Metyrapone stimulation tests
- André Lacroix, MD
André Lacroix, MD
- Section Editor — Adrenal Disease
- Professor of Medicine
- University of Montreal, Quebec, Canada
The metyrapone stimulation test is based upon the principle that decreasing serum cortisol concentrations is expected to produce an increase in adrenocorticotropic hormone (ACTH) secretion. The utilization of the metyrapone test has become less frequent as a result of the larger availability of plasma ACTH assays. The limited accessibility to metyrapone in certain countries as well as the limited number of clinical laboratories who have maintained the urinary 17-hydroxycorticosteroid (17-OHCS) and serum 11-deoxycortisol tests have also further limited the use of the metyrapone tests. The insulin tolerance test is the gold-standard to evaluate the integrity of the hypothalamic-pituitary axis, but it requires close surveillance with inherent risks of severe hypoglycemia; it also has specific contraindications in patients with epilepsy and coronary disease and high costs, so other alternative tests have been developed. The metyrapone test is considered to be a sensitive alternative test to evaluate the ACTH reserve and it is a useful clinical test to evaluate the response of the hypothalamic-pituitary-adrenal axis in various pathologies [1-3].
Metyrapone stimulation test protocols and interpretation will be reviewed here. Other tests to evaluate the hypothalamic-pituitary-adrenal axis are discussed separately. (See "Evaluation of the response to ACTH in adrenal insufficiency" and "Insulin-induced hypoglycemia test".)
Metyrapone blocks the conversion of 11-deoxycortisol to cortisol by CYP11B1 (11-beta-hydroxylase, P-450c11), the last step in the synthesis of cortisol, and induces a rapid fall of cortisol and an increase of its immediate precursor 11-deoxycortisol in serum (figure 1 and figure 2).
Because it is essentially devoid of glucocorticoid activity, 11-deoxycortisol does not inhibit adrenocorticotropic hormone (ACTH) secretion. Thus, in healthy individuals, the fall in serum cortisol concentrations leads sequentially to decreased negative feedback at hypothalamic and pituitary levels, which increases corticotropin-releasing hormone (CRH) and ACTH secretion and adrenal steroidogenesis; the resultant secretion of cortisol precursors, in particular, 11-deoxycortisol (the substrate of CYP11B1), can be measured by radioimmunoassay, high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), or fast liquid chromatography-tandem mass spectrometry (LC-MS/MS) in blood or its metabolites in urine .
The increase in serum 11-deoxycortisol concentrations provides an index of the increase in ACTH release; a failure of these values to rise can indicate either ACTH deficiency or primary adrenal disease. Thus, if the metyrapone test is abnormal, the ability of the adrenal gland to respond to exogenous ACTH must be assessed to distinguish between these disorders. (See "Evaluation of the response to ACTH in adrenal insufficiency".)
- Fiad TM, Kirby JM, Cunningham SK, McKenna TJ. The overnight single-dose metyrapone test is a simple and reliable index of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf) 1994; 40:603.
- Berneis K, Staub JJ, Gessler A, et al. Combined stimulation of adrenocorticotropin and compound-S by single dose metyrapone test as an outpatient procedure to assess hypothalamic-pituitary-adrenal function. J Clin Endocrinol Metab 2002; 87:5470.
- Gibney J, Healy ML, Smith TP, McKenna TJ. A simple and cost-effective approach to assessment of pituitary adrenocorticotropin and growth hormone reserve: combined use of the overnight metyrapone test and insulin-like growth factor-I standard deviation scores. J Clin Endocrinol Metab 2008; 93:3763.
- LIDDLE GW, ESTEP HL, KENDALL JW Jr, et al. Clinical application of a new test of pituitary reserve. J Clin Endocrinol Metab 1959; 19:875.
- Jubiz W, Meikle AW, West CD, Tyler FH. Single-dose metyrapone test. Arch Intern Med 1970; 125:472.
- Steiner H, Bähr V, Exner P, Oelkers PW. Pituitary function tests: comparison of ACTH and 11-deoxy-cortisol responses in the metyrapone test and with the insulin hypoglycemia test. Exp Clin Endocrinol 1994; 102:33.
- Staub JJ, Noelpp B, Girard J, et al. The short metyrapone test: comparison of the plasma ACTH response to metyrapone and insulin-induced hypoglycaemia. Clin Endocrinol (Oxf) 1979; 10:595.
- Feek CM, Bevan JS, Ratcliffe JG, et al. The short metyrapone test: comparison of the plasma ACTH response to metyrapone with the cortisol response to insulin-induced hypoglycaemia in patients with pituitary disease. Clin Endocrinol (Oxf) 1981; 15:75.
- Dolman LI, Nolan G, Jubiz W. Metyrapone test with adrenocorticotrophic levels. Separating primary from secondary adrenal insufficiency. JAMA 1979; 241:1251.
- Mahajan DK, Wahlen JD, Tyler FH, West CD. Plasma 11-deoxycortisol radioimmunoassay for metyrapone tests. Steroids 1972; 20:609.
- Endert E, Ouwehand A, Fliers E, et al. Establishment of reference values for endocrine tests. Part IV: Adrenal insufficiency. Neth J Med 2005; 63:435.
- Suliman AM, Smith TP, Labib M, et al. The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Clin Endocrinol (Oxf) 2002; 56:533.
- Zöllner EW, Lombard C, Galal U, et al. Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids--more common than expected? J Pediatr Endocrinol Metab 2011; 24:529.
- Cegla J, Jones B, Seyani L, et al. Comparison of the overnight metyrapone and glucagon stimulation tests in the assessment of secondary hypoadrenalism. Clin Endocrinol (Oxf) 2013; 78:738.
- Jubiz W, Matsukura S, Meikle AW, et al. Plasma metyrapone, adrenocorticotropic hormone, cortisol, and deoxycortisol levels. Sequential changes during oral and intravenous metyrapone administration. Arch Intern Med 1970; 125:468.
- Giordano R, Picu A, Bonelli L, et al. Hypothalamus-pituitary-adrenal axis evaluation in patients with hypothalamo-pituitary disorders: comparison of different provocative tests. Clin Endocrinol (Oxf) 2008; 68:935.
- Dickstein G, Lahav M, Orr ZS. Single-dose metyrapone test at 06.00 h: an accurate method for assessment of pituitary-adrenal reserve. Acta Endocrinol (Copenh) 1986; 112:28.
- Soule S, Van Zyl Smit C, Parolis G, et al. The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism. Clin Endocrinol (Oxf) 2000; 53:221.
- Spiger M, Jubiz W, Meikle AW, et al. Single-dose metyrapone test: review of a four-year experience. Arch Intern Med 1975; 135:698.
- Nolan GE, Smith JB, Chavre VJ, Jubiz W. Spurious overestimation of plasma cortisol in patients with chronic renal failure. J Clin Endocrinol Metab 1981; 52:1242.
- Owen LJ, Halsall DJ, Keevil BG. Cortisol measurement in patients receiving metyrapone therapy. Ann Clin Biochem 2010; 47:573.
- Avgerinos PC, Yanovski JA, Oldfield EH, et al. The metyrapone and dexamethasone suppression tests for the differential diagnosis of the adrenocorticotropin-dependent Cushing syndrome: a comparison. Ann Intern Med 1994; 121:318.
- Malchoff CD, Orth DN, Abboud C, et al. Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone, metyrapone, and corticotropin-releasing factor. Am J Med 1988; 84:760.
- Bertagna C, Orth DN. Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 1981; 71:855.