Version May 2024
INTRODUCTION — The metyrapone stimulation test is based upon the principle that it inhibits conversion of 11-deoxycortisol to cortisol. The resultant decrease in serum cortisol concentrations should be followed by an increase in corticotropin (ACTH) secretion and the immediate precursor of cortisol, 11-deoxycortisol [1]. An inability of the hypothalamic-pituitary-adrenal (HPA) axis to respond appropriately to the decreased glucocorticoid feedback is shown by lower-than-normal increases in 11-deoxycortisiol. Compared with the insulin-induced hypoglycemia test, the metyrapone stimulation test has been considered to be more physiological, with fewer adverse side effects.
During the last 10 years, the availability of metyrapone and measurements of 11-deoxycortisol in blood and urine decreased or stopped in many countries. At the same time, synthetic ACTH and cortisol assays were widely available [2,3]. As a result, the ACTH stimulation test often was used instead of metyrapone.
However, with enhanced availability of metyrapone and more specific techniques to measure serum 11-deoxycortisol, the test may be performed more frequently [2,3]. This topic will focus on the physiological mechanisms that underlie its usefulness as an alternative test to evaluate ACTH secretory reserve, particularly when the insulin-induced hypoglycemia test may be contraindicated or inconvenient [4-6]. Other tests to evaluate the HPA axis are discussed separately. (See "Diagnosis of adrenal insufficiency in adults" and "Insulin-induced hypoglycemia test protocol".)
GENERAL PRINCIPLES — As described above, the metyrapone stimulation test is based upon the principle that decreasing serum cortisol concentrations normally cause an increase in corticotropin-releasing hormone (CRH) secretion from the hypothalamus and corticotropin (ACTH) secretion from the anterior pituitary due to a decrease in glucocorticoid negative feedback. The test is performed primarily to detect partial defects in pituitary ACTH secretion.
11-deoxycortisol, the substrate for CYP11B1, increases due to metyrapone inhibition of the enzyme. Because it is essentially devoid of glucocorticoid activity, it does not inhibit ACTH secretion. Thus, in healthy individuals, the decreased negative feedback after metyrapone increases CRH and ACTH secretion and adrenal steroidogenesis. However, due to the block of CYP11B1, only cortisol precursors are secreted. In particular, serum 11-deoxycortisol concentrations can be measured by immunoassay, high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), or fast liquid chromatography-tandem mass spectrometry (LC-MS/MS). Alternatively, its urinary metabolites may be measured [7].
The increase in serum 11-deoxycortisol concentration provides an index of the increase in ACTH release; a lack of increase can indicate either ACTH deficiency or primary adrenal disease. Thus, if the metyrapone test is abnormal, additional tests are needed to distinguish between these disorders. (See "Diagnosis of adrenal insufficiency in adults".)
PROCEDURE — The metyrapone test is performed as an overnight, single-dose test based on blood levels of 11-deoxycortisol. It should not be used in a patient who is taking supraphysiologic doses of glucocorticoid. Metyrapone is currently available through its distributor HRA Pharma (Paris, France) in many countries worldwide. In the United States, it can be obtained via its specialty pharmacy (https://metopirone.com/home-hcp/accessing-metopirone [phone 1-800-320-2112]).
Metyrapone administration may result in hypotension, nausea, and vomiting in patients with adrenal insufficiency; as a result, it should not be utilized in patients suspected of having severe adrenal insufficiency. (See 'Metyrapone side effects' below.)
Overnight, single-dose metyrapone test — This test is safe for outpatient use [4-6,8-10]. Metyrapone is taken orally (30 mg/kg body weight, or 2 grams for <70 kg, 2.5 grams for 70 to 90 kg, and 3 grams for >90 kg body weight) at midnight with a glass of milk or a small snack [11]. Serum 11-deoxycortisol and cortisol are measured between 7:30 and 9:30 AM the next morning; plasma corticotropin (ACTH) can also be measured [1,4,8-12].
Some cortisol immunoassays have significant cross-reactivity with 11-deoxycortisol and may lead to a spuriously high cortisol result. To avoid this problem, specific cortisol immunoassays or tandem mass spectrometry (which does not cross-react with 11-deoxycortisol) should be used [13]. Note that these specific serum 11-deoxycortisol assays are typically only available in reference laboratories, and it can take up to a week to get the results. Other dosing regimens have been used [2].
A normal response to the overnight, single-dose test consists of:
●A morning (7:30 to 9:30 AM) serum 11-deoxycortisol concentration of 7 to 22 mcg/dL (200 to 635 nmol/L) [4,6,8,11,14].
●A simultaneous serum cortisol concentration of less than 5 mcg/dL (138 nmol/L); this confirms adequate metyrapone blockade and thereby documents compliance and normal metabolism of metyrapone.
Metyrapone side effects — By reducing cortisol production more dramatically in patients with adrenal insufficiency than in healthy people, metyrapone can result in symptoms of adrenal insufficiency, such as hypotension, nausea, vomiting, abdominal discomfort or cramping, and muscle and joint pain in these patients. Metyrapone also can cause dizziness, sedation, allergic rash, or, rarely, decreased white blood cell count or bone marrow suppression. In one study, hydrocortisone 10 mg was administered once samples were collected, before discharging the patient [2]. This may be helpful in patients in whom severe adrenal insufficiency is suspected, or in patients with adverse reactions suggestive of adrenal insufficiency. However, studies that have not used this approach do not report a higher incidence of adverse outcomes.
INTERPRETATION — The metyrapone test is a sensitive test of pituitary corticotropin (ACTH) secretory reserve; it was more sensitive than insulin tolerance test in certain studies [6] or slightly less in other studies [15]. This difference depends upon the degree of pituitary ACTH increase in response to negative feedback inhibition by cortisol; hypocortisolemia is a less potent stimulus of ACTH release than hypoglycemia or other stresses. Thus, a patient with partial hypopituitarism may maintain normal daily ACTH and cortisol secretion and respond to insulin-induced hypoglycemia with an appropriate increase in ACTH and cortisol secretion, yet be unable to increase ACTH secretion appropriately when cortisol biosynthesis is blocked by metyrapone [8]. Conversely, a patient who responds normally to metyrapone almost always responds normally to hypoglycemia or other stresses.
Normal response — When used to diagnose hypoadrenalism, a normal response to the metyrapone tests indicates an intact hypothalamic-pituitary-adrenal (HPA) axis; such a patient does not have any form of adrenal insufficiency and requires no further investigation. An abnormal test could reflect either primary or secondary adrenal insufficiency. Distinction between the two can be determined by finding a high basal or metyrapone-stimulated plasma ACTH concentration, which would indicate primary adrenal insufficiency [4,5,16].
Partial defects in ACTH secretion — The metyrapone test is a sensitive method to detect partial defects in pituitary corticotropin (ACTH) secretion [4-6,17]. Thus, morning basal plasma ACTH and serum cortisol concentrations, basal urinary excretion of cortisol, and the responses to insulin-induced hypoglycemia and both the 1 and 250 mcg ACTH stimulation tests may all be normal, but the metyrapone test may be subnormal [10,18]. An example would be a patient with a suspected pituitary mass who has no clinical manifestations of ACTH deficiency, an intermediate 8 AM serum cortisol concentration, but an abnormal metyrapone test. (See "Diagnostic testing for hypopituitarism" and "Diagnosis of adrenal insufficiency in adults".)
Serum 11-deoxycortisol concentrations less than 7 mcg/dL (202 nmol/L) with concomitantly suppressed cortisol values indicate adrenal insufficiency.
However, in one study, the sum of 11-deoxycortisol and of cortisol >15 mcg/dL (450 nmol/L) following a single-dose, overnight metyrapone test yielded better diagnostic accuracy than using 11-deoxycortisol levels alone [5]. In a study of 31 patients with various HPA axis abnormalities comparing insulin tolerance test with overnight metyrapone test, a cutoff of 144 nmol/L (5 mcg/dL) for 11-deoxycortisol yielded the highest sensitivity of 82.4 percent to detect patients responding normally to insulin tolerance test, but only 64.3 percent of those with subnormal response to insulin tolerance test [15].
In the evaluation of mild secondary adrenal insufficiency after pituitary surgery, it is best to wait for six weeks to perform the overnight metyrapone test. In one study, 37 percent of patients with an abnormal test on day 6 after metyrapone subsequently had a normal response [19].
In a study examining potential secondary adrenal insufficiency in 40 opioid users with non-cancer pain, 22 percent were found to have adrenal insufficiency using 250 mcg ACTH 1-24 test and the overnight metyrapone test, but the tests were concordant in only half. The small number of patients and the lack of comparison with insulin-induced hypoglycemia limit the ability to determine which test is superior [20].
In 21 subjects with Prader-Willi syndrome evaluated for possible central adrenal insufficiency, six (29 percent) had peak cortisol <15.5 mcg/dL (428 nmol/L) after injection of 1 mcg ACTH 1-24, but normal overnight metyrapone 11-deoxycortisol results in 20 of 21 subjects. The lack of clinical symptoms of adrenal insufficiency suggested that the overnight metyrapone test was more reliable in this condition [21].
Primary versus secondary adrenal insufficiency — Theoretically, the ACTH response to metyrapone may distinguish between primary and secondary insufficiency, but it is neither used nor recommended for this purpose. In general, patients with partial secondary adrenal insufficiency have ACTH responses from 10 to 200 pg/mL (2 to 44 pmol/L), while patients with primary adrenal insufficiency have higher responses [4,5,16]. However, healthy individuals have an ACTH response of 42 to 690 pg/mL (9 to 210 pmol/L) [22]. Because of this overlap, the ACTH response alone cannot be used to distinguish between healthy individuals and those with adrenal insufficiency. As noted, the modern, high-sensitivity immunometric ACTH assay has rendered the metyrapone test unnecessary in most patients for differentiating primary and secondary adrenal insufficiency. (See "Determining the etiology of adrenal insufficiency in adults", section on 'Establish the level of defect'.)
False-negative results — The increase in serum 11-deoxycortisol concentrations may be exaggerated in some individuals, including those with hypothyroidism, hypoglycemia, diabetes mellitus, congestive heart failure, obesity, and chronic renal failure [23,24]. As a result, findings in such individuals may falsely be considered normal.
False-positive results — There are settings in which false-positive results can be obtained:
●Unappreciated recent exposure to supraphysiologic doses of synthetic glucocorticoids by any route can result in a subnormal response as a result of suppression of the corticotropes.
●One of the more common causes of a false-positive result is unusually rapid clearance of metyrapone from the plasma, which occurs in approximately 4 percent of healthy individuals [23,25]. This results in inadequate blockade of cortisol biosynthesis and an 8 AM serum cortisol concentration of greater than 7.5 mcg/dL (210 nmol/L). Metyrapone is metabolized by hepatic cytochrome P450 enzymes that are induced by many of the same drugs that increase steroid metabolism (eg, phenobarbital, phenytoin, rifampin, mitotane). Therefore, these drugs should be stopped well before the metyrapone test is performed.
●Cortisol levels measured by conventional immunoassays can theoretically be falsely elevated by the interference of increased 11-deoxycortisol levels induced by metyrapone. Since the cross-reactivity of 11-deoxycortisol in the typical cortisol immunoassay is <5 percent and often <2 percent [2], this is usually a minor issue in most patients. Furthermore, the wider availability of liquid chromatography-tandem mass spectrometry (LC-MS/MS) steroid assays eliminates this concern [26]. However, obtaining a serum cortisol concentration by LC-MS/MS may require a special request to the local clinical laboratory; most laboratories routinely use a platform immunoassay.
Postoperative assessment of patients with Cushing disease — Recurrence of Cushing disease after pituitary surgery is common, and early identification of relapse is important [27]. It has been suggested that an increase in 11-deoxycortisol to greater than 5.2 mcg/dL (150 nmol/L) with a metyrapone test administered 14 days after pituitary surgery is predictive of relapse [28]. However, other approaches are likely to be more useful. (See "Primary therapy of Cushing disease: Transsphenoidal surgery and pituitary irradiation", section on 'Biochemical criteria'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Adrenal insufficiency".)
SUMMARY
●General principles of test – Metyrapone blocks the conversion of 11-deoxycortisol to cortisol by CYP11B1 (11-beta-hydroxylase, P450c11), the last step in the synthesis of cortisol, and induces a rapid fall of cortisol (figure 1). (See 'General principles' above.)
The metyrapone stimulation test is based upon the principle that decreasing serum cortisol concentrations normally produce an increase in corticotropin-releasing hormone (CRH) and corticotropin (ACTH) secretion due to a decrease in glucocorticoid negative feedback.
●Indications for test – The test is performed primarily to detect partial defects in pituitary ACTH secretion and may be more physiological and less dangerous than insulin-induced hypoglycemia. In many countries, the metyrapone stimulation test has been used infrequently during the last 10 years, but this may change with the improved availability of metyrapone and a more specific measurement of serum 11-deoxycortisol performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). (See 'Introduction' above.)
●Normal response – In healthy individuals, the decrease in serum cortisol concentrations leads sequentially to increases in ACTH secretion, adrenal steroidogenesis, and the secretion of cortisol precursors; in particular, 11-deoxycortisol, which can be measured by immunoassay, high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), or LC-MS/MS. (See 'Interpretation' above.)
●Interpretation – The increase in serum 11-deoxycortisol concentrations provides an index of the increase in ACTH release; a lack of increase in 11-deoxycortisol can indicate either ACTH deficiency or primary adrenal disease. Distinction between the two can be determined by finding a high basal or stimulated plasma ACTH concentration, which would indicate primary adrenal insufficiency. (See 'Primary versus secondary adrenal insufficiency' above.)
ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
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