Dexamethasone suppression tests
- André Lacroix, MD
André Lacroix, MD
- Section Editor — Adrenal Disease
- Professor of Medicine
- University of Montreal, Quebec, Canada
Dexamethasone suppression tests are used to assess the status of the hypothalamic-pituitary-adrenal (HPA) axis and for the differential diagnosis of adrenal hyperfunction. The low-dose dexamethasone suppression tests are used to assess nonsuppressible cortisol production by adrenal incidentalomas and to differentiate patients with Cushing's syndrome of any cause from patients who do not have Cushing's syndrome. The high-dose dexamethasone suppression tests help to distinguish patients with Cushing's disease (Cushing's syndrome caused by pituitary hypersecretion of corticotropin [ACTH]) from most patients with the ectopic ACTH syndrome (Cushing's syndrome caused by nonpituitary ACTH-secreting tumors).
This topic will review the basic principles of the dexamethasone suppression tests. Additional information on their role in determining the diagnosis and the cause of subclinical and clinical Cushing's syndrome is discussed separately. (See "The adrenal incidentaloma" and "Establishing the diagnosis of Cushing's syndrome" and "Establishing the cause of Cushing's syndrome".)
DEXAMETHASONE SUPPRESSION TESTS
The dexamethasone suppression tests assess the pituitary corticotroph cell response to glucocorticoid negative feedback inhibition of corticotropin (ACTH) secretion. Dexamethasone is a potent glucocorticoid, about 30 to 40 times more potent than cortisol. Thus, the average daily maintenance dose of dexamethasone for a patient with adrenal insufficiency is 0.5 mg, versus 20 mg for hydrocortisone.
Dexamethasone and steroid measurements — Measurements of serum, salivary, and urinary cortisol by current assays are unaffected by the presence of dexamethasone. Antibodies used in current cortisol immunoassays are directed toward the D ring of the molecule and react very poorly with dexamethasone, which has a 16-alpha-methyl modification of the D ring. Structurally-based assays such as mass spectrometry or high pressure liquid chromatography fully discriminate the two steroids.
Low-dose dexamethasone suppression tests — The binding of dexamethasone to glucocorticoid receptors in hypothalamic paraventricular nuclei and in pituitary corticotroph cells inhibits corticotropin-releasing hormone (CRH) and ACTH secretion. In humans, dexamethasone has no inhibitory effect on steroid production when exogenous ACTH is infused .
- Tuck ML, Sowers JR, Asp ND, et al. Mineralocorticoid response to low dose adrenocorticotropin infusion. J Clin Endocrinol Metab 1981; 52:440.
- Cronin C, Igoe D, Duffy MJ, et al. The overnight dexamethasone test is a worthwhile screening procedure. Clin Endocrinol (Oxf) 1990; 33:27.
- Montwill J, Igoe D, McKenna TJ. The overnight dexamethasone test is the procedure of choice in screening for Cushing's syndrome. Steroids 1994; 59:296.
- Hindmarsh PC, Brook CG. Single dose dexamethasone suppression test in children: dose relationship to body size. Clin Endocrinol (Oxf) 1985; 23:67.
- Pasquali R, Ambrosi B, Armanini D, et al. Cortisol and ACTH response to oral dexamethasone in obesity and effects of sex, body fat distribution, and dexamethasone concentrations: a dose-response study. J Clin Endocrinol Metab 2002; 87:166.
- Sahin M, Kebapcilar L, Taslipinar A, et al. Comparison of 1 mg and 2 mg overnight dexamethasone suppression tests for the screening of Cushing's syndrome in obese patients. Intern Med 2009; 48:33.
- Meikle AW, Lagerquist LG, Tyler FH. Apparently normal pituitary-adrenal suppressibility in Cushing's syndrome: dexamethasone metabolism and plasma levels. J Lab Clin Med 1975; 86:472.
- Blethen SL, Chasalow FI. Overnight dexamethasone suppression test: normal responses and the diagnosis of Cushing's syndrome. Steroids 1989; 54:185.
- Wood PJ, Barth JH, Freedman DB, et al. Evidence for the low dose dexamethasone suppression test to screen for Cushing's syndrome--recommendations for a protocol for biochemistry laboratories. Ann Clin Biochem 1997; 34 ( Pt 3):222.
- Invitti C, Pecori Giraldi F, de Martin M, Cavagnini F. Diagnosis and management of Cushing's syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis. J Clin Endocrinol Metab 1999; 84:440.
- Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93:1526.
- Ceccato F, Barbot M, Zilio M, et al. Screening Tests for Cushing's Syndrome: Urinary Free Cortisol Role Measured by LC-MS/MS. J Clin Endocrinol Metab 2015; 100:3856.
- Findling JW, Raff H, Aron DC. The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing's syndrome. J Clin Endocrinol Metab 2004; 89:1222.
- Görges R, Knappe G, Gerl H, et al. Diagnosis of Cushing's syndrome: re-evaluation of midnight plasma cortisol vs urinary free cortisol and low-dose dexamethasone suppression test in a large patient group. J Endocrinol Invest 1999; 22:241.
- Oki Y, Hashimoto K, Hirata Y, et al. Development and validation of a 0.5 mg dexamethasone suppression test as an initial screening test for the diagnosis of ACTH-dependent Cushing's syndrome. Endocr J 2009; 56:897.
- Barrou Z, Guiban D, Maroufi A, et al. Overnight dexamethasone suppression test: comparison of plasma and salivary cortisol measurement for the screening of Cushing's syndrome. Eur J Endocrinol 1996; 134:93.
- Moro M, Putignano P, Losa M, et al. The desmopressin test in the differential diagnosis between Cushing's disease and pseudo-Cushing states. J Clin Endocrinol Metab 2000; 85:3569.
- Laudat MH, Cerdas S, Fournier C, et al. Salivary cortisol measurement: a practical approach to assess pituitary-adrenal function. J Clin Endocrinol Metab 1988; 66:343.
- Castro M, Elias PC, Quidute AR, et al. Out-patient screening for Cushing's syndrome: the sensitivity of the combination of circadian rhythm and overnight dexamethasone suppression salivary cortisol tests. J Clin Endocrinol Metab 1999; 84:878.
- Raff H, Homar PJ, Burns EA. Comparison of two methods for measuring salivary cortisol. Clin Chem 2002; 48:207.
- Streeten DH, Stevenson CT, Dalakos TG, et al. The diagnosis of hypercortisolism. Biochemical criteria differentiating patients from lean and obese normal subjects and from females on oral contraceptives. J Clin Endocrinol Metab 1969; 29:1191.
- Isidori AM, Kaltsas GA, Mohammed S, et al. Discriminatory value of the low-dose dexamethasone suppression test in establishing the diagnosis and differential diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 2003; 88:5299.
- Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA 1993; 269:2232.
- Newell-Price J, Trainer P, Perry L, et al. A single sleeping midnight cortisol has 100% sensitivity for the diagnosis of Cushing's syndrome. Clin Endocrinol (Oxf) 1995; 43:545.
- Kennedy L, Atkinson AB, Johnston H, et al. Serum cortisol concentrations during low dose dexamethasone suppression test to screen for Cushing's syndrome. Br Med J (Clin Res Ed) 1984; 289:1188.
- Elamin MB, Murad MH, Mullan R, et al. Accuracy of diagnostic tests for Cushing's syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab 2008; 93:1553.
- Meikle AW. Dexamethasone suppression tests: usefulness of simultaneous measurement of plasma cortisol and dexamethasone. Clin Endocrinol (Oxf) 1982; 16:401.
- LIDDLE GW. Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab 1960; 20:1539.
- Liddle GW. The adrenals. In: Textbook of Endocrinology, Williams RW (Ed), WB Saunders, Philadelphia 1981. p.242.
- Bruno OD, Rossi MA, Contreras LN, et al. Nocturnal high-dose dexamethasone suppression test in the aetiological diagnosis of Cushing's syndrome. Acta Endocrinol (Copenh) 1985; 109:158.
- Dichek HL, Nieman LK, Oldfield EH, et al. A comparison of the standard high dose dexamethasone suppression test and the overnight 8-mg dexamethasone suppression test for the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab 1994; 78:418.
- Tyrrell JB, Findling JW, Aron DC, et al. An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing's syndrome. Ann Intern Med 1986; 104:180.
- Aron DC, Raff H, Findling JW. Effectiveness versus efficacy: the limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab 1997; 82:1780.
- Flack MR, Oldfield EH, Cutler GB Jr, et al. Urine free cortisol in the high-dose dexamethasone suppression test for the differential diagnosis of the Cushing syndrome. Ann Intern Med 1992; 116:211.
- Orth DN. Ectopic hormone production. In: Endocrinology and Metabolism, Felig P, Baxter JD, Broadus AE, Frohman LA (Eds), McGraw-Hill, New York 1987. p.1692-1735.
- de Keyzer Y, Lenne F, Auzan C, et al. The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome. J Clin Invest 1996; 97:1311.
- Wajchenberg BL, Mendonca BB, Liberman B, et al. Ectopic adrenocorticotropic hormone syndrome. Endocr Rev 1994; 15:752.
- Abou Samra AB, Dechaud H, Estour B, et al. Beta-lipotropin and cortisol responses to an intravenous infusion dexamethasone suppression test in Cushing's syndrome and obesity. J Clin Endocrinol Metab 1985; 61:116.
- Jung C, Alford FP, Topliss DJ, et al. The 4-mg intravenous dexamethasone suppression test in the diagnosis of Cushing's syndrome. Clin Endocrinol (Oxf) 2010; 73:78.
- Croughs RJ, Docter R, de Jong FH. Comparison of oral and intravenous dexamethasone suppression tests in the differential diagnosis of Cushing's syndrome. Acta Endocrinol (Copenh) 1973; 72:54.
- Biemond P, de Jong FH, Lamberts SW. Continuous dexamethasone infusion for seven hours in patients with the Cushing syndrome. A superior differential diagnostic test. Ann Intern Med 1990; 112:738.
- Atkinson AB, McAteer EJ, Hadden DR, et al. A weight-related intravenous dexamethasone suppression test distinguishes obese controls from patients with Cushing's syndrome. Acta Endocrinol (Copenh) 1989; 120:753.
- Bailey RE. Periodic hormonogenesis--a new phenomenon. Periodicity in function of a hormone-producing tumor in man. J Clin Endocrinol Metab 1971; 32:317.
- Brown RD, Van Loon GR, Orth DN, Liddle GW. Cushing's disease with periodic hormonogenesis: one explanation for paradoxical response to dexamethasone. J Clin Endocrinol Metab 1973; 36:445.
- Scott RS, Espiner EA, Donald RA. Intermittent Cushing's disease with spontaneous remission. Clin Endocrinol (Oxf) 1979; 11:561.
- Hermus AR, Pieters GF, Borm GF, et al. Unpredictable hypersecretion of cortisol in Cushing's disease: detection by daily salivary cortisol measurements. Acta Endocrinol (Copenh) 1993; 128:428.
- Manenschijn L, Koper JW, van den Akker EL, et al. A novel tool in the diagnosis and follow-up of (cyclic) Cushing's syndrome: measurement of long-term cortisol in scalp hair. J Clin Endocrinol Metab 2012; 97:E1836.
- Dimaraki EV, Jaffe CA. Troglitazone induces CYP3A4 activity leading to falsely abnormal dexamethasone suppression test. J Clin Endocrinol Metab 2003; 88:3113.
- Ma RC, Chan WB, So WY, et al. Carbamazepine and false positive dexamethasone suppression tests for Cushing's syndrome. BMJ 2005; 330:299.
- Manenschijn L, van den Akker EL, Lamberts SW, van Rossum EF. Clinical features associated with glucocorticoid receptor polymorphisms. An overview. Ann N Y Acad Sci 2009; 1179:179.
- Selvais P, Donckier J, Buysschaert M, Maiter D. Cushing's disease: a comparison of pituitary corticotroph microadenomas and macroadenomas. Eur J Endocrinol 1998; 138:153.
- Woo YS, Isidori AM, Wat WZ, et al. Clinical and biochemical characteristics of adrenocorticotropin-secreting macroadenomas. J Clin Endocrinol Metab 2005; 90:4963.
- Katznelson L, Bogan JS, Trob JR, et al. Biochemical assessment of Cushing's disease in patients with corticotroph macroadenomas. J Clin Endocrinol Metab 1998; 83:1619.
- al-Saadi N, Diederich S, Oelkers W. A very high dose dexamethasone suppression test for differential diagnosis of Cushing's syndrome. Clin Endocrinol (Oxf) 1998; 48:45.
- Stratakis CA, Sarlis N, Kirschner LS, et al. Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med 1999; 131:585.
- Fehm HL, Voight KH, Lang RE, et al. Paradoxical ACTH response to glucocorticoids in Cushing's disease. N Engl J Med 1977; 297:904.
- DEXAMETHASONE SUPPRESSION TESTS
- Dexamethasone and steroid measurements
- Low-dose dexamethasone suppression tests
- - Overnight screening test
- - Two-day, low-dose test
- - Diagnostic accuracy of low-dose dexamethasone tests
- Serum dexamethasone
- High-dose dexamethasone suppression tests
- - Overnight 8 mg test
- - Two-day, high-dose test
- Intravenous dexamethasone suppression tests
- SOURCES OF ERROR
- Unusual responses
- Paradoxical responses to dexamethasone
- SUMMARY AND RECOMMENDATIONS