What is the purpose and procedure of the glucagon stimulation test (GST) in diagnosing adrenal insufficiency or growth hormone deficiency?

Glucagon Stimulation Test for Diagnosing Adrenal Insufficiency and Growth Hormone Deficiency

The glucagon stimulation test (GST) is a reliable alternative to the insulin tolerance test for evaluating both adrenal insufficiency and growth hormone deficiency, with peak cortisol responses typically occurring between 150-180 minutes after glucagon administration and a cortisol cutoff of 500 nmol/L (18 μg/dL) indicating normal adrenal function. 1

Purpose of the Glucagon Stimulation Test

The GST serves two main diagnostic purposes:

1. Evaluation of adrenal insufficiency: When uncertainty exists about partial primary adrenal insufficiency (PAI) or secondary adrenal insufficiency, the GST can be used as an alternative to the ACTH stimulation test 2

2. Assessment of growth hormone deficiency: The GST is particularly useful for evaluating GH-IGF-1 axis function and is considered a good alternative to the insulin tolerance test (ITT) 3

Procedure and Administration

Standard Protocol:

• Dose:

  • Adults: 1-1.5 mg glucagon administered intramuscularly 4
  • Weight-based dosing: 0.03 mg/kg (may be more effective in older, overweight, or glucose-intolerant patients) 4
  • Children: Typically weight-based dosing is preferred 5

• Administration route: Intramuscular injection into the upper arm, thigh, or buttocks 6

• Sampling schedule:

  • Baseline blood samples for cortisol and GH
  • Additional samples at 30,60,90,120,150,180, and 210 minutes after glucagon injection 7
  • Peak cortisol response typically occurs between 150-180 minutes 4
  • Peak GH response may occur later than with the ITT 3

Interpretation of Results

For Adrenal Insufficiency:

• Normal response: Peak cortisol level exceeding 500 nmol/L (18 μg/dL) 2, 1
• Some studies suggest a lower cutoff of 320-350 nmol/L may be appropriate, but this remains controversial 5
• A peak cortisol cutoff of 167 ng/mL has been proposed with 89% sensitivity and 79% specificity compared to ITT 8

For Growth Hormone Deficiency:

• Peak GH responses are typically higher in GST than in ITT 3
• Cut-off values should be individualized based on the specific assay used

Safety Considerations and Side Effects

The GST is generally considered safer than the ITT but still has potential side effects:

• Common side effects (occur in approximately 43% of patients) 7:

  • Nausea (29.6%)
  • Vomiting (27.2%)
  • Abdominal cramps (18.5%)
  • Hunger (13.6%)

• Risk factors for side effects:

  • Age over 50 years (significantly higher prevalence of adverse effects) 7
  • Female gender (particularly younger females) 4

• Contraindications:

  • Pheochromocytoma (may stimulate catecholamine release) 6
  • Insulinoma (may cause hypoglycemia) 6
  • Glucagonoma (may cause secondary hypoglycemia) 6
  • Known hypersensitivity to glucagon 6

Advantages and Limitations

Advantages:

• Safer alternative to ITT, especially in patients with seizure disorders or cardiovascular disease
• Can evaluate both HPA axis and GH-IGF-1 axis with a single test 3
• Good reproducibility comparable to other stimulation tests 3

Limitations:

• Takes more time than ACTH stimulation test (up to 3-4 hours) 3, 7
• May not be optimal for diagnosing secondary adrenal insufficiency in children (56% sensitivity, 83% specificity at 320 nmol/L cutoff) 5
• Higher incidence of side effects compared to ACTH stimulation test

Clinical Considerations

• For patients with suspected adrenal insufficiency, morning cortisol and ACTH levels should be checked first before proceeding to stimulation testing 1
• In cases of suspected acute adrenal crisis, treatment should never be delayed for diagnostic testing 2
• The GST should be used cautiously in elderly patients due to higher incidence of side effects 7
• Blood glucose should be monitored during the test, as both hyperglycemia and hypoglycemia can occur 6, 4

The GST represents a valuable diagnostic tool when evaluating both adrenal and growth hormone function, particularly when the insulin tolerance test is contraindicated or when a single test evaluating both axes is preferred.