Corticotropin-releasing Hormone Stimulation

Rationale: The corticotropin-releasing hormone (CRH) stimulation test has been used as a diagnostic test in both adrenal insufficiency and Cushing syndrome. In 95% of normal subjects, baseline ACTH increases two- to fourfold within 30-60 minutes of CRH administration.1-4 Plasma cortisol typically peaks at >20 μg/dL within the same period.


Adrenal Insufficiency. Patients with adrenal insufficiency exhibit one of three patterns of response to CRH stimulation depending on the cause.1

  1. Individuals with primary adrenal insufficiency have high baseline ACTH (which increases in response to CRH), with low cortisol levels before and after CRH.
  2. Individuals with secondary (pituitary) adrenal insufficiency exhibit low baseline ACTH levels that do not respond to CRH. Cortisol levels in these patients are not affected by CRH.
  3. Patients with tertiary (hypothalamic) disease (ie, CRH deficiency) typically exhibit low baseline ACTH levels and an exaggerated and prolonged response to CRH. Serum cortisol levels in these patients typically do not reach 20 μg/dL.

Cushing Syndrome. The CRH stimulation test has been used to identify the source of excess ACTH in ACTH-dependent Cushing syndrome.5 Pituitary tumors tend to be sensitive to CRH stimulation while ectopic tumors do not usually respond. Patients with hypercortisolism due to oversecretion of ACTH by the pituitary (Cushing disease) generally respond to CRH with a >20% rise in cortisol (average of 30- and 45-minute value relative to average of minus 15- and minus 1-minute value) and a >35% increase in ACTH (average of 15- and 30-minute value relative to average of minus 5- and minus 1-minute value). In most cases, patients with primary adrenal hypercortisolism or ectopic ACTH syndrome do not respond to CRH.

Protocol: Patient should fast for at least four hours prior to the test.3 Ovine* or human CRH at 1.0 μg/kg body weight is injected intravenously as a bolus over 30 seconds. Blood samples should be collected at 15 minutes and one minute before CRH administration and at 15, 30, 45, 60, 90, and 120 minutes after for measurements of cortisol and ACTH.

*Ovine CRH is not FDA-approved (6/00). While earlier studies suggested that ovine CRH produced superior stimulation compared to human CRH,3 more recent data indicate that the two perform comparably.4

Orderable Tests: Cortisol, Eight Specimens (210823) (Minus 15-, minus 1-, 15-, 30-, 45-, 60-, 90-, 120-minute); Adrenocorticotropic Hormone (ACTH), Plasma, Eight Specimens (267708) (Minus 15-, minus 1-, 15-, 30-, 45-, 60-, 90-, 120-minute).

Note: The CRH stimulation test can be performed at any time of day. The ACTH increment is similar morning and evening, but peak values are higher in the morning. Cortisol levels peak at similar values in the morning and evening.


1. Grinspoon SK, Biller BM. Clinical review 62: Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab. 1994 Oct; 79(4):923-931. PubMed 7962298

2. Perry LA, Grossman AB. The role of the laboratory in the diagnosis of Cushing's syndrome. Ann Clin Biochem. 1997 Jul; 34(Pt 4):345-359. PubMed 9247665

3. Nieman LK, Oldfield EH, Wesley R, Chrousos GP, Loriaux DL, Cutler GB Jr. A simplified morning ovine corticotropin-releasing hormone stimulation test for the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab. 1993 Nov; 77(5):1308-1312. PubMed 8077325

4. Trainer PJ, Faria M, Newell-Price J, et al. A comparison of the effects of human and ovine corticotropin-releasing hormone on the pituitary-adrenal axis. J Clin Endocrinol Metab. 1995 Feb; 80(2):412-417. PubMed 7852498

5. Orth DN, Kovacs WJ, Debold CR. The adrenal cortex: Evaluation of adrenocortical function. In: Wilson JD, Foster DW, eds. Textbook of Endocrinology. 8th ed. Philadelphia, Pa: WB Saunders; 1992: 575-591.


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