Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Diagnosis of adrenal insufficiency in adults

Lynnette K Nieman, MD
Section Editor
André Lacroix, MD
Deputy Editor
Kathryn A Martin, MD


The clinical presentation of adrenal insufficiency is variable, depending on whether the onset is acute, leading to adrenal crisis, or chronic, with symptoms that are more insidious and vague. Therefore, the diagnosis of adrenal insufficiency depends upon a critical level of clinical suspicion. Adrenal crisis should be considered in any patient who presents with peripheral vascular collapse (vasodilatory shock), whether or not the patient is known to have adrenal insufficiency. Likewise, isolated corticotropin (ACTH) deficiency, although rare, should be considered in any patient who has unexplained severe hypoglycemia or hyponatremia. (See "Clinical manifestations of adrenal insufficiency in adults".)


Exogenous glucocorticoids — Prolonged administration of pharmacologic doses of synthetic glucocorticoids is by far the most common cause of corticotropin (ACTH) deficiency and consequent adrenal insufficiency. (See "Causes of primary adrenal insufficiency (Addison's disease)" and "Causes of secondary and tertiary adrenal insufficiency in adults".)

However, patients treated with glucocorticoid therapy rarely present with adrenal crisis, although sudden withdrawal of glucocorticoids can result in exacerbation of the disorder for which they were being given (eg, asthma, inflammatory disease, or organ transplantation), symptoms of glucocorticoid deficiency, or hypotension. (See "Clinical manifestations of adrenal insufficiency in adults".)

The principles involved in weaning patients from chronic high-dose glucocorticoid therapy are discussed elsewhere. (See "Glucocorticoid withdrawal".)

Critical illness — Subnormal corticosteroid production during critical illness in the absence of structural defects in the hypothalamic-pituitary-adrenal axis has been termed "functional adrenal insufficiency" or "relative adrenal insufficiency." There is currently no consensus on the diagnostic criteria for this entity. A detailed discussion of this issue is found separately. (See "Glucocorticoid therapy in septic shock".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: May 31, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Barnett AH, Espiner EA, Donald RA. Patients presenting with Addison's disease need not be pigmented. Postgrad Med J 1982; 58:690.
  2. Merenich JA, Hannon RN, Gentry RH, Harrison SM. Azidothymidine-induced hyperpigmentation mimicking primary adrenal insufficiency. Am J Med 1989; 86:469.
  3. Samuels MH. Effects of variations in physiological cortisol levels on thyrotropin secretion in subjects with adrenal insufficiency: a clinical research center study. J Clin Endocrinol Metab 2000; 85:1388.
  4. Bleicken B, Hahner S, Ventz M, Quinkler M. Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients. Am J Med Sci 2010; 339:525.
  5. Oelkers W. Adrenal insufficiency. N Engl J Med 1996; 335:1206.
  6. Saenger P, Levine LS, Irvine WJ, et al. Progressive adrenal failure in polyglandular autoimmune disease. J Clin Endocrinol Metab 1982; 54:863.
  7. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002; 23:327.
  8. De Bellis A, Bizzarro A, Rossi R, et al. Remission of subclinical adrenocortical failure in subjects with adrenal autoantibodies. J Clin Endocrinol Metab 1993; 76:1002.
  9. Galbois A, Rudler M, Massard J, et al. Assessment of adrenal function in cirrhotic patients: salivary cortisol should be preferred. J Hepatol 2010; 52:839.
  10. Tan T, Chang L, Woodward A, et al. Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease. J Hepatol 2010; 53:841.
  11. Klose M, Lange M, Rasmussen AK, et al. Factors influencing the adrenocorticotropin test: role of contemporary cortisol assays, body composition, and oral contraceptive agents. J Clin Endocrinol Metab 2007; 92:1326.
  12. Hägg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency. Clin Endocrinol (Oxf) 1987; 26:221.
  13. JENKINS D, FORSHAM PH, LAIDLAW JC, et al. Use of ACTH in the diagnosis of adrenal cortical insufficiency. Am J Med 1955; 18:3.
  14. Deutschbein T, Unger N, Mann K, Petersenn S. Diagnosis of secondary adrenal insufficiency: unstimulated early morning cortisol in saliva and serum in comparison with the insulin tolerance test. Horm Metab Res 2009; 41:834.
  15. Finucane FM, Liew A, Thornton E, et al. Clinical insights into the safety and utility of the insulin tolerance test (ITT) in the assessment of the hypothalamo-pituitary-adrenal axis. Clin Endocrinol (Oxf) 2008; 69:603.
  16. Erturk E, Jaffe CA, Barkan AL. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab 1998; 83:2350.
  17. Watts NB, Tindall GT. Rapid assessment of corticotropin reserve after pituitary surgery. JAMA 1988; 259:708.
  18. Schmidt IL, Lahner H, Mann K, Petersenn S. Diagnosis of adrenal insufficiency: Evaluation of the corticotropin-releasing hormone test and Basal serum cortisol in comparison to the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease. J Clin Endocrinol Metab 2003; 88:4193.
  19. Le Roux CW, Meeran K, Alaghband-Zadeh J. Is a 0900-h serum cortisol useful prior to a short synacthen test in outpatient assessment? Ann Clin Biochem 2002; 39:148.
  20. Streeten DH, Anderson GH Jr, Bonaventura MM. The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test. J Clin Endocrinol Metab 1996; 81:285.
  21. Udelsman R, Ramp J, Gallucci WT, et al. Adaptation during surgical stress. A reevaluation of the role of glucocorticoids. J Clin Invest 1986; 77:1377.
  22. Levy A. Perioperative steroid cover. Lancet 1996; 347:846.
  23. Glowniak JV, Loriaux DL. A double-blind study of perioperative steroid requirements in secondary adrenal insufficiency. Surgery 1997; 121:123.
  24. Veldhuis JD, Iranmanesh A, Johnson ML, Lizarralde G. Amplitude, but not frequency, modulation of adrenocorticotropin secretory bursts gives rise to the nyctohemeral rhythm of the corticotropic axis in man. J Clin Endocrinol Metab 1990; 71:452.
  25. Park YJ, Park KS, Kim JH, et al. Reproducibility of the cortisol response to stimulation with the low dose (1 microg) of ACTH. Clin Endocrinol (Oxf) 1999; 51:153.
  26. Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991; 72:773.
  27. Wade M, Baid S, Calis K, et al. Technical details influence the diagnostic accuracy of the 1 microg ACTH stimulation test. Eur J Endocrinol 2010; 162:109.
  28. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101:364.
  29. Crowley S, Hindmarsh PC, Honour JW, Brook CG. Reproducibility of the cortisol response to stimulation with a low dose of ACTH(1-24): the effect of basal cortisol levels and comparison of low-dose with high-dose secretory dynamics. J Endocrinol 1993; 136:167.
  30. May ME, Carey RM. Rapid adrenocorticotropic hormone test in practice. Retrospective review. Am J Med 1985; 79:679.
  31. Thaler LM, Blevins LS Jr. The low dose (1-microg) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 1998; 83:2726.
  32. Oelkers W, Diederich S, Bähr V. Diagnosis and therapy surveillance in Addison's disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone. J Clin Endocrinol Metab 1992; 75:259.
  33. Rasmuson S, Olsson T, Hagg E. A low dose ACTH test to assess the function of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf) 1996; 44:151.
  34. Hurel SJ, Thompson CJ, Watson MJ, et al. The short Synacthen and insulin stress tests in the assessment of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf) 1996; 44:141.
  35. Tordjman K, Jaffe A, Grazas N, et al. The role of the low dose (1 microgram) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 1995; 80:1301.
  36. Broide J, Soferman R, Kivity S, et al. Low-dose adrenocorticotropin test reveals impaired adrenal function in patients taking inhaled corticosteroids. J Clin Endocrinol Metab 1995; 80:1243.
  37. Cunningham SK, Moore A, McKenna TJ. Normal cortisol response to corticotropin in patients with secondary adrenal failure. Arch Intern Med 1983; 143:2276.
  38. Lindholm J, Kehlet H. Re-evaluation of the clinical value of the 30 min ACTH test in assessing the hypothalamic-pituitary-adrenocortical function. Clin Endocrinol (Oxf) 1987; 26:53.
  39. Agha A, Tomlinson JW, Clark PM, et al. The long-term predictive accuracy of the short synacthen (corticotropin) stimulation test for assessment of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab 2006; 91:43.
  40. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med 2003; 139:194.
  41. Fleseriu M, Gassner M, Yedinak C, et al. Normal hypothalamic-pituitary-adrenal axis by high-dose cosyntropin testing in patients with abnormal response to low-dose cosyntropin stimulation: a retrospective review. Endocr Pract 2010; 16:64.
  42. Mayenknecht J, Diederich S, Bähr V, et al. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 1998; 83:1558.
  43. Abdu TA, Elhadd TA, Neary R, Clayton RN. Comparison of the low dose short synacthen test (1 microg), the conventional dose short synacthen test (250 microg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab 1999; 84:838.
  44. Dökmetaş HS, Colak R, Keleştimur F, et al. A comparison between the 1-microg adrenocorticotropin (ACTH) test, the short ACTH (250 microg) test, and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery. J Clin Endocrinol Metab 2000; 85:3713.
  45. Spiger M, Jubiz W, Meikle AW, et al. Single-dose metyrapone test: review of a four-year experience. Arch Intern Med 1975; 135:698.
  46. 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.
  47. 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.
  48. 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.
  49. Taylor AL, Fishman LM. Corticotropin-releasing hormone. N Engl J Med 1988; 319:213.
  50. Schulte HM, Chrousos GP, Avgerinos P, et al. The corticotropin-releasing hormone stimulation test: a possible aid in the evaluation of patients with adrenal insufficiency. J Clin Endocrinol Metab 1984; 58:1064.
  51. Schlaghecke R, Kornely E, Santen RT, Ridderskamp P. The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone. N Engl J Med 1992; 326:226.
  52. Alaioubi B, Mann K, Petersenn S. Diagnosis of adrenal insufficiency using the GHRP-6 Test: comparison with the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease. Horm Metab Res 2010; 42:198.
  53. Berg C, Meinel T, Lahner H, et al. Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery. Eur J Endocrinol 2010; 162:477.
  54. Streeten DH. What test for hypothalamic-pituitary-adrenocortical insufficiency? Lancet 1999; 354:179.
  55. Vita JA, Silverberg SJ, Goland RS, et al. Clinical clues to the cause of Addison's disease. Am J Med 1985; 78:461.
  56. Hsu CW, Ho CL, Sheu WH, et al. Adrenal insufficiency caused by primary aggressive non-Hodgkin's lymphoma of bilateral adrenal glands: report of a case and literature review. Ann Hematol 1999; 78:151.
  57. Sun ZH, Nomura K, Toraya S, et al. Clinical significance of adrenal computed tomography in Addison's disease. Endocrinol Jpn 1992; 39:563.
  58. Espinosa G, Santos E, Cervera R, et al. Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients. Medicine (Baltimore) 2003; 82:106.
  59. Leal AM, Bellucci AD, Muglia VF, Lucchesi FR. Unique adrenal gland imaging features in Addison's disease caused by paracoccidioidomycosis. AJR Am J Roentgenol 2003; 181:1433.
  60. Kawashima A, Sandler CM, Ernst RD, et al. Imaging of nontraumatic hemorrhage of the adrenal gland. Radiographics 1999; 19:949.
  61. Presotto F, Fornasini F, Betterle C, et al. Acute adrenal failure as the heralding symptom of primary antiphospholipid syndrome: report of a case and review of the literature. Eur J Endocrinol 2005; 153:507.
  62. Guttman PH. Addison's disease. A statistical analysis of five hundred and sixty-six cases and a study of the pathology. Arch Pathol 1930; 10:742.
  63. Pagani JJ. Non-small cell lung carcinoma adrenal metastases. Computed tomography and percutaneous needle biopsy in their diagnosis. Cancer 1984; 53:1058.
  64. Walker BF, Gunthel CJ, Bryan JA, et al. Disseminated cryptococcosis in an apparently normal host presenting as primary adrenal insufficiency: diagnosis by fine needle aspiration. Am J Med 1989; 86:715.
  65. Laureti S, Aubourg P, Calcinaro F, et al. Etiological diagnosis of primary adrenal insufficiency using an original flowchart of immune and biochemical markers. J Clin Endocrinol Metab 1998; 83:3163.
  66. Falorni A, Laureti S, De Bellis A, et al. Italian addison network study: update of diagnostic criteria for the etiological classification of primary adrenal insufficiency. J Clin Endocrinol Metab 2004; 89:1598.