Stimulation tests for adrenal insufficiency

Adrenal capacity (ACTH stimulation tests)

Rapid IV ACTH test*^[1] – Used for the diagnosis of adrenal insufficiency

IV cosyntropin (synthetic ACTH) – 250 micrograms^¶ infused IV over 1 minute.

Sample blood for serum cortisol and plasma ACTH at baseline and for serum cortisol at 1 hour after completion of infusion.

Normal response – Serum cortisol at 1 hour is 7 to 10 micrograms/dL (190 to 275 nmol/L) higher than the baseline level and >14.5 micrograms/dL (>400 nmol/L) using an LC-MS/MS assay or >18 micrograms/L (500 nmol/L) using an immunoassay^Δ.

Notes:

In most forms of adrenal insufficiency (primary and most cases of central), basal cortisol is low and fails to rise after ACTH stimulation. An abnormal result provides definitive evidence of adrenal insufficiency (high specificity). A normal result does not necessarily exclude adrenal insufficiency (moderate sensitivity)^[2].
This test also can be used to assess the hypothalamic-pituitary-adrenal axis after recovery from a chronic course (longer than 1 month) of pharmacologic doses of glucocorticoid medication.
In patients with central adrenal insufficiency of short duration, basal cortisol is low and may or may not rise after ACTH stimulation.
A low-dose ACTH stimulation test was designed to improve sensitivity and may be particularly useful for patients with mild adrenal insufficiency or central adrenal insufficiency of short duration^◊.

ACTH secretory ability

Glucagon stimulation test^[3]– May be used for simultaneous evaluation of both ACTH and growth hormone secretion in children with suspected multiple pituitary hormone deficiency

The test is performed in the morning, after fasting since midnight. Obtain baseline 8:00 AM serum cortisol and glucose.

Give glucagon 0.1 mg/kg IM and obtain blood samples at 15, 30, 45, 60, 90, 120, 150, and 180 minutes for glucose and cortisol levels. If desired, samples for growth hormone measurement can be obtained at the same time points to screen for growth hormone deficiency.

Normal response – The cortisol level normally decreases during the first 60 to 90 minutes and then reaches a peak of >20 micrograms/dL (>550 nmol/L) by 180 minutes. Hypoglycemia is a risk during the second one-half of the test. The adequacy of the test requires a rise from baseline glucose (approximately 80 mg/dL) to a peak of 150 mg/dL followed by an endogenous, insulin-induced drop in glucose to approximately 60 mg/dL, which stimulates counterregulatory hormones, including cortisol and growth hormone.

ACTH: adrenocorticotropic hormone; IV: intravenous; IM: intramuscular; LC-MS/MS: liquid chromatography-tandem mass spectrometry.
* Normal ranges and protocols are from Esoterix Laboratories, Calabasas Hills, California and are used with permission. Normal ranges may vary among laboratories.
¶ Some clinicians use a 250 microgram dose of cosyntropin for all age groups. Other institutions use doses based on weight, age, or body surface area (eg, 15 micrograms/kg in neonates, 125 micrograms in children up to 2 years, and 250 micrograms for those 2 years and older). The dose does not appear to be important, since all commonly used doses are pharmacologic and safe.
Δ The cutoff of 14.5 micrograms/dL for stimulated cortisol is based on an assay using LC-MS/MS technology. Other modern assay techniques using monoclonal antibodies yield cutoffs between 14.6 and 14.8. Older immunoassays using polyclonal antibodies yielded the traditional cutoff of 18 micrograms/dL.
◊ A low-dose ACTH stimulation test was designed to improve sensitivity. It consists of administration of 1 microgram cosyntropin infused IV over 1 minute, with blood sampling at baseline, 30 minutes, and 60 minutes.

References:

Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101:364.
Ospina NS, Al Nofal A, Bancos I, et al. ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis. J Clin Endocrinol Metab 2016; 101:427.
Vanderschueren-Lodeweyckx M, Wolter R, Malvaux P, et al. The glucagon stimulation test: Effect on plasma growth hormone and on immunoreactive insulin, cortisol, and glucose in children. J Pediatr 1974; 85:182.
Javorsky BR, Raff H, Carroll TB, et al. New Cutoffs for the Biochemical Diagnosis of Adrenal Insufficiency after ACTH Stimulation using Specific Cortisol Assays. J Endocr Soc 2021; 5:bvab022.

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Stimulation tests for adrenal insufficiency