Dexamethasone/Corticotropin-Releasing Hormone Test

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) pushed over 30 seconds. ^[1]

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

See the Medscape Drugs & Diseases topic Adrenocorticotropin (ACTH).

The CRH test must be performed only after a patient has fasted for a minimum of 4 hours. ^[4] Synthetic ovine CRH (1 mcg per kg body weight or 100 mcg total dose) is injected as an intravenous bolus over 30 seconds. Blood specimens for analysis of corticotropin (also known as adrenocorticotropic hormone [ACTH]) and cortisol levels are collected at 15 (or 5) and 0 minutes prior to and then at 15, 30, 45, 60, 90, and 120 minutes after CRH administration. ^[5] Note that if only plasma ACTH is measured in Cushing syndrome, 5- and 0-minute samples prior to and 15- and 30-minute samples after CRH administration are sufficient. ^{[4, 6]} If only serum cortisol level is measured, samples at 5 and 0 minutes prior to and 15 and 30 minutes after CRH administration are again sufficient. ^[3]

The CRH test can be performed at any time of the day. Corticotropin increments are similar in the morning and evening, but peak values are higher in the morning; cortisol values peak similarly in the morning and evening. ^[7] 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 tube.

Adrenal insufficiency (hypocortisolism)

CRH testing is also used to differentiate hypothalamic adrenal insufficiency (in which patients have a subnormal cortisol response and a prolonged and delayed corticotropin response) and pituitary-related adrenal insufficiency (in which patients demonstrate no response). ^[8]  Corticotropin and cortisol levels in primary, secondary, and tertiary adrenal insufficiency are as follows ^[9] :

• Primary adrenal insufficiency - High baseline corticotropin levels that increase in response to CRH; cortisol levels remain low before and after CRH
• Secondary (pituitary) adrenal insufficiency - Low baseline corticotropin levels that do not respond to CRH; cortisol levels are not affected by CRH
• Tertiary (hypothalamic) disease - Low baseline corticotropin levels that show exaggerated, prolonged responses to CRH; serum cortisol levels do not exceed 20 mcg/dL

Cushing disease/syndrome (hypercortisolism)

A CRH stimulation test alongside a high-dose dexamethasone suppression test enhances diagnostic accuracy with regard to the site of hormone excess in patients with hypercortisolism. ^{[4, 8, 10, 5]}  Results are as follows:

• Cushing disease (pituitary) - CRH stimulation can cause a greater than 35% increase in corticotropin and a greater than 20% rise in cortisol
• Primary adrenal hypercortisolism (adenoma/carcinoma) - Low baseline corticotropin and high baseline cortisol levels are not affected by CRH stimulation
• Ectopic corticotropin secretion - High baseline corticotropin and high baseline cortisol levels are not affected by CRH stimulation

Table 2. Responses to CRH Testing ^[7] (Open Table in a new window)

CRH testing is difficult and costly; its main uses include as a means of 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. ^[11] The test best suited to distinguish between ectopic corticotropin secretion and Cushing disease is the inferior petrosal sinus sampling (IPSS) test, which helps to localize the site within the pituitary where partial surgical resection, if desired, must be performed. Combining desmopressin with CRH testing has helped in making the differential diagnosis of Cushing syndrome. ^[12]

The CRH test is useful in differentiating corticotropin-dependent and corticotropin-independent Cushing syndrome, and it also helps in the investigation of pediatric Cushing disease. It is mainly used to enable localization of the side of pituitary gradient when used in combination with bilateral IPSS. ^[13]

Diagnostic accuracy of the CRH test in patients with Cushing syndrome is comparable to the high-dose dexamethasone test. ^[14]

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

CRH is a 41–amino acid peptide hormone that is a corticotropin secretagogue. There is sequence homology among species, specifically in the region required for biologic activity (amino-terminal region). ^[15]

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. ^[1] It is measured by radioimmunoassay or enzyme-linked immunoassay. ^[16] In humans, CRH is bound to a plasma CRH-binding protein. ^{[17, 18]}  Note that human CRH is not approved by the US Food and Drug Administration (FDA).

Indications

CRH tests are performed for the following purposes:

• To diagnose adrenal insufficiency (primary, secondary [pituitary], or tertiary [hypothalamic]) ^[9]
• To diagnose the etiology of Cushing syndrome

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. ^[1] Allergic reactions have not been reported.