When is Adrenocorticotropic hormone (ACTH) testing recommended and how is it interpreted in patients with suspected adrenal or pituitary dysfunction?

From the Guidelines

Adrenocorticotropic hormone (ACTH) testing is recommended in patients with suspected Cushing syndrome to determine its etiology, specifically to confirm ACTH dependency and differentiate between pituitary and adrenal causes. When evaluating patients with suspected adrenal or pituitary dysfunction, particularly those with cortisol abnormalities, ACTH testing is a crucial diagnostic tool 1. The test helps differentiate between primary adrenal insufficiency, secondary adrenal insufficiency, and conditions of cortisol excess like Cushing's syndrome.

• In patients with confirmed Cushing syndrome, a normal or elevated 09:00 h plasma ACTH supports the diagnosis of Cushing disease, which is ACTH-dependent 1.
• For suspected adrenal insufficiency, measuring ACTH levels alongside a morning cortisol test can help distinguish between primary and secondary adrenal insufficiency.
• In primary adrenal insufficiency, ACTH levels are typically elevated, while cortisol is low, reflecting the pituitary's attempt to stimulate failing adrenal glands.
• In secondary adrenal insufficiency, both ACTH and cortisol are low, indicating pituitary failure to produce ACTH.
• ACTH stimulation tests, using synthetic ACTH, can also be valuable in diagnosing adrenal insufficiency, with a normal response ruling out primary adrenal insufficiency.
• When interpreting ACTH test results, it is essential to consider the clinical context, as values can be affected by stress, timing, medications, and concurrent illnesses 1.

From the FDA Drug Label

Assess ability of patient's adrenals to respond to exogenous ACTH before Metopirone is employed as a test Approximately 8 hours after administration of Metopirone, evaluate the values of ACTH and 11-desoxycortisol Because of an overlap between a normal ACTH response and an abnormal ACTH response, the ACTH response alone cannot be used to distinguish between healthy individuals and those with adrenal insufficiency

Adrenocorticotropic hormone (ACTH) testing is recommended in patients with suspected adrenal or pituitary dysfunction.

• The ability of a patient's adrenals to respond to exogenous ACTH should be assessed before Metopirone is employed as a test 2.
• ACTH levels should be evaluated approximately 8 hours after administration of Metopirone, along with 11-desoxycortisol levels 2.
• However, ACTH response alone cannot be used to distinguish between healthy individuals and those with adrenal insufficiency due to the overlap between normal and abnormal responses 2.

From the Research

Adrenocorticotropic Hormone (ACTH) Testing

• ACTH testing is recommended in patients with suspected adrenal or pituitary dysfunction, particularly when basal serum cortisol levels are inconclusive 3.
• The ACTH stimulation test is commonly performed to evaluate patients with suspected adrenal insufficiency, and its interpretation should take into account the clinical presentation and technical factors that can affect cortisol values 3.
• The test can help distinguish between primary and secondary adrenal insufficiency, with primary adrenal insufficiency characterized by decreased cortisol levels and increased ACTH levels 4.

Interpretation of ACTH Test Results

• The diagnostic accuracy of the high- and low-dose ACTH stimulation tests is similar, with both tests having low sensitivity and high specificity for secondary adrenal insufficiency 5.
• The tests are adequate to rule in, but not rule out, secondary adrenal insufficiency, and the likelihood ratios for a positive test are reasonable, but the likelihood ratio for a negative test is suboptimal 5.
• Reference values for endocrine tests, including the short Synacthen test, overnight metyrapone test, and insulin tolerance test, have been established to aid in the evaluation of patients suspected of adrenal insufficiency 6.

Clinical Applications of ACTH Testing

• ACTH testing is useful in the diagnosis of Cushing syndrome, where plasma corticotropin levels can help distinguish between adrenal causes of hypercortisolism and corticotropin-dependent forms of hypercortisolism 7.
• In patients with suspected Addison disease, ACTH testing can confirm the diagnosis, and treatment requires replacement of mineralocorticoids and glucocorticoids, as well as stress-dose glucocorticoids during times of stress 4.
• The clinical manifestations of adrenal insufficiency can be subtle, and a high clinical suspicion is needed to avoid misdiagnosing a life-threatening adrenal crisis 4.