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Dexamethasone/Corticotropin-Releasing Hormone Test 

  • Author: Rakesh Vadde, MBBS; Chief Editor: Eric B Staros, MD  more...
 
Updated: May 15, 2013
 

Reference Range

Testing corticotropin-releasing hormone (CRH) levels involves measuring the response to an intravenous bolus injection of synthetic ovine CRH at doses of 1 mcg (200 nmol) per kg of body weight (or total dose of 100 mcg).[1]

Table 1. Serum Corticotropin[2, 3] (Open Table in a new window)

Plasma Concentration Peak Level Increase From Baseline Time to Peak Level
Corticotropin 10-120 pg/mL (2.2-24 pmol) 35-900% 10-30 min postinjection
Cortisol 13-36 mcg/dL (360-1000 nmol/L) 20-600% 30-60 min postinjection
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Collection and Panels

See the Medscape Reference topic Adrenocorticotropin (ACTH).

Patients should fast for a minimum of 4 hours prior to the test,[4] following which ovine or human (human corticotropin-releasing hormone [CRH] is not approved by US Food and Drug Administration [FDA]) is injected intravenously over 30 seconds. Blood for specimens is collected at 15 minutes and 1 minute before CRH administration and at 30, 45, 60, 90, and 120 minutes after CRH administration for measuring corticotropin and cortisol levels. Recent studies have shown that ovine CRH and human CRH perform comparably.[5]

The test can be performed at any time of the day. Corticotropin increments are similar in morning and evening, but peak values are higher in the morning; cortisol values peak similarly in the morning and evening. Details are below:

  • Specimen: Plasma, frozen
  • Volume: 0.8 mL
  • Minimum volume: 0.3 mL (Note: This volume does not allow for repeat testing.)
  • Container: Plastic or siliconized glass lavender-top (ethylenediaminetetraacetic [EDTA]) tube (see below)
    Vacuette ethylenediaminetetraacetic (EDTA) 4-mL tu Vacuette ethylenediaminetetraacetic (EDTA) 4-mL tube.
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Interpretation

In patients with pituitary Cushing syndrome, cortisol and corticotropin levels are normal or increased. These levels are suppressed in the presence of other conditions, such as ectopic Cushing syndrome, pseudo-Cushing syndrome, and adrenal syndrome. For patients with pseudo-Cushing syndrome, low-dose dexamethasone suppression testing alongside corticotropin-releasing hormone (CRH) testing aids in diagnosis. CRH testing is also used to differentiate hypothalamic adrenal insufficiency, in which patients have subnormal cortisol response and a prolonged and delayed corticotropin response, and pituitary adrenal insufficiency, in which patients demonstrate no response.

Table 2. Responses to CRH Testing[6] (Open Table in a new window)

Diagnosis Corticotropin Response Cortisol Response
Pituitary Cushing syndrome Normal or increased Normal or increased
Adrenal Cushing syndrome Suppressed Suppressed
Ectopic Cushing syndrome Suppressed Suppressed
Pseudo-Cushing syndrome Suppressed Suppressed
Pituitary Adrenal insufficiency Suppressed Suppressed
Hypothalamic adrenal insufficiency Normal Low

 

Although CRH testing is both difficult and costly, it is mainly used in certain settings such as finding the cause of corticotropin-dependent Cushing syndrome, distinguishing between pseudo-Cushing syndrome and Cushing syndrome, and identifying the difference between central and primary adrenal insufficiency.

CRH testing has a sensitivity of 86% and a specificity of 90% in assessing corticotropin-dependent Cushing syndrome.[7] The test best suited to distinguish between ectopic corticotropin secretion and Cushing disease is the inferior petrosal sinus sampling test, which helps localize the site within the pituitary for partial surgical resection, if desired. Combining desmopressin with CRH testing has helped with the differential diagnosis of Cushing syndrome.[8]

CRH is useful in differentiating corticotropin-dependent and independent Cushing syndrome, and it also helps in the investigation of pediatric Cushing disease. It helps enable localization of the side of pituitary gradient when used with bilateral inferior petrosal sinus sampling (IPSS).[9]

Diagnostic accuracy of the CRH test in patients with Cushing syndrome is comparable to the high-dose dexamethasone test.[10]

A low-dose dexamethasone suppression test prior to CRH testing further helps identify a corticotropin-secreting tumor. This combined test helps to distinguish true Cushing syndrome from pseudo-Cushing syndrome (increased cortisol level related to a non–hypothalamic-pituitary-adrenal (HPA) disorder, such as depression).

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Background

Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide with noted sequence homology among species, specifically in the region required for biologic activity (amino-terminal region), and is a major secretagogue of pituitary corticotropin.[11] Because of homology among species, human and ovine sequences are both used to stimulate pituitary production and adrenal cortisol production.[1] Synthetic ovine CRH is equipotent to human CRH and has a more prolonged duration of action than human CRH, which makes it useful for clinical testing.[12] Human CRH is not approved by FDA.

Indications/Applications

1. To diagnose primary, secondary (pituitary), and tertiary (hypothalamic) adrenal insufficiency conditions[13] :

  • In primary adrenal insufficiency, there are high baseline corticotropin levels, which increase in response to CRH; cortisol levels remain low before and after CRH
  • In secondary adrenal insufficiency, there are low baseline corticotropin levels, which do not respond to CRH; cortisol levels are not affected by CRH
  • In tertiary disease, there are low baseline corticotropin levels, which show exaggerated, prolonged responses to CRH; serum cortisol levels do not exceed 20 mcg/dL

2. To differentiate pituitary Cushing disease (which responds by causing a >20% rise in cortisol and a >35% increase in corticotropin to CRH) from other conditions such as primary adrenal hypercortisolism or ectopic corticotropin syndrome, which does not respond to CRH[14]

Considerations

Because CRH testing is rare and complex, diagnostic cut points are less quantitative than qualitative. Before a definitive treatment decision can be made, results from CRH testing must be considered alongside various other clinical data.

At the recommended dose level, ovine CRH has no adverse effects; however, some have reported mild brief facial flushing immediately after injection.[12] Allergic reactions have not been reported.

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Contributor Information and Disclosures
Author

Rakesh Vadde, MBBS Fellow in Pulmonary Medicine, Interfaith Medical Center

Rakesh Vadde, MBBS is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Coauthor(s)

M Frances J Schmidt, MD Chief of Pulmonary Medicine, Pulmonary Fellowship Program, Teaching Attending Physician, Department of Medicine, Interfaith Medical Center

M Frances J Schmidt, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians

Disclosure: Nothing to disclose.

Vikram V Oke, MD Fellow in Pulmonary Medicine, Interfaith Medical Center

Vikram V Oke, MD is a member of the following medical societies: American College of Physicians, Indian Medical Association

Disclosure: Nothing to disclose.

Chief Editor

Eric B Staros, MD Associate Professor of Pathology, St Louis University School of Medicine; Director of Clinical Laboratories, Director of Cytopathology, Department of Pathology, St Louis University Hospital

Eric B Staros, MD is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology

Disclosure: Nothing to disclose.

References
  1. Nieman LK, Cutler GB Jr, Oldfield EH, Loriaux DL, Chrousos GP. The ovine corticotropin-releasing hormone (CRH) stimulation test is superior to the human CRH stimulation test for the diagnosis of Cushing's disease. J Clin Endocrinol Metab. 1989 Jul. 69(1):165-9. [Medline].

  2. Kaye TB, Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann Intern Med. 1990 Mar 15. 112(6):434-44. [Medline].

  3. Sheldon WR Jr, DeBold CR, Evans WS, DeCherney GS, Jackson RV, Island DP. Rapid sequential intravenous administration of four hypothalamic releasing hormones as a combined anterior pituitary function test in normal subjects. J Clin Endocrinol Metab. 1985 Apr. 60(4):623-30. [Medline].

  4. 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):1308-12. [Medline].

  5. 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):412-7. [Medline].

  6. DeCherney GS, DeBold CR, Jackson RV, Sheldon WR Jr, Island DP, Orth DN. Diurnal variation in the response of plasma adrenocorticotropin and cortisol to intravenous ovine corticotropin-releasing hormone. J Clin Endocrinol Metab. 1985 Aug. 61(2):273-9. [Medline].

  7. Reimondo G, Paccotti P, Minetto M, Termine A, Stura G, Bergui M. The corticotrophin-releasing hormone test is the most reliable noninvasive method to differentiate pituitary from ectopic ACTH secretion in Cushing's syndrome. Clin Endocrinol (Oxf). 2003 Jun. 58(6):718-24. [Medline].

  8. Newell-Price J, Morris DG, Drake WM, Korbonits M, Monson JP, Besser GM. Optimal response criteria for the human CRH test in the differential diagnosis of ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metab. 2002 Apr. 87(4):1640-5. [Medline].

  9. Peters CJ, Storr HL, Grossman AB, Savage MO. The role of corticotrophin-releasing hormone in the diagnosis of Cushing’s syndrome. Eur J Endocrinol. 2006 Nov. 155:S93-8.

  10. Hermus AR, Pieters GF, Pesman GJ, Smals AG, Benraad TJ, Kloppenborg PW. The corticotropin-releasing-hormone test versus the high-dose dexamethasone test in the differential diagnosis of Cushing's syndrome. Lancet. 1986 Sep 6. 2(8506):540-4. [Medline].

  11. Vale W, Rivier C, Brown MR, Spiess J, Koob G, Swanson L. Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res. 1983. 39:245-70. [Medline].

  12. Nieman LK, Cutler GB Jr, Oldfield EH, Loriaux DL, Chrousos GP. The ovine corticotropin-releasing hormone (CRH) stimulation test is superior to the human CRH stimulation test for the diagnosis of Cushing's disease. J Clin Endocrinol Metab. 1989 Jul. 69(1):165-9. [Medline].

  13. Grinspoon SK, Biller BM. Clinical review 62: Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab. 1994 Oct. 79(4):923-31. [Medline].

  14. Orth DN, Kovacs WJ, Debold CR. The Adrenal Cortex: Evaluation of Adrenocortical Function. Wilson JD, Foster DW, eds. Textbook of Endocrinology. 8th ed. Philadelphia, PA: WB Saunders; 1992. 575-91.

 
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Vacuette ethylenediaminetetraacetic (EDTA) 4-mL tube.
Table 1. Serum Corticotropin [2, 3]
Plasma Concentration Peak Level Increase From Baseline Time to Peak Level
Corticotropin 10-120 pg/mL (2.2-24 pmol) 35-900% 10-30 min postinjection
Cortisol 13-36 mcg/dL (360-1000 nmol/L) 20-600% 30-60 min postinjection
Table 2. Responses to CRH Testing [6]
Diagnosis Corticotropin Response Cortisol Response
Pituitary Cushing syndrome Normal or increased Normal or increased
Adrenal Cushing syndrome Suppressed Suppressed
Ectopic Cushing syndrome Suppressed Suppressed
Pseudo-Cushing syndrome Suppressed Suppressed
Pituitary Adrenal insufficiency Suppressed Suppressed
Hypothalamic adrenal insufficiency Normal Low
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