History and Epidemiology

Neuroendocrine disorders, primarily hypopituitarism, were first diagnosed by the German researcher Cyran in 1918 (Benvenga 2005; Lieberman et al. 2001; Makulski et al. 2008). Until recently, damage to the hypothalamus and pituitary gland following trauma was often not diagnosed until the post-mortem examination (Yuan 1991). Research indicates neuroendocrine disorders vary post traumatic brain injury (TBI) (Sandel et al. 2007), and what was once thought to be a rare occurrence is now increasingly diagnosed (Benvenga 2005; Bondanelli et al. 2005; Ghigo et al. 2005). In the early 1950s, the incidence of hypopituitarism post injury was thought to be 1%; however, more recent rates have been quoted at between 20% and 70% (Makulski et al. 2008; Sirois 2009). In a review of the literature, Schneider et al. (2007) found that the pooled prevalence of hypopituitarism was 27% post TBI and 47% post stroke. The pituitary gland is most often affected with dysfunction occurring at the hypothalamic stalk or pituitary level. 

Blood and urine analysis are the most common means used to diagnose neuroendocrine disorders. Disorders can be seen in the early days post injury, while the patient is still in the acute stage of recovery, or in the later sub-acute stage. Overall, neuroendocrine abnormalities, hypopituitarism and growth hormone deficiencies are common among those with TBI, especially those who have sustained moderate to severe injuries (Popovic et al. 2005). The figure below shows the pituitary gland under normal conditions (a,b) and how it can be altered following a traumatic injury (c). 

Figure: Pituitary Gland: Normal Condition and Post-Traumatic Condition


Signs and Symptoms

Neuroendocrine dysfunction may be observed as fatigue, temperature lability, disturbances in appetite, weight fluctuations, hypothalamic and pituitary disorders, disorders of fluid regulation, hypertension or hypotension, increased anxiety and depression, cognitive deficiencies, reduced bone and muscle mass, and immunologic disorders (Sesmilo et al. 2007; Sirois 2009). The table below lists the clinical presentation of hypopituitarism. 

Table: Clinical Presentation of Hypopituitarism

  • Fatigue
  • Sleep Disturbance
  • Decreased muscle mass, increased fat mass
  • Reduced exercise tolerance and muscle strength
  • Amenorrhea, decreased libido, erectile dysfunction
  • Decreased cognitive function, concentration, memory
  • Mood disturbances, depression, irritability
  • Social isolation, decreased quality of life


Neuroendocrine disorders post TBI result from specific injuries to the areas that regulate physiological functions in various regions of the brain, specifically injuries along the hypothalamic-pituitary axis (Sandel et al. 2007). Symptoms will vary depending on the area of the brain that has been affected by the injury. Current research suggests that anyone who suffers a brain injury (due to a stroke or TBI) and has a Glasgow Coma Scale (GCS) score between 3 and 12 should be tested for hormonal disorders or deficiencies (Behan et al. 2008). However, some discretion needs to take place in those patients with the most severe disability (i.e., vegetative state) (Sesmilo et al. 2007). Individuals at greatest risk for post-traumatic hypopituitarism (PTHP) are those who have sustained a diffuse axonal injury, a basal skull fracture, or who were older at the time of injury. Length of stay in the intensive care unit, longer hospitalization, and a prolonged loss of consciousness may also play a role in the development of hypopituitarism (Klose et al. 2007).

In the acute phase, very early hormonal alterations may reflect adaptive responses to injury and critical illness, and are not necessarily associated with long-term PTHP. Various studies have shown that the majority of patients with low-grade or isolated deficiencies recover during the first 6 months post injury and tend to have a much better prognosis than those who do not recover (Aimaretti et al. 2004; Bondanelli et al. 2004; Ghigo et al. 2005). In one study, 5.5% of patients who showed no signs of PTHP deficiencies at 3 months did so at 12 months. The same study showed that 13.3% of patients who demonstrated isolated deficiencies at 3 months developed multiple deficiencies at 12 months (Ghigo et al. 2005). Growth hormone deficiency has been shown to be the most common deficit (Bondanelli et al. 2004; Ghigo et al. 2005).

Due to the nature of its features and the delay of its presentation, hypopituitarism may be missed following a stroke or an acquired brain injury (ABI) (Schneider et al. 2007); thus, the diagnosis of hypopituitarism following an ABI remains a challenge. Some of the key indicators, such as low serum-like growth factor, may already be low in older patients due to normal aging. Studies examining this issue indicate that TBI severity, as measured by the GCS or EEGs, is not an accurate indicator of the likelihood of developing hypopituitarism. However, there is a non-significant trend to show an association with TBI severity (Sirois 2009).

Association with Severity

There is no significant association between the development of PTHP and TBI severity, the type of accident, or the type of injury. While it has been shown by some researchers that PTHP patients had significantly lower GCS than unaffected survivors (Klose et al. 2007; Sirois 2009), it has not been a consistent finding (Bondanelli et al. 2007; Ghigo et al. 2005). The incidence of skull fractures and neurosurgical procedures has been reported to be similar in patients with hypopituitarism when compared to those with normal pituitary function (Bondanelli et al. 2007).

Benvenga et al. (2000) have noted that PTHP is primarily a disorder seen much more often with male survivors between the ages of 11 and 39. This is likely related to the fact that young males tend to sustain head injuries most often. Currently there is no evidence that specific types of head injuries are more likely to lead to hypopituitarism (Ghigo et al. 2005). Due to the life threatening consequences associated with pituitary dysfunction, it represents a negative prognostic factor (Benvenga et al. 2000).