Neuroendocrine Laboratory Testing

Diagnosis 

Diagnosis of neuroendocrine dysfunction is based on clinical evaluation, laboratory testing, and neuroimaging. According to Sesmilo et al. (2007) baseline hormonal testing should be performed in all patients, as described in the table below. However, there is some dispute in the literature as to how soon after injury testing should be considered, how often it should be conducted, and who should be tested. As indicated previously, clinical assessment of hypopituitarism is difficult since the signs and symptoms are often nonspecific and mimic the neuropsychological sequelae of TBI. Thus it is reasonable to consider performing baseline hormonal evaluation in patients with more severe injuries. Early after injury, the most important anterior hormones to screen may be TSH, GH and ACTH axes, as these will more quickly lead to symptoms that can affect recovery; although baseline testing of all hormones allow for an easier follow-up.

Table: Hormonal Testing Post ABI (Sesmilo et al. 2007)

Pituitary-Gonadal Axis 

Males: LH, FSH and testosterone
Females: For those who have irregular menstrual cycles, LH, FSH, and estradiol

Pituitary-Adrenal Axis  Cut-off values are different in the acute phase than in the rehabilitation phase. Evaluations are best performed with early morning plasma cortisol measurements or 24-hour urinary free cortisol measurements. 
Pituitary-Thyroid Axis  It has been suggested that baseline testing should include thyroid function tests (TSH, fT4, fT3) and repetition of testing where appropriate. 

Screening for Hypopituitarism Post ABI

Hypopituitarism is a common and treatable condition resulting from an ABI. Guidelines for screening patients who have sustained an ABI or a stroke include: severity of injury, location of injury (basal skull fractures, diffuse axonal injury, or increased intracranial pressure), GCS (especially scores between 3 and 12), length of time spent in the intensive care unit (ICU), and length of time post injury (Schneider et al. 2007).

Given that hypopituitarism can evolve over time following injury, it is important to begin screening as soon as possible. In the acute stage, screening for adrenal insufficiency is particularly important due to its life threatening potential (Bernard et al. 2006). During this stage of recovery, cortisol levels of less than 7.2 µg/dL may indicate adrenal insufficiency. Treatment should also be considered and initiated in cases where hyponatremia, hypotension, and hypoglycaemia are present, even if cortisol levels are between 7.2 and 18 µg/dL (Schneider, Aimaretti, et al. 2007). For those who have extended stays in the ICU and increased intracranial pressure, diffuse axonal injury, or basal skull fractures assessing pituitary function may be necessary and should be considered. While in the acute stage of recovery it is not necessary to assess growth, gonadal or thyroid hormones as there is no evidence to suggest supplementation of these hormones during this phase is beneficial (Ghigo et al. 2005; Schneider et al. 2007); however, during the post recovery stage, at 3 and 6 months, a clinical assessment for hypopituitarism should be completed (Powner & Boccalandro 2008; Powner et al. 2006; Schneider et al. 2007). This is especially important if any of the following symptoms are noted: loss of secondary hair, impaired sexual function, weight changes, polydipsia, or amenorrhea.

Hormonal screening should include morning serum cortisol, fT3, fT4, TSH, FSH, LH, PRL, Insulin-like Growth Factor (IGF-1), testosterone in men and estradiol in women. In patients with polyuria or suspected DI, sodium and plasma osmolality and urine density should also be evaluated. Low IGF-1 levels strongly predict severe GH deficiency (in the absence of malnutrition). Normal IGF-1 levels may be found in patients with GH deficiency; therefore, provocative tests are necessary in patients with another identified pituitary hormone deficit. Provocative testing is recommended if IGF-1 levels are below the 25th percentile of age-related normal limits (Ghigo et al. 2005).

Figure: Screening for hypopituitarism based on severity of head injury (Estes & Urban 2005; Sirois 2009)
 

Neuroimaging

In a review of the literature, Makulski et al. (2008) concluded that magnetic resonance imaging (MRI) is the preferred imaging technique for the pituitary gland, as it can readily distinguish between the anterior and posterior lobes. MRI allows for both visualization of structural abnormalities and indirect imaging of the blood supply. The most common pathological findings are hemorrhage of the hypothalamus and posterior lobe, and infarction of the anterior lobe (Maiya et al. 2008; Makulski et al. 2008). While widely regarded as the best imaging technique, MRI may still fail to show pathological abnormalities in some patients with PTHP (Makulski et al. 2008).

Although neuroimaging (MRI or CT scans) can be successful in locating lesions within various sections of the brain, they do not reveal all pathology. Benvenga et al. (2000) found that 6% to 7% of those with PTHP showed no abnormalities on MRI. With regard to testing, blood tests remain the gold standard. Benvenga et al. (2000) suggested monitoring individuals for hypopituitarism if they are male and under the age of 40, have sustained their injury in a motor vehicle collision, and are within the first year post injury.

Provocative Testing

Growth Hormone Assessment

Approximately 20% of those with a TBI or SAH are at risk for severe growth hormone deficiency (GHD); provocative testing has been recommended in order to rule it out. Due to the expense of this test, it is recommended once other hormonal tests, such as the IGF-1, have been completed, and only to rule out other transitory hormone deficits (Sesmilo et al. 2007). 

Insulin Growth Factor (IGF)-1

It has been suggested that a relationship exists between IGF-1 and GHD; however, Bondanelli et al. (2007) reported no relationship between IGF-1 and GHD, as only 30% of patients with GHD were found to have low IGF-1 levels. This finding was supported by previous studies indicating that low IGF-1 does not necessarily predict GHD status in those who have sustained an ABI (Bondanelli et al. 2005; Popovic et al. 2005).

Pituitary Function Testing (Serum Cortisol, ACTH)

The diagnosis of adrenocortical insufficiency requires provocative tests in addition to measurement of early morning basal serum cortisol levels. The normal basal morning serum cortisol values are between 150 nmol/L and 800 nmol/L (5.3–28.6 lg/dL). Basal morning serum cortisol <100 nmol/L (<3.6 lg/dL) is indicative of secondary adrenocortical insufficiency; if this value is >500 nmol/L (>18 lg/dL) adrenocortical insufficiency can be excluded. When basal serum cortisol values are borderline, a provocative test is necessary (Auernhammer & Vlotides 2007).

Short ACTH stimulation test

In healthy subjects, stimulated serum cortisol has been shown to be between 550 nmol/L and 1110 nmol/L (19.6–39.6 lg/dL). Adrenocortical insufficiency is confirmed with a serum cortisol <500 nmol/L (18 lg/dL). Standard ACTH tests should be conducted at least 4 weeks after pituitary surgery (Auernhammer & Vlotides 2007).

Insulin-Induced Hypoglycemia Test

During an insulin-induced hypoglycemia test, the top serum cortisol levels in healthy people are between 555 nmol/L and 1,015 nmol/L (19.8–36.2 lg/dL) (Auernhammer & Vlotides 2007). Adrenocortical insufficiency is diagnosed when there is a serum cortisol increase of <500 nmol/L. Although this test has been shown to be the gold standard, caution is recommended when using the test, especially for the cardiac and epileptic patient where this test has been found to be contraindicated.

Metyrapone

Metyrapone has been shown to block the last step in the biochemical pathway between cholesterol and cortisol, leading to a reduction in serum cortisol, an increase of ACTH secretion and an increase of cortisol precursors such as 11b-deoxycortisol. The peak serum 11b-deoxycortisol levels in healthy people range between 195 nmol/L and 760 nmol/L. During the test, serum 11-deoxycortisol may increase to >200 nmol to exclude adrenal insufficiency. Another variant of the test is the ‘‘multiple dose metyrapone test’’, which requires other diagnostic cut-offs of serum 11b-deoxycortisol levels. In order to support this multistep testing, patients must be hospitalized. Metyrapone may cause gastrointestinal upset and may lead to adrenal insufficiency (Auernhammer & Vlotides 2007). This test is considered only when other tests are inconclusive.

Corticotropin-Releasing Hormone (CRH) Test

Responses to this test vary widely between patients. Serum cortisol may increase to <350–420 nmol/L (<12.5–15 lg/dL) as evidence of secondary adrenocortical insufficiency, or it may increase to >515-615 nmol/L (18.5–22.0 lg/dL) excluding secondary adrenocortical insufficiency (Auernhammer & Vlotides 2007).

 

Table: Tests of Pituitary Function (Auernhammer & Vlotides 2007)

Tests Methods

GH test 

  • IGF-1 is low
  • Assess family history: looking at age and weight related issues of individual and family members
  • Other pituitary deficits with normal IGF
Insulin-induced hypoglycemia test
  • Insulin (0.1–0.15 IU/kg) intravenously sufficient to cause adequate hypoglycemia (<40mg/dL) (<2.2 nmol/L)
  • Blood samples are collected for measurement of serum cortisol at –15, 0, 30, 45, 60 and 90 min

Metyrapone test 

  • 30 mg/kg orally at midnight with a snack to minimize gastrointestinal discomfort
  • Blood for serum 11b-deoxycortisol, ACTH and cortisol are obtained at 8 AM
CRH test
  • 100 µg recombinant human CRH is given intravenously
  • Blood samples for serum cortisol are collected at –15, 0, 30, 45 and 60 min

ACTH stimulation test  

  • 250 µg recombinant human ACTH and serum cortisol, given intravenously
  • Responses are assessed at 0, 30 and 60 min