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Injuries to the central nervous system (CNS), both within the brain and the spinal cord, trigger a cascade of events which alter the normal homeostatic function of the neuroendocrine system. These systems regulate cellular nutrition, energy consumption, oxygenation, and waste removal, which in turn control tissue growth and repair. Subsequently, these changes impact normal organ system functions that lead to various hematological, metabolic, and endocrine complications. Some complications such as VTE and osteoporosis after CNS injury are also covered elsewhere separately as a specific topic.


Hematological, metabolic, and endocrine complications can result from traumatic brain injury (TBI) and spinal cord injury (SCI), as well as non-traumatic disorders involving the brain or spinal cord such as stroke and CNS cancer.

Endocrine complications after traumatic brain injury (TBI) include post-traumatic hypopituitarism (PTHP), which refers to dysfunction of the hypothalamic-pituitary axis after traumatic brain injury (TBI).

Epidemiology including risk factors and primary prevention

The prevalence of endocrine dysfunction after TBI in clinical studies varies greatly. In one systematic review, the prevalence of hypopituitarism was 35.3% after severe TBI, 10.9% after moderate TBI and 16.8% after mild TBI.1 Risk factors for posttraumatic hypopituitarism include severe TBI, diffuse axonal injury, and basal skull fracture2. With aneurysmal subarachnoid hemorrhage (SAH), clinical severity does not correlate with neuroendocrine dysfunction.1

Individuals with SCI are at risk for several endocrine bony disorders in the weeks to months after injury. Male children, adolescents, and young adults are at highest risk for immobilization hypercalcemia, which affects approximately 10-25% of patients with SCI.3,4 Similarly, patients with acute SCI are at risk of losing bone density, thought to be a result of interrupted neuronal sympathetic afferent innervation, which causes impaired bony nutrients and gas exchange, and thus triggers osteoclast activity and bone resorption.5 About 20% of patients with SCI develop clinically significant heterotopic ossification (HO), or inappropriate bone formation, with about 3-5% developing HO-related ankylosis. HO is more common in those with more complete injury, severe spasticity, and infectious complications. It is thought that the neurologic trauma results in increased activity of osteoblasts via increased expression of bone morphogenic proteins, which then promote calcium deposition and mineralization of the bone matrix.6 More chronically, individuals with SCI may develop osteoporosis, and are at high risk of fractures, with an incidence of fracture at least twice that of the general population. Up to 50% of individuals with SCI will experience a fracture, most commonly at the distal femur or proximal tibia, with high rates of complication, including amputation, fracture nonunion, pressure injury, and impaired function.7,8 Additionally, individuals with chronic SCI have a similar or higher risk of cardiometabolic disease as compared to the general population, with sources reporting a prevalence between 25-75%. This is likely related to an obligate sedentary lifestyle, central adiposity, reduced muscle mass, and elevated inflammatory biomarkers.9


The spectrum of acute and potentially life-threatening changes after brain injury varies widely, relating to the severity of injury. Acutely, anemia can occur through blood loss from concurrent vascular trauma or surgery, and sub acutely as a result of GI bleeding.10 This is likely secondary to increased vagal tone, resulting in increased gastric secretions and diminished oral intake. Most remaining metabolic, endocrine, and hematologic complications evolve over weeks and months post-injury.

The pituitary gland is especially susceptible to injury due to its location within the sella turcica. Damage to the pituitary or the hypothalamus results in impaired production and secretion of hormones from these glands.11 Neuroendocrine dysfunction can occur due to primary and/or secondary injury to the hypothalamus and pituitary gland, leading to posttraumatic hypopituitarism. Mechanisms of injury include direct trauma, shearing injuries, hypoxia, autoimmunity, compression from hemorrhage or edema.12 Those who suffer head trauma, local vascular compromise, and radiation therapy can experience this.

The complications that arise from SCI are associated with reduced or absent weight bearing, loss of sympathetic control, and lack of muscular activity. These factors contribute to a disruption in circulation and transport of blood constituents, nutrients, hormones and cellular metabolites that may normally act as stimulators or feedback inhibitors of glandular and organ function.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Hormone imbalances:

In the acute setting, patients with TBI may have adrenal insufficiency that can be life threatening. Patients should be evaluated for adrenal insufficiency if hyponatremia, hypoglycemia, and hypotension are present.

Signs of hypopituitarism in the chronic phase are often non-specific. Posttraumatic pituitary dysfunction can be transient, often resolving by 3 months after injury, but in some cases, it can worsen over weeks to months after injury.13

Commonly encountered electrolyte disorders in patients with TBI or SCI include:

  • Hypercalcemia: Immobilization after SCI results in increased osteoclastic activity, causing bone resorption and transient hypercalciuria for up to 18 months after injury. If the rate of resorption is extremely high (common in adolescents or young adults) or there is co-existing renal impairment, hypercalcemia results.3
  • Serum sodium (Na+) abnormalities can be seen in both TBI and SCI14:
    • SIADH: abnormally high level of ADH leads to retention of water which causes hyponatremia (euvolemic)14–16
    • Cerebral salt wasting: sodium and extracellular fluid loss leading to hyponatremia, increased urine sodium excretion and urine volume (hypovolemic) (PMID 29078838)
    • Medications may lead to hyponatremia. Commonly used medications after brain injury and SCI that may be associated with hyponatremia include antidepressants, antipsychotics and antiepileptics, which may be used to treat sleep or pain in addition to the psychological or behavioral effects of injury14,17
    • ACTH deficiency results in decreased secretion of corticosteroids from the adrenal glands and decreased sodium retention by the kidneys. Paralysis also causes an overall reduction in blood pressure, which in turn increases secretion of ADH, resulting in hyponatremia.
    • More severe high cervical SCI can impair supraspinal sympathetic control of renal function, contributing to hyponatremia14
    • Diabetes insipidus (DI) occurs due to ADH deficiency and can result in hypernatremia.
    • Both low and high sodium levels have been associated with higher mortality and poorer outcome
    Cerebral Salt WastingSIADH
    Blood volumeDecreasedNormal/expanded*
    Urine sodium concentrationElevatedElevated
    Plasma osmolalityReducedReduced
    Urine volumePolyuriaOliguria or normal (can be variable)
    TreatmentSodium and fluid resuscitation; controversial Contraindicated: vaptansFluid restriction; can also add oral salt repletion.  If severe, ADH inhibitors; vaptans (vasopressin receptor antagonist)
    *Volume status can be difficult to assess as it maybe extracellular.

    Other disorders commonly encountered after TBI:

    • Immobilization after both TBI and SCI can lead to thromboembolic disease. VTE is discussed in a separate section.
    • Metabolic syndrome has been associated with SCI and also in patients with growth hormone deficiency after TBI, SAH, and CNS cancer survivors.9,13,18
    • TBI and SCI are also associated with heterotopic ossification. This is discussed in a separate section.

    Specific secondary or associated conditions and complications

    • Individuals with SCI or brain injury may be at risk of certain chronic conditions: Impaired glucose tolerance, insulin resistance, and type 2 Diabetes Mellitus, which results from an obligate sedentary lifestyle in SCI9 and may be related to growth hormone deficiency in TBI13
    • Osteoporosis, resulting in increased incidence of lower extremity and spinal fractures below the neurologic level of injury in SCI.8 In brain injury, those with growth hormone deficiency are at risk for fractures and skeletal fragility13
    • Hyperlipidemia. (PMID 30459501)
    • Cardiovascular disease (due to adrenergic dysfunction, poor diet, and physical inactivity). Individuals with SCI are at risk of dyslipidemia, including low HDL-c, high triglycerides, and high C-reactive protein.9
    • Venous thrombo-embolism (risk diminishes with time, and generally not significantly higher than in general population 1 year post-injury).
    • Testosterone deficiency
    • Hypogonadism

    Essentials of Assessment


    Proper history taking is essential in the diagnosis and management of potential complications. An inventory of new and chronic complaints helps to elucidate evolving complications. Key information to elicit from patients is:

    • Pre- and post-injury medical and surgical history
    • Medication history and current medications
    • New onset shortness of breath
    • New onset neurological symptoms, including dizziness, headaches, pain, or weakness.
    • New onset of cardiovascular signs or symptoms, including change in blood pressure, heart rate, palpitations, shortness of breath, or swelling
    • New onset of extremity swelling, warmth or erythema
    • Worsening fatigue
    • Hair loss
    • Change in menstrual cycle (oligomenorrhea or amenorrhea)
    • Impaired sexual function including erectile dysfunction
    • Recent weight changes: weight gain or weight loss
    • Decreased muscle mass
    • Change in stool color or blood in stools
    • Polyuria, polydipsia
    • Mood changes such as depression or apathy
    • History of fragility fractures or new fracture
    • Poor recovery
    • Decrease in cognitive performance
    • Increased abdominal fat

    Physical examination

    In addition to other aspects of the general physical and neurological examination pertinent to the underlying CNS condition, it is important to assess and document findings related to specific metabolic and endocrine complications such as weight and Body Mass Index (BMI) calculation, presence of gynecomastia, testicular atrophy, or decreased pubic and axillary hair.

    Laboratory studies

    Patients with moderate to severe TBI and signs or symptoms associated with hypopituitarism should undergo screening.19


    • The need to order imaging studies should always be made on a case-by-case basis. CT and MRI are used to detect extent of head injury including injury to the hypothalamus and the pituitary gland. CT scans can be helpful in identifying certain skull fractures that are more likely to be associated with injury to the hypothalamus-pituitary axis. Hypoxia and shearing injuries can also lead to a disruption that does not show on imaging.
    • For osteoporosis, dual-energy x-ray absorptiometry (DXA) scan is currently the best available clinical tool for the diagnosis of osteoporosis. Furthermore, monitoring of bone mineral density (BMD) over time has shown to be helpful in management of disease. Recommendations for SCI include DXA scan of total hip, femoral neck, distal femur, and proximal tibia once patients are medically stable post-injury and repeated every 1-2 years.21
    • Plain x-rays for suspected fractures.
    • Venous doppler for suspected blood clot.

    Early predictions of outcomes

    The severity of TBI seems to be related to the likelihood of developing post-traumatic hypopituitarism. Patients with hypopituitarism showed impaired quality of life and adverse metabolic profile.13 Amenorrhea in women maybe associated with poorer outcome.22 Also, GH deficiency is correlated with lower quality of life and increased rates of depression.23


    • Optimization of the home setting to reduce risk of falls or injury.
    • Adaptive devices to facilitate access to and compliance with medications.
    • Adequate heating and air conditioning to minimize metabolic demand.
    • Provision of facilities for aerobic exercise can help improve cardiovascular health.24

    Social role and social support system

    Education should be provided directly to patients and also to caregivers in order to recognize complications associated with TBI and SCI. Caregiver involvement is vital as they can monitor for changes and reinforce health maintenance strategies. For instance, diabetic teaching provided to the family and the patient has been shown to improve compliance.25

    Professional Issues

    Management of hematological, endocrine and metabolic complications after TBI and SCI often requires a multi-disciplinary team. In TBI or dual-diagnosis patients with cognitive and communication deficits, it can be challenging to gather information regarding symptoms. Additionally, individuals with SCI may lack typical signs and symptoms due to sensory impairment. Regular and accurate documentation of symptoms and physical findings is crucial in caring for patients with neurologic injury.

    Rehabilitation Management and Treatments

    Available or current treatment guidelines

    Treatment for the various conditions listed are as follows:

    • Osteoporosis: Daily vitamin D (cholecalciferol 1,000-2,000 IU daily) and calcium (1,000-1,200mg daily) supplementation is recommended for individuals with SCI to protect against bone loss. Specific dosing may vary if patients have hypovitaminosis D or hypercalcemia. Weight bearing with a standing frame or electrical stimulation may help prevent bone loss, but the frequency and duration needed is often impractical for patients. Oral bisphosphonate antiresorptive therapy (alendronate, zoledronic acid, denosumab) can be used to prevent secondary bone mineral loss if aligned with the patient’s goals.26
    • Renal Calculi due to Hypercalcemia: IV fluids (Acute management), dietary modifications tailored to each individual patient depending on most likely cause of stone formation (uric acid stones, struvite stones, etc.).
    • Diabetes Mellitus: Strict glucose monitoring. Oral agents (Metformin, Glipizide, etc.), Insulin therapy (particularly for patients with long-standing disease, poor response to oral medications or noncompliance). Diet and lifestyle modification27,28 When oral agents are used for SCI population, potential side effects of GI complications and volume depletion should be monitored closely.29
    • Anemia: Iron supplementation (if iron deficiency anemia) or treat underlying condition; B12 supplementation in Vitamin B12 deficiency.30
    • Adrenal insufficiency: if aldosterone deficit is present, then treat with fludrocortisone, hydrocortisone, dexamethasone, or prednisone
    • Hyperlipidemia: Diet and lifestyle modification. Statin therapy
    • Diabetes Insipidus (DI): Desmopressin in Central DI.
    • SIADH (Acute): Fluid restriction to 800 ml/day. Hydration with IV normal saline. Salt tablets in occasional cases.16
    • Testosterone replacement therapy has shown to increase lean tissue mass and energy expenditure in hypogonadal men.29
    • Hypothyroidism: levothyroxine

    At different disease stages


    Coordination of care

    Lifelong care for patients with SCI and TBI after the acute management and initial rehabilitation requires collaboration between physiatrists, medical and surgical specialists and therapists. This care is most effectively coordinated by a physiatrist and a primary care physician who can help facilitate access to other sub-specialists as is appropriate for patient goals.

    Patient & family education

    Patient and family education should be geared with a goal-oriented approach to ensure that patients can deal with complications in the most effective manner. Common areas of focus include:

    • Diabetic education
    • Anticoagulation administration
    • Clot prevention and management
    • Insulin administration and glucose monitoring
    • Diet and lifestyle modifications
    • Monitoring wound and skin

    Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

    Practice pearls include:

    • Assess for worsening fatigue and diminished functional endurance on a routine basis to evaluate for underlying anemia and neuroendocrine dysfunction, especially if there is poor recovery.
    • Regularly monitor patient’s diet, lifestyle, and weight for possible glucose intolerance.
    • Regular specific inquiry about patient mood, libido, menses and general perception of energy level may alert the clinician to evolving hormonal abnormality.

    Cutting Edge/ Emerging and Unique Concepts and Practice

    Along with electrolyte and hormonal changes monitoring, there also has been evaluation of biomarkers that may contribute to these abnormalities.  Combining biomarkers, in addition to other clinical data, may help to create a better prognostic model.

    Gaps in the Evidence-Based Knowledge

    Although it appears clear that the rate of overall bone loss and subsequent evolution of osteoporosis in patients with SCI diminishes with time, this process does not appear to reach a steady state and efforts to prevent or even reverse bone density loss have been pursued for many years. The role for empiric use of bisphosphonates and duration of treatment remains controversial.  The overall benefit and optimal utilization of weight-bearing activities, and muscular action through functional electrical stimulations remains controversial. Studies of medication management in dyslipidemia in SCI are lacking.


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    Original Version of the Topic

    Stephen R. Lebduska, MD, Bhargav Mudda, MD. Hematological, metabolic and endocrine complications. 9/20/2014.

    Previous Revision(s) of the Topic

    Cherry Junn, MD. Hematological, metabolic and endocrine complications. 12/12/2019.

    Author Disclosure

    Cherry Junn, MD
    Nothing to Disclose

    Lesley Abraham, MD
    Nothing to Disclose

    Kate Delaney, MD
    Nothing to Disclose