ACTH Stimulation with Metyrapone

Metyrapone (Metopirone) is a potent blocker of an enzyme involved in cortisol production. Cortisol production is therefore reduced. When this drug is given, the resulting decrease in cortisol production should stimulate pituitary secretion of Adrenocorticotropic Hormone (ACTH) by way of a negative-feedback mechanism. Cortisol itself cannot be synthesized because of the metyrapone inhibition at the 11-beta-hydroxylation step, but an abundance of cortisol precursors (11-deoxycortisol and OCHS) will be formed. These cortisol precursors can be detected in the urine or in the blood. This test is similar to the ACTH stimulation test.


In patients with adrenal hyperplasia caused by pituitary overproduction of ACTH, the cortisol precursors are greatly increased. This is because the normal adrenal-pituitary feedback response mechanism is still intact. No response to metyrapone occurs in patients with Cushing syndrome resulting from adrenal adenoma or carcinoma, because the tumors are autonomous and therefore insensitive to changes in ACTH secretion. This test has no significant advantage over the ACTH stimulation test in the differential diagnosis of Cushing disease.
This test is also used to evaluate the pituitary reserve capacity to produce ACTH. It can document that adrenal insufficiency exists as a result of pituitary disease (secondary adrenal insufficiency) rather than primary adrenal pathology. This test should not be performed if primary adrenal insufficiency is likely. A severe, life-threatening adrenal crisis could be precipitated. A normal response to ACTH should be demonstrated before metyrapone is given.

 

For the blood test, a dose of metyrapone is given to the patient at 11 PM the night before the blood specimen is to be collected. The blood specimen is collected in the morning.

 

For the urine test however, a 24-hour urine specimen is collected for a 17-OCHS baseline level. Then a 24-hour urine specimen is collected for the 17-OCHS level when an oral dose of Metyrapone is given to the patient. And again a 24-hour urine specimen is collected 1 day after the oral administration of a dose of Metyrapone, which may be given every 4 hours for 24 hours.

 

 

 

Conditions that Prevent performing ACTH Stimulation with Metyrapone

  • ACTH Stimulation with Metyrapone cannot be used with patients with Addison Disease or Addisonian Crisis because Metyrapone inhibits Cortisol production.
  • ACTH Stimulation with Metyrapone cannot be used with patients with possible Primary Adrenal Ansufficiency because Metyrapone could reduce the production of what little cortisol is produced and precipitate an adrenal crisis.

 

 

 

Causes of ACTH Stimulation with Metyrapone False Results

  • Recent administration of radioisotopes will interfere with test results performed by radioimmunoassay (RIA).
  • Chlorpromazine (Thorazine) interferes with the response to metyrapone and should not be administered during the testing.

 

 

 

Normal Findigns of ACTH Stimulation with Metyrapone

Urine: Baseline excretion of urinary 17-hydroxycorticosteroid (OCHS) more than doubled.
Blood: 11-Deoxycortisol increased to >7 mcg/dL and cortisol <10 mcg/dL.

 

 

 

Causes of ACTH Stimulation with Metyrapone High Findings

  • Adrenal hyperplasia: Cortisol precursors will be significantly increased as a result of accentuating the ACTH effect.
  • Adrenal Tumor: Tumors are autonomous and are not affected by inhibitory or stimulatory feedback. There is no apparent change in cortisol precursors.
  • Ectopic ACTH Syndrome: This syndrome occurs when neoplasms (usually lung cancer) produce ACTH without regard to regulatory mechanisms. There is no apparent change in cortisol precursors.
  • Secondary adrenal insufficiency: There will be no significant change in cortisol precursors, because there is no pituitary function to stimulate the production of ACTH.