cases of TBI remains controversial. Schneider et al. demonstrated a high rate (16.8%) of PTHP following a mild TBI (8) although most of the endocrine abnormalities on mild TBI cases were not confirmed by second dynamic tests. In one well-executed study, the frequency of PTHP after simple mild TBI was found to be very low (22). However, it has been suggested that “complicated” cases labeled as mild TBI should also be included in the screening process (33). Features of a complicated mild TBI as described in this review included those patients admitted to hospital for >24 h, patients admitted to the ICU or those requiring neurosurgical intervention, patients suffering pituitary dysfunction within 2 weeks of their TBI, or patients with new anatomical changes on their brain scans. Therefore, selected cases of complicated mild TBI could also be offered screening but this will clearly have considerable resource implications.

Traumatic brain injury is one of the world’s leading causes of morbidity and mortality among young men. PTHP is now recognized as a common, but often underdiagnosed, complication which may contribute significantly to the morbidity and possibly the mortality following moderate and severe TBI. Endocrine evaluation and management should be part of standard multidisciplinary care for these patients. Among patients with severe and moderate TBI, acute cortisol deficiency should be diagnosed and managed promptly while a more comprehensive assessment of the pituitary function should be undertaken in the post-acute phase. Randomized clinical trials examining the effect of GH replacement in patients with post-traumatic GH deficiency are needed to assess the potential impact on recovery, rehabilitation, and quality of life.

MQ carried out a detailed literature review on the topic of post-traumatic hypopituitarism and created various drafts under the title “Post-traumatic hypopituitarism—who should be screened, when, and how?” AA corrected each draft and provided additional literature which added to the scope of the review.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.