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Post Head Injury Endocrine Complications Clinical Presentation

  • Author: Milton J Klein, DO, MBA; Chief Editor: Consuelo T Lorenzo, MD  more...
Updated: Feb 12, 2016


Approximately 30-50% of patients who survive post–traumatic brain injury (post-TBI) demonstrate endocrine complications. Most post-TBI endocrinopathies do not have typical specific history patterns.

Diabetes insipidus

Diabetes insipidus (DI) is an exception, as it does have a specific history. DI most commonly is associated with severe TBI and basilar skull fractures with cranial nerve involvement, craniofacial trauma, and postcardiopulmonary arrest. Delayed onset of DI is associated with a poor prognosis due to hypothalamic involvement causing permanent DI.

Acute DI following a mild to moderate TBI indicates a posterior pituitary lesion with only a temporary antidiuretic hormone (ADH) deficiency.


Anterior hypopituitarism (AH) also has a specific history. AH usually is associated with moderate to severe TBI. With improvement of emergency and neurosurgical care for these patients, there are more survivors demonstrating AH. AH may present weeks to months after the TBI, typically in the acute or chronic rehabilitation phase. Any patient with unexplained malaise or a setback with regard to functional status should be examined and tested for AH or the other post-TBI endocrinopathies. In summary, risk factors for AH include relatively serious TBI (Glasgow Coma Scale score < 10), diffuse brain swelling, and hypotensive or hypoxic episode.

A literature review by the American Association of Clinical Endocrinologists and the American College of Endocrinology found that although TBI-induced hypopituitarism seems to occur most frequently in relation to severe TBI, hypopituitarism is also a risk for patients with mild TBI and for those who have suffered repeated TBIs or whose brain injury is sports or blast related.[21]

A study by Silva et al indicated that persons who sustain TBI in motor vehicle accidents, as well as those with posttraumatic seizures, focal cortical contusions, petechial brain hemorrhages, and/or intracranial hemorrhage, are more likely to suffer serious pituitary dysfunction, such as adrenal insufficiency and DI.[22]

Syndrome of inappropriate antidiuretic hormone

Syndrome of inappropriate antidiuretic hormone is the most common TBI-associated neuroendocrinopathy causing hyponatremia. The incidence is reportedly as high as 33%.[23]

Cerebral salt wasting

Cerebral salt wasting (CSW) is a less common cause of hyponatremia in the post-TBI population. These patients are dehydrated and lose weight.

Primary adrenal insufficiency

Primary adrenal insufficiency (PAI) is rare and presents with the superimposed psychiatric symptoms of depression, confusion, and apathy. PAI is associated with fatigue, weakness, anorexia, and weight loss. These problems may present insidiously over a prolonged period. The acute presentation of PAI includes nausea, vomiting, and hypertension.

Related Medscape Reference topics:

Adrenal Insufficiency

Adrenal Insufficiency and Adrenal Crisis

Cerebral Salt-Wasting Syndrome

Diabetes Insipidus [Endocrinology]

Diabetes Insipidus [Pediatrics: General Medicine]

Hypopituitarism [Emergency Medicine]

Hypopituitarism [Pediatrics: General Medicine]

Hypopituitarism (Panhypopituitarism)


Syndrome of Inappropriate Antidiuretic Hormone Secretion [Emergency Medicine]

Syndrome of Inappropriate Antidiuretic Hormone Secretion [Pediatrics: General Medicine]

Syndrome of Inappropriate Secretion of Antidiuretic Hormone [Nephrology]



See the list below:

  • Physical examination findings may be obscured by the altered cognitive status of patients who have had a traumatic brain injury (TBI).
  • Common post-TBI findings, such as lethargy, fatigue, and slowed mental processing time, also are associated with endocrine complications.
  • In extreme cases, hyponatremia can cause seizures, confusion, and coma.
  • Primary adrenal insufficiency (PAI) may present with acute psychiatric problems, such as psychosis, depression, apathy, or a schizophrenialike syndrome.
  • General physical examination findings may include myxedematous, addisonian-appearing, or slowed mentation.
  • Vital signs include the following:
    • Slowed pulse
    • Hypothermia
    • Orthostatic hypotension
  • Dermatologic findings include the following:
    • Pale, soft, waxy skin
    • Hyperpigmentation
    • Decreased axillary and pubic hair
    • Areolar depigmentation
    • Decreased male facial hair
    • Decreased sweating and sebum secretion
  • Neurologic findings include the following:
    • Mental status changes (eg, lethargy, confusion, slowed mentation)
    • Muscle weakness (may be proximal due to endocrine myopathy)
    • Hyporeflexia or areflexia
    • Hypotonia


The most common post–traumatic brain injury (post-TBI) endocrine complications are as follows:

  • Syndrome of inappropriate antidiuretic hormone (SIADH) [23]
    • SIADH is the most common neuroendocrine complication following TBI, with a reported incidence of as high as 33%. In the TBI rehabilitation setting, SIADH is the most common cause of hyponatremia.
    • Hyponatremia often is seen in the rehabilitation setting among survivors of either traumatic or nontraumatic brain injury (eg, hemorrhagic stroke, brain tumors, CNS infections). This problem is associated most often with SIADH. Approximately 30% of patients who undergo neurosurgery demonstrate SIADH. SIADH also can be induced by medications such as carbamazepine, major tranquilizers, and antidepressants.[24]
    • Hyponatremia can cause several problems, including cerebral ischemia (by volume depletion), lassitude, seizures, confusion, and coma.
    • SIADH causes renal water conservation, with a secondary hyponatremia because of dilution. In patients who are not dehydrated or using diuretics, the laboratory diagnosis is based upon a urine osmolality greater than serum osmolality. The serum osmolality in patients with SIADH is less than 280 osm/kg, serum sodium is less than 135 mEq/L, and urine sodium is greater than 25 mEq/L.
    • The treatment in most cases is fluid restriction and, in unusual situations, IV hypertonic saline.
  • Cerebral salt wasting (CSW) [16, 25]
    • Although most cases of hyponatremia due to brain injury are caused by SIADH, a less common etiology is CSW syndrome. Peters and colleagues first described CSW in 1950.[15] CSW is caused by impaired renal tube function that results in the inability of the kidneys to conserve salt. The etiology may be attributable to direct neural influence on renal tube function. Salt wasting with volume depletion is the hallmark of this syndrome. Clinically, patients manifesting CSW are dehydrated, lose weight, have orthostatic hypotension, and demonstrate a negative fluid balance. In cases of CSW and SIADH, the laboratory values often are the same for serum/urine osmolalities and electrolytes; however, elevated serum blood urea nitrogen (BUN), serum potassium, and serum protein concentration also are supportive of the diagnosis of CSW. Additionally, serum uric acid is normal in patients with CSW and is low in persons with SIADH.
    • Treatment of this type of hyponatremia with associated dehydration consists of replacement of fluids and salt, which is best managed by IV normal saline or, in rare cases, by IV hypertonic saline. Rehydration significantly reduces the risk of cerebral ischemia or cerebrovascular accident.
  • Diabetes insipidus (DI) [4, 5, 6, 7, 8, 9, 26]
    • DI is rare, with an estimated 1 case per 100,000 hospital admissions. Posttraumatic DI occurs in 2-16% of all cases. The most common etiologies of posttraumatic DI include severe closed head injury, frequently with basilar skull fractures; craniofacial trauma; thoracic injury; postcardiopulmonary arrest; and intraventricular hemorrhage in neonatal patients. DI frequently is associated with cranial nerve injuries. The usual onset is 5-10 days following trauma.
    • Characteristic features of DI include polyuria, low urine osmolality, high serum osmolality, normal serum glucose, and normal to elevated serum sodium. Urine output usually is greater than 90 mL/kg/d, with a specific gravity of less than 1.010 and an osmolality of 50-200 mOsm.
  • Anterior hypopituitarism (AH) [10, 11, 12, 13, 14]
    • AH, or panhypopituitarism, is not as rare a complication after a closed head injury; it usually follows moderate to severe craniocerebral trauma. With improvements in emergency and acute neurosurgical care for patients with head injuries, a greater number of severely involved patients are surviving than had previously done so. This subset of patients is most susceptible to the development of AH. The mechanism through which AH develops in patients with severe head injuries is an interruption of the major blood supply to the anterior lobe of the pituitary gland because of trauma to the unprotected stalk connecting the anterior pituitary to the median eminence of the hypothalamus.
    • Additionally, the hypothalamus secretes releasing and inhibitory hormones into the portal or stalk circulation, for controlling the release of the anterior pituitary hormones. Although the pituitary gland is well protected by the bony sella turcica, the pituitary stalk is not covered by dura mater and lies in the subarachnoid space. Severe craniocerebral injury may traumatize the stalk directly, or an anterior lobe infarction can occur due to impaired portal system circulation secondary to shock and cerebral edema.
    • The arterial blood supply of the posterior lobe of the pituitary comes directly from the inferior hypophyseal arteries branching from the internal carotid arteries. The posterior pituitary hormones are secreted by the hypothalamus.
    • Autopsy studies of 100 patients who died from craniocerebral trauma demonstrated pituitary lesions in approximately 60% of the group studied. Of those subjects with pituitary lesions, 59 demonstrated capsular hemorrhage, 42 demonstrated posterior lobe hemorrhages, and 22 revealed anterior lobe ischemic necrosis. Most patients (20 of 22) with anterior lobe ischemic necrosis died within the first 7 days following injury because of the severity of the craniocerebral trauma associated with shock and severe cerebral edema. Clinical AH is so rare in association with closed head injuries because most of these patients do not survive secondary to the severity of their injuries. This clinical syndrome presents itself only when two thirds of the anterior pituitary has been destroyed.
    • The syndrome of AH may manifest an insidious onset weeks to months after the original closed head injury. The patient may become progressively lethargic or anorexic and may demonstrate hypothermia, bradycardia, or hypotension with hyponatremia. These symptoms result in a significant setback if they occur during the acute phase of rehabilitation of a patient who has sustained a closed head injury. Any unexplained onset of malaise and generally decreased vital signs with associated stagnation of the rehabilitation progress in a patient following closed head injury should prompt the clinician to suspect the presence of AH.
    • AH following TBI can be obscured by the cognitive impairment of the patient and can contribute to delayed progress in rehabilitation.
    • The endocrine workup for AH includes serum hormonal assays, such as cortisol (0900), testosterone, triiodothyronine (T3), thyroxine (T4), thyrotropin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (females). Insulinlike growth factor-I (IGF-I) is a screening assay for growth hormone (GH) deficiency. Advanced provocative GH testing may be necessary to confirm this diagnosis. Also perform a complete blood cell (CBC) count and serum electrolyte evaluation.
    • Treatment involves multiple hormonal replacement therapy, as well as monitoring of the patient's serum levels and clinical response. The patient usually responds with improved vital signs, improved constitutional symptoms, and increased endurance for participation and progress in the rehabilitation program. The hormonal replacement therapy usually is required long-term.
  • Primary adrenal insufficiency (PAI) [17]
    • PAI usually presents with the psychiatric symptoms of depression, confusion, and apathy.
    • Additional features include self-mutilation, paranoia, psychosis, and schizophrenic behaviors.
    • The mechanism of the psychiatric presentation is related to factors such as hypoglycemia, elevated exogenous endorphins, and axonal conduction changes.
    • Progressive deficiency of glucocorticoid and mineralocorticoid hormonal activity leads to hypotension, fatigue, anorexia/nausea, hyperpigmentation, and progressive, generalized weakness. Diagnosis of PAI is difficult in patients with TBI, because these particular symptoms may be ascribed to the TBI itself.
    • The most common cause of PAI is autoimmune or idiopathic adrenalitis (in 65-84% of cases). The next most common etiology is adrenal parenchymal destruction secondary to tuberculosis, sarcoidosis, malignancy, acute sepsis (including systemic fungal infections), and acquired immunodeficiency syndrome (AIDS).
    • Acute adrenal crisis may result from bilateral adrenal hemorrhage from trauma, sepsis, surgery, or acute burns. If this problem is unrecognized, acute adrenal crisis may lead to acute shock and death. Adrenal failure usually is permanent in patients who survive the acute phase of the adrenal crisis.
    • Several rare hereditary syndromes are associated with PAI, such as familial glucocorticoid insufficiency, adrenoleukodystrophy, and adrenomyeloneuropathy. PAI results from a deficiency of glucocorticoid and mineralocorticoid hormonal activity, combined with a reduction of feedback to the anterior pituitary gland. The cortisol deficiency results in excessive secretion of corticotropin from the anterior pituitary gland and excessive secretion of corticotropin-releasing hormone from the hypothalamus.
    • The presentation of PAI may be acute, characterized by nausea, vomiting, and hypertension. Alternatively, this clinical entity may present insidiously, with slow development of nonspecific symptoms over a prolonged period. The most common features include fatigue, weakness, anorexia, and weight loss. Additional findings include hyponatremia, hyperkalemia, skin hyperpigmentation, and gastric motility impairment that leads to complete gastric stasis.
    • Physiatrists must be aware of PAI, even though it is rare, because the presentation of adrenal insufficiency can be similar to the presentation of TBI. The symptoms limiting rehabilitation of patients following TBI can be attributed to the brain injury itself or to deconditioning secondary to prolonged bedrest. Treatment of this underlying problem by mineralocorticoid and glucocorticoid replacement therapy can result in a significant improvement of rehabilitation progress and outcome.
  • Other post-TBI endocrine complications
    • Early puberty is defined as secondary sexual development in females younger than 8 years and in males younger than 9 years. Precocious puberty can occur in children with head injuries because of an inappropriate secretion of gonadotropin-releasing hormone (GRH), resulting in the subsequent release from the anterior pituitary of LH and FSH. These hormones cause the early onset of puberty by increasing levels of gonadal steroids and gametogenesis.
    • Hypogonadism also can occur following head trauma. In one study, approximately one third of female patients who had head injuries (ie, 26 of 78) experienced temporary amenorrhea, usually for no longer than 3 months. This phenomenon is secondary to hypothalamic dysfunction, resulting in absent or decreased secretion of GRH.
    • In male patients, gonadotropin and testosterone levels are low immediately following head injury. Later, in response to exogenous GRH, the anterior pituitary responds with the release of high levels of LH and FSH, which is typical of hypothalamic dysfunction. At 3-6 months after the head injury, 5 of 21 male patients demonstrated persistently low serum testosterone levels. Depending on the clinical situation, consider appropriate testosterone replacement therapy.
  • Summary
    • Approximately 30-50% of patients with moderate-to-severe head injury demonstrate endocrine complications. These problems may not present in a classic textbook fashion in persons who are severely impaired following TBI. The only clue to determining endocrine complications may be an unexplained failure to progress or a setback in the TBI rehabilitation program.
    • The most common endocrine abnormality is SIADH, followed by DI.
    • SIADH is the most common cause of hyponatremia; however, other causes include fluid overload or extracellular fluid depletion from GI or renal loss of sodium.
    • Criteria for diagnosis of SIADH include low serum osmolality, hyponatremia, and inappropriately concentrated urine (with urine sodium >25 mEq/L).
    • Hyponatremia that remains unresponsive to standard treatment for SIADH should point the clinician to other causes of hyponatremia.
    • Another clue to recognizing adrenal insufficiency is hyperkalemia associated with the hyponatremia secondary to a loss of mineralocorticoid activity at the kidney, causing urine sodium loss, impaired excretion of potassium, and hydrogen ion retention.
    • Azotemia also may be associated with adrenal insufficiency.
Contributor Information and Disclosures

Milton J Klein, DO, MBA Consulting Physiatrist, Heritage Valley Health System-Sewickley Hospital and Ohio Valley General Hospital

Milton J Klein, DO, MBA is a member of the following medical societies: American Academy of Disability Evaluating Physicians, American Academy of Medical Acupuncture, American Academy of Osteopathy, American Academy of Physical Medicine and Rehabilitation, American Medical Association, American Osteopathic Association, American Osteopathic College of Physical Medicine and Rehabilitation, American Pain Society, Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Kat Kolaski, MD Assistant Professor, Departments of Orthopedic Surgery and Pediatrics, Wake Forest University School of Medicine

Kat Kolaski, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

Chief Editor

Consuelo T Lorenzo, MD Medical Director, Senior Products, Central North Region, Humana, Inc

Consuelo T Lorenzo, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

Additional Contributors

Patrick J Potter, MD, FRCSC Associate Professor, Department of Physical Medicine and Rehabilitation, University of Western Ontario School of Medicine; Consulting Staff, Department of Physical Medicine and Rehabilitation, St Joseph's Health Care Centre

Patrick J Potter, MD, FRCSC is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, College of Physicians and Surgeons of Ontario, Canadian Association of Physical Medicine and Rehabilitation, Canadian Medical Association, Ontario Medical Association, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

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Effects of hyponatremia on the brain and adaptive responses. Within minutes after the development of hypotonicity, water gain causes swelling of the brain and a decrease in osmolality of the brain. Partial restoration of brain volume occurs within a few hours as a result of cellular loss of electrolytes (rapid adaptation). The normalization of brain volume is completed within several days through loss of organic osmolytes from brain cells (slow adaptation). Low osmolality in the brain persists despite the normalization of brain volume. Proper correction of hypotonicity reestablishes normal osmolality without risking damage to the brain. Overly aggressive correction of hyponatremia can lead to irreversible brain damage.
Formula*   Clinical Use
Change in serum Na+ = Infusate Na+ — serum Na+


total body water +1

Estimate the effect of 1 L on any infusate serum Na+
Change in serum Na+ = (Infusate Na+ + infusate K+)—serum Na+


total body water +1

Estimate the effect of 1 L of any infusate containing Na+ and K+ on serum Na+
Infusate Infusate Na+ Extracellular—Fluid


  mmol/L %
5% sodium chloride in water 855 100†
3% sodium chloride in water 515 100†
0.9% sodium chloride in water 154 100
Ringer lactate solution 130 97
0.45% sodium chloride in water 77 73
0.2% sodium chloride in 5% dextrose in water 34 55
5% dextrose in water 0 40
*The number in formula 1 is a simplification of the expression (infusate Na+ —serum Na+) X 1 liter, with the value yielded by the equation in mmol/L. The estimated total body water (in liters) is calculated as a fraction of body weight. The fraction is 0.6 in children; 0.6 and 0.5 in nonelderly men and women, respectively; and 0.5 and 0.45 in elderly men and women, respectively.†In addition to its complete distribution in the extracellular compartment, this infusate induces osmotic removal of water from the intracellular compartment.
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