Neuroendocrine dysfunction following mild TBI: When to screen for it

The Centers for Disease Control and Prevention (CDC) reports that >1.7 million cases of traumatic brain injury (TBI) occur annually in the United States.¹ More than 266,000 military service members sustained at least one TBI from 2000 to 2012.² Most TBIs (80%-85%), military and civilian, are classified as mild (mTBI), and most mTBI patients (80%-85%) experience a complete functional recovery within 3 months of injury.^1,3 The remaining 15% to 20% of mTBI patients experience persistent symptoms and difficulty in rehabilitation, particularly if there are concomitant disorders, such as post-traumatic stress disorder (PTSD), sleep disorders, acute stress disorder, substance abuse disorder, and depression.^4,5 Symptoms that mTBI and these other disorders have in common can make differential diagnosis difficult, requiring a high degree of clinical awareness by primary care providers. An additional concern following mTBI is neuroendocrine dysfunction (NED). This association has not been widely discussed and therefore may go largely undiagnosed.⁶ Consider NED in the setting of prolonged symptoms or in patients experiencing difficulty with rehabilitation following mTBI.^7,8

NED following mTBI is more common than once thought

The term “neuroendocrine dysfunction,” as discussed in this article, refers to a variety of conditions caused by imbalances in the body’s hormone production directly related to the pituitary, hypothalamus, and their axes following TBI. Until the past decade, the incidence of TBI-associated pituitary dysfunction was thought to be an uncommon event, usually associated with catastrophic head injuries. Studies of NED in TBI patients focused primarily on moderate or severe TBI, usually from motor vehicle incidents, falls, and assaults.⁷ Other research has since shown that NED occurs more commonly than once believed.⁹ And while the risk of NED may be higher for patients who sustain more severe brain injuries, NED also occurs in mTBI.^7,9,10,11 Interestingly, a recent literature review indicated that the incidence of NED in mTBI was 16.8%, while the incidence with moderate TBI was reported at 10.9%.⁷ Other research has noted that the incidence of NED in mTBI may be as high as 42%.^9,12 No evidence suggests that the severity of NED is related to a specific hormonal dysfunction, nor is there evidence that NED may be associated with a specific mechanism of injury.

Anterior pituitary deficiencies (GH and gonadotropin) account for the majority of chronic neuroendocrine disorders following mTBI.Pituitary anatomy is susceptible to injury and dysfunction

The anatomic and physiologic complexities of the hypothalamus and pituitary gland increase their susceptibility to injury from TBI. The pituitary gland is connected to the hypothalamus by a blood vessel-containing stalk, making the pituitary gland—particularly the anterior portion—susceptible to damage during a head injury.¹³ The hypothalamus secretes thyrotropin-releasing hormone (TRH) and luteinizing-releasing hormone (LRH) to stimulate or suppress the production of anterior pituitary gland hormones, which in turn stimulate the release of hormones and other substances from target organs. Anterior pituitary hormones are growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and prolactin (PRL). The posterior pituitary secretes oxytocin and vasopressin, also known as antidiuretic hormone (ADH).¹³

Impact from a direct blow with an object or from a concussive blast can cause focal trauma or rotational shearing of tissue internally. Resultant vascular injury, rupture, cerebral edema, vasospasm, pituitary swelling, or inflammation may then initiate an endocrine response that drives a cascade of complex hormonal processes.^5,7,8 Anterior pituitary deficiencies account for the majority of chronic neuroendocrine disorders following mTBI. GH and gonadotropin deficiencies are the most common, but TSH deficiency (secondary hypothyroidism) and ACTH deficiency (adrenal insufficiency) may occur as well, although in <10% of cases with TBI associated NED.¹²

Clinical features of NED mimic those of other conditions

The symptoms of NED include fatigue, insomnia, impaired cognition, memory loss, difficulty concentrating, and emotional and mood disturbances (TABLE).^7,12,14-17 Various combinations of these symptoms may occur and are similar to those of other post-mTBI conditions, such as sleep problems, postconcussive syndrome (PCS), and memory and attention difficulties.¹⁸ The onset of NED may be immediate (eg, in diabetes insipidus [DI] or syndrome of inappropriate antidiuretic hormone [SIADH], which are very rare in mTBI) and potentially life-threatening (eg, in sodium and potassium imbalances), or may be nonspecific and take years to manifest.^6,10,15,19 Additionally, symptoms of NED may spontaneously resolve or persist. Studies have demonstrated pituitary dysfunction in the acute postinjury phase as well as its development as late as 2 to 3 years after injury.^7,8,11,20