9.3 Neuroendocrine Laboratory Testing

9.3.1 Diagnosis 

What hormonal testing is recommended for all those who sustain an ABI?



Pituitary-Gonadal Axis

1.    Male Patients: LH, FSH and testosterone are used to evaluate the pituitary gonadal axis. 

2.    Female Patients: for those who have irregular cycles LH, FSH, and estradiol needs to be measured 8.

Pituitary-Adrenal Axis 

1.    The cut off values used for diagnosing adrenal insufficiency is different in the acute phase following a TBI than in the rehabilitation phase. Pituitary-adrenal evaluations are best performed with early morning plasma cortisol measurements. Or 24 hour urinary free cortisol test can also be used8.

Pituitary-Thyroid Axis 

1.    It has been suggested, baseline testing should include thyroid function tests (TSH, fT4, fT3) and repetition of testing where appropriate 8.

Diagnosis is based on clinical evaluation, laboratory testing and neuroimaging. According to Sesmilo et al. 8baseline hormonal testing should be performed in all patients; however, there is some dispute in the literature as to when it should be completed (how soon after injury), how often and who should be tested. As mentioned previously, clinical assessment of hypopituitarism is difficult because the signs and symptoms are often nonspecific and often mimic the neuropsychological sequelae of TBI. It is therefore reasonable to consider performing baseline hormonal evaluation in more severe TBI or SAH patients. Early post injury the most important anterior hormones to screen may be thyroid, growth and Adrenocorticoid axes as these will lead more quickly to symptoms that may affect recovery although baseline testing of all hormones allow more easy clinical follow-up.

9.3.2 Screening for Hypopituitarism Post ABI

What are the guidelines for screening patients who have sustained an AB?

1.  Hypotituitarism is a common and treatable condition resulting from an ABI.

2.  Guidelines for screening patients who have sustained an ABI or a stroke include:

a)    severity of injury, location of injury (those with basal skull fractures, diffuse axonal injury, or increased intracranial pressure),

b)    GSC (especially those who score between 3 and 12), length of time spent in the intensive care unit (ICU)

c)    and the amount of time that has passed since the injury occurred 15.

Because hypotituitarism can evolve over time post injury, it is important to begin screening as soon as possible. In the acute stage, due to its life threatening potential, screening for adrenal insufficiency is important 12. During this stage of recovery, cortisol levels of less than 7.2ug/dL may indicate adrenal insufficiency. Treatment should also be considered and initiated in those cases where hyponatremia, hypotension and hypoglycaemia are present and cortisol levels are between 7.2 and 18ug/dL 15. 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 15;20; however, during the post recovery stage, at 3 and 6 months, a clinical assessment for hypopituitarism should be completed 10;27;28. This is especially important if any of the following are noted: loss of secondary hair, impaired sexual function, weight changes, polydipsia, or amenorrhea.

For mild TBI it has been suggested to test only patients who spend more than 24 hours in hospital, who have an abnormal CT scan, or who initially have symptoms suggesting post-traumatic hypopituitarism.

Hormonal screening should include 0900 AM serum cortisol, fT3, fT4, TSH, FSH, LH, testosterone in men and E2 in women, prolactin, and IGF-I.  In patients with polyuria or suspected diabetes insipidus, urine density, sodium and plasma osmolality should also be evaluated. Low IGF-I levels strongly predict severe growth hormone deficiency (in the absence of malnutrition). Normal IGF-I levels may be found in patients with growth hormone deficiency; therefore, provocative tests are necessary in patients with another identified pituitary hormone deficit. Provocative testing is recommended if IGF-I levels are below the 25th percentile of age related normal limits 20.

9.3.4 Neuroimaging

Which is the preferred neuroimaging technique to determine pituitary gland dysfunction?

1.    It has been found that magnetic resonance imaging (MRI) is the preferred imaging technique for the pituitary gland as it can readily distinguish between the anterior and posterior lobes3.

2.    An MRI allows for both visualization of structural abnormalities and indirect imaging of the blood supply.

3.    The most common pathological findings are haemorrhage of the hypothalamus and posterior lobe and infarction of the anterior lobe of the pituitary 3;11.

4.    While widely regarded as the best imaging technique, MRI may still fail to show pathological abnormalities in some patients with post traumatic hypopituitarism3.

Although neuroimaging (MRI or CT scans) can be very successful in locating lesions within various sections of the brain, they do not reveal all.  Benvenga et al. 23have found 6 to 7% of those with post traumatic hypopituitarism have no abnormalities on MRI; therefore further testing is necessary. With regards to testing, blood tests remain for the gold standard. Benvenga et al. 23suggest monitoring individuals for hypoituitarism 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 of injury.


9.3.5 Provocative Testing

Growth Hormone Assessment

What test can be done to rule out severe growth hormone deficiency?

1.  It has been noted that approximately 20% of those with a TBI or SAH are at risk for severe growth hormone deficiency; therefore, to rule this out provocative testing has been recommended.

2.  Due to the expense of this test, it is recommended when other hormonal tests, such as the IGF-I, have been completed and only to rule out other transitory hormone deficits 8.

Insulin Growth Factor (IGF)-1

It has been suggested that a relationship exists between IGF-1 and growth hormone deficiency; however, in a study conducted by Bondanelli et al. 22no relationship was found 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-I does not necessarily predict GH status in those who have sustained an ABI19;26.

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 to 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 29.

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); thus a normal response is >550 nmol/l.

Adrenocortical insufficiency is confirmed with a serum cortisol <500 nmol/l (18 lg/dl). Standard ACTH tests should be done 4 weeks at the earliest after pituitary surgery 29.

Insulin-Induced HypoglycemiaTest

During an insulin-induced hypoglycaemia test the top serum cortisol levels in healthy people are between 555 nmol/l to 1,015 nmol/l (19.8–36.2 lg/dl) 29. Adrenocortical insufficiency is diagnosed when there is a serum cortisol increase of <500nmol/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 contra-indicated.


Metyrapone has been shown to block the last step in the biochemical pathway from cholesterol to 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 to 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’’ require other diagnostic cut-offs of serum 11-deoxycortisol levels. In order to sustain this multi-step testing patients must  be hospitalized. Metyrapone may cause gastrointestinal upset and may lead to adrenal insufficiency29. Currently this test is considered only if 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 29.


Table 9.7  Tests of Pituitary Function 29



Growth hormone assessment


·    IGF-1 is low

·    Assess family history: looking at age related issues and weight issues (obesity) 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 (<40 mg/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

‘‘overnight 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.

Corticotropin-releasing hormone (CRH) test

100µgrecombinant human CRH is given intravenously.  Blood samples for serum cortisol are collected at –15, 0, 30, 45 and 60 min.

Short ACTH stimulation test


250 µg recombinant human ACTH and serum cortisol, given intravenously. The responses are assessed at 0, 30 and 60 min.