The metyrapone stimulation test is based upon the principle that decreasing serum cortisol concentrations is expected to produce an increase in corticotropin (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 research tool 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 11-deoxycortisol in serum (figure 1 and figure 2).
Because it is essentially devoid of glucocorticoid activity, 11-deoxycortisol does not inhibit corticotropin (ACTH) secretion. Thus, in healthy individuals, the fall in serum cortisol concentrations leads sequentially to increases in ACTH secretion, adrenal steroidogenesis, and the secretion of cortisol precursors, in particular, 11-deoxycortisol, the substrate of CYP11B1, which can be measured by radioimmunoassay, high-performance liquid chromatography (HPLC), or in urine as a 17-hydroxycorticosteroid (17-OHCS) .
The increase in serum 11-deoxycortisol concentrations or in urinary 17-OHCS excretion 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".)