Acute neuroendocrine changes after traumatic brain injury

Abstract

Introduction: Post-traumatic hypopituitarism (PTHP) is a significant, but often neglected consequence of traumatic brain injury (TBI).

Research question: We aimed to provide a comprehensive overview of epidemiology, pathophysiology, clinical features and diagnostic approaches of PTHP.

Materials and methods: MEDLINE, EMBASE, Cochrane Library and Web of Science were searched. 45 articles of human studies evaluating acute endocrine changes following mild, moderate and severe TBI were selected.

Results: Severity of TBI seems to be the most important risk factor of PTHP. Adrenal insufficiency (AI) was present in 10% of TBI patients (prevalence can be as high as 50% after severe TBI), and hypocortisolemia is a predictor of mortality and long-term hypopituitarism. Suppression of the thyroid axis in 2-33% of TBI patients may be an independent predictor of adverse neurological outcome, as well. 9-36% of patients with severe TBI exhibit decreased function of the somatotrophic axis with a divergent effect on the central nervous system. Arginine-Vasopressin (AVP) deficiency is present in 15-51% of patients, associated with increased mortality and unfavorable outcome. Due to shear and injury of the stalk hyperprolactinemia is relatively common (2-50%), but it bears little clinical significance. Sex hormone levels remain within normal values.

Discussion and conclusion: PTHP occurs frequently after TBI, affecting various axis and determining patients' outcome. However, evidence is scarce regarding exact epidemiology, diagnosis, and effective clinical application of hormone substitution. Future studies are needed to identify patients at-risk, determine the optimal timing for endocrine testing, and refine diagnostic and treatment approaches to improve outcome.

Keywords: Acute pituitary disfunction; Neuroendocrine changes; Post-traumatic hypopituitarism; Traumatic brain injury.

Fig. 1

Flow chart of the systematic search strategy.

Fig. 2

Proposed mechanisms of post-traumatic hypopituitarism (PTHP) and their relationships. Mechanical injuries cause direct pituitary damage, as well as mass lesions that lead to increased ICP and hypoxic-ischemic injuries, exacerbated by the long course of portal vessels. Neuroinflammation damages tanycytes that regulate hypothalamic hormone release at the median eminence. Focal and global destruction of the blood-brain barrier exposes antigens that could trigger autoimmune reactions against the pituitary gland. BBB: blood-brain barrier.

Fig. 3

Summary of endocrine changes in the acute phase of traumatic brain injury (TBI). Effects of TBI lead to various alterations in each axis of the hypothalamo-pituitary system (HPA). Derangements of the HPA axis can present as secondary hypocortisolemia as well as compensatorily elevated glucocorticoid levels. Cortisol peaked within 24 h, while adrenal insufficiency ensued during the first 10 post-injury days. Hypothyroidism is also a common feature and conveyed poor prognosis, although no clear temporal pattern was observed. If involved, prolactin production displays an increase due to disinhibition. This phenomenon can manifest within a few days after the injury and may persist up to several months in severe cases. Examination of the somatotroph axis often shows suppression within the first few days, followed by peripheral GH resistance, demonstrated by elevated GH and decreased IGF-1 levels at 3 months follow-up. As part of the stress response, gonadotrophins are usually suppressed during the first 10 post-injury days and tend to slowly normalize afterwards. Insufficient or overly active ADH production and release leads to sodium and water homeostasis imbalances, seen as AVP-D or SIADH, respectively. These derangements are usually transient and confined to the in-hospital period in the majority of cases. TBI: traumatic brain injury, CRH: corticotropin-releasing hormone, ACTH: adrenocorticotropic hormone, TRH: thyrotropin-releasing hormone, TSH: thyroid stimulating hormone, fT3,4: free triiodothyronine, free thyroxine, DA: dopamine, PRL: prolactin, GHRH: growth hormone-releasing hormone, SST: somatostatin, GH: growth hormone, IGF-1: insulin-like growth factor 1, GnRH: gonadotropin hormone-releasing hormone, FSH: follicle-stimulating hormone, LH: luteinizing hormone, E2: estradiol, P: progesterone, T: testosterone, ADH: antidiuretic hormone.