Posttraumatic Neuroendocrine Dysfunction: Impact on Recovery

Article

Traumatic brain injury-induced dysregulation of the neuroendocrine system and may contribute to the exacerbation of posttraumatic morbidity.

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Traumatic brain injury (TBI) is a major cause of disability, with an estimated 5.3 million individuals living with disabilities secondary to a TBI in the United States alone.1 While many TBI survivors may seem to make a full physical recovery, a substantial proportion continue to suffer from more subtle disabilities, which are likely to impact daily functioning. Such invisible disabilities may include long-lasting symptoms of cognitive deficits (memory, attention/concentration, executive functioning, etc), disturbed affect, hypervigilance, fatigue, and autonomic dysregulation. These chronic symptoms are often linked to TBI-induced dysregulation of the neuroendocrine system and may contribute to the exacerbation of posttraumatic morbidity.

Regulation of the Neuroendocrine System

When a brain injury occurs, biomechanical forces frequently impact the diencephalon, which is located deep within the center of the brain, just above the brainstem. This area of the brain is highly involved in the tight regulation of the neuroendocrine system, the disruption of which may delay or interfere with recovery by altering the release and subsequent signaling of essential hormones. Two primary structures in the diencephalon, the hypothalamus and pituitary gland, make up a feedback loop (the hypothalamic-pituitary system) that sends signals from the hypothalamus (known as releasing hormones) to the pituitary gland, which then releases/distributes hormones to other bodily systems including the adrenal and thyroid glands, reproductive organs, skin, bone, and muscle. Disruption of these signals will have widespread effects on mood, memory, metabolism, muscle mass, energy, stress, libido, and reproduction.

The posttraumatic dysregulation of the neuroendocrine system has been referred to as “posttraumatic hypopituitarism” (PTHP) and is now increasingly recognized as a common sequela of TBI. Though more attention has been given to PTHP, symptoms may often be overlooked, attributed instead to the TBI itself, adverse effects of medications, or symptoms of other common TBI sequela, such as sleep-wake disturbances. While PTHP can occur in mild injuries and cases with no obvious anatomical damage, it is more frequently observed in moderate to severe injuries. Suspected posttraumatic neuroendocrine dysfunction requires close monitoring, as symptoms may evolve (surfacing even 1 year post-injury) or resolve over time, though alterations at 6 months post-injury seem to be stable and relatively permanent.2

Hypothalamic Pituitary System Axis Dysfunction

The hypothalamic-pituitary system comprises several different axes, which are defined by the signaling pathways involved. For example, the hypothalamic-pituitary-adrenal (HPA) axis is a signaling loop from the hypothalamus to the pituitary gland to the adrenal glands [and back]. Disruption of several of these axes have been observed post-TBI.

Hypothalamic-Pituitary Somatotropic Axis

The most common example of hypothalamic-pituitary-somatotropic (HPS) axis dysfunction post-TBI, is growth hormone (GH) deficiency (GHD), with up to 45% of chronic TBI patients presenting with a severe deficiency.3 GH is synthesized in the anterior pituitary gland and stimulates the production and release of insulin-like growth factor-1 (IGF-1). GH has been identified as crucial in nervous system development, neuroprotection, and neuro-regeneration, as well as in the regulation of appetite, cognitive function, energy, memory, mood, sleep, and general well-being. In fact, GH receptors have been found on the surface of most cells, indicating that levels of GH will impact nearly all tissues and organs.4 Patients with TBI also presenting with GHD are more likely to have low levels of other hormones, suggestive of pituitary damage and/or altered circuitry regulating endocrine responses. Additionally, patients with GHD often have issues with decreases in muscle mass and bone density, fatigue, impairments in memory, attention, and cognitive flexibility, leading to a significant decrease in quality of life.

Hypothalamic-Pituitary Gonadal Axis

Hypothalamic pituitary gonadal (HPG) axes dysregulation involves alterations in hypothalamic release of gonadotropin releasing hormone (GnRH), which will impact sex hormones. In men, hypogonadism is typically associated with low levels of testosterone; in women, it is associated with decreases in estradiol. Male hypogonadism presents acutely and persists in up to 37% of male patients with TBI.5 Suppression of the HPG axis in women has been attributed to chronic increases in levels of cortisol. While posttraumatic anovulation observed in response to changes in cortisol levels typically resolves, up to 46% of female patients with TBI experience a complete cessation of menstruation (amenorrhea) and up to 68% report irregular cycles.6 Menstrual cycle changes may be influenced by injury severity and be predictive of outcome. Gonadal hormones have also been tied to normal brain development, cognition, and mood.

Hypothalamic-Pituitary Adrenal Axis

The hypothalamic-pituitary-adrenal (HPA) axis is known primarily for its role in regulating our stress response. When we experience something stressful, the hypothalamus releases corticotropin-releasing hormone (CRH), which triggers the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. This signal then travels to the adrenal glands where cortisol is released. Cortisol then initiates several changes in our body that help us deal with stress. For example, increasing blood pressure and heart rate. Hyper-responsiveness of the HPA system has been observed post-TBI and may contribute to depression, anxiety, mood swings, irritability, and impaired learning/memory.7

Hypothalamic-Pituitary Thyroid Axis

Although observed less frequently post-TBI, given the widespread metabolic effects of thyroid hormones, persistent disruption of the hypothalamic pituitary thyroid (HPT) axis can have substantial consequences.8 Thyroid hormones regulate systemic glucose metabolism and may also regulate brain glucose, which is required for optimal cognitive processing; thus, brain injury induced alterations of thyroid function will have a negative impact on cognitive function. Dysregulation of thyroid hormones has also been shown to impair mood and energy levels. Thyroid hormone activity is influenced by other endocrine signals and compounds, such as cortisol and gonadal hormones, meaning that, in many cases, a disruption in 1 axis is likely to influence another.

Diagnosis and Treatment of PTHP

Any medical provider may initiate diagnostic testing and/or hormone replacement; however, it is best that patients with PTHP be treated by an endocrinologist knowledgeable in this field. The American Association of Clinical Endocrinologists has recommended that all patients with moderate to severe TBI be assessed during the acute and chronic phases of their recovery.9 Individuals who have sustained a mild TBI who are experiencing symptoms should be offered assessment.9 Diagnosis is obtained via blood tests (ie, IGF-1: GH; LH, FSH, Prolactin, morning free Testosterone [male], estradiol [female]: Gonadotropins; morning cortisol: Adrenals; TSH and free T4: Thyroid). Treatment is accomplished through hormone replacement, which may be as simple as a daily pill, or could be more complex, as in the case of GHD, which requires daily injections. Importantly, early diagnosis of pituitary dysfunction and subsequent treatment can improve outcomes.10

Concluding Thoughts

Given the widespread effects of pituitary hormones throughout the body, it follows that disruption of these signaling pathways will have a notable impact on the response to rehabilitation and, ultimately, outcome potential. Posttraumatic pituitary dysfunction in the acute and chronic recovery phases has been linked to reduced quality of life and rehabilitation outcomes with direct adverse effects on health outcomes including ischemic heart disease and shortened life span.11-14 Considering the high prevalence of neuroendocrine dysfunction post-TBI, the association with poor outcomes, and the relative ease of treatment, dysregulation of the neuroendocrine system is more frequently becoming an area of early identification and treatment in attempts to stave off long-term neurological consequences.

Dr Howell is a senior neuroscientist at the Centre for Neuro Skills. She is a specialist in brain injury rehabilitation, neurodegenerative disease, and clinical research.

References

1. Centers for Disease Control and Prevention. Report to Congress: Traumatic Brain Injury in the United States. Accessed April 19, 2022. https://www.cdc.gov/traumaticbraininjury/data/index.html

2. Wilkinson CW, Pagulayan KF, Petrie EC, et al. High prevalence of chronic and target-organ hormone abnormalities after blast-related mild traumatic brain injury. Front Neurol. 2012;3:11.

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5. Wagner AK, Brett CA, McCullough EH, et al. Persistent hypogonadism influences estradiol synthesis, cognition and outcome in males after severe TBI. Brain Inj. 2012;26(10):1226-1242.

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10. Krahulik D, Zapletalova J, Frysak Z, Vaverka M. Dysfunction of hypothalamic-hypophysial axis after traumatic brain injury in adults. J Neurosurg. 2010;113(3):581-584.

11. Masel BE, DeWitt DS. Traumatic brain injury: a disease process, not an event. J Neurotrauma. 2010;27(8):1529-1540.

12. Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol (Oxf). 1992;37(5):387-397.

13. Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, et al. Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review. JAMA. 2007;298(12):1429-1438.

14. Urban RJ, Harris P, Masel B. Anterior hypopituitarism following traumatic brain injury. Brain Inj. 2005;19(5):349-358.

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