Adrenal Insufficiency

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Symptoms consistent with adrenal insufficiency (eg, hypotension, weakness)
  • Presence of disease process associated with adrenal insufficiency

Laboratory Testing

  • Initial testing
    • Measure early morning serum cortisol
      • Cortisol ≥5 µg/dL makes primary adrenal insufficiency less likely
        • If serious consideration is given to this diagnosis, perform stimulation testing
    • Follow abnormal cortisol results with adrenocorticotropic hormone (ACTH) testing
      • If ACTH >300 pg/dL – adrenal failure likely
      • If ACTH <10 pg/dL – pituitary failure likely
      • If ACTH between 10 pg/dL and 300 pg/dL – administer ACTH (cosyntropin) stimulation test
  • Testing based on ACTH result
    • ACTH stimulation test (cosyntropin)
      • Measures cortisol response to cosyntropin (250 µg using serial cortisol measures at 0, 30, and 60 minutes)
        • Cortisol <5 µg/dL – primary severe adrenal failure
        • Cortisol >20 µg/dL – normal; adrenal insufficiency unlikely
        • Cortisol ≤20 µg/dL but ≥5 µg/dL – evaluate for pituitary failure; secondary adrenal insufficiency likely
      • Evaluation for pituitary failure
        • Insulin tolerance testing (ITT)
          • Not recommended in children <6 years
        • Metyrapone overnight testing
          • If 11 deoxycortisol >7 µg/dL – adrenal failure unlikely; MRI/CT of adrenal glands
          • If 11 deoxycortisol ≤7 µg/dL – pituitary failure likely; order MRI/CT
            • If still not clear – corticotropin releasing hormone (CRH) stimulus testing
              • If ACTH <10 pg/mL – pituitary failure likely
  • Autoimmune etiology confirmation – presence of 21-hydroxylase antibodies confirm autoimmune etiology

Imaging Studies

  • MRI/CT based on stimulation testing results
    • If stimulation testing or absolute cortisol suggests adrenal failure – MRI/CT of adrenal glands
    • If stimulation testing suggests pituitary failure – MRI/CT of pituitary

Differential Diagnosis

Adrenal insufficiency is defined as hypofunction of the adrenal gland with decreased or absent cortisol secretion.


  • Incidence – estimated at 5-10/100,000 (Charmandari, 2014)
  • Sex – M:F, equal


  • Primary or secondary insufficiency


  • Primary adrenal insufficiency
    • Autoimmune
      • Addison disease
        • Frequent association with other endocrine diseases
        • Autoantibodies to 21-hydroxylase – frequently present
      • Autoimmune polyendocrine syndromes
        • Epidemiology
          • Incidence – 1-2/100,000
          • Age – 30s
          • Sex – M<F, 1:3
        • Classification
          • Type 1 associated characteristics
          • Type 2 associated characteristics
          • Type 4 associated characteristics
            • Other  autoimmune disorders excluding thyroid disease and type 1 DM
          • Types 1 and 2 may also include other autoimmune disorders – vitiligo, chronic atrophic gastritis, alopecia
    • Infection
    • Anatomic destruction of the gland
      • Surgical removal
      • Bilateral hemorrhage into the gland – may be associated with anticoagulant therapy
      • Invasion of the gland
        • Metastases – lung, stomach, breast, and colon most common
        • Infiltrative disorders – lymphoma, amyloid iron overload
    • Genetic disorders (eg, adrenoleukodystrophy, congenital adrenal hyperplasia [CAH])
    • Medications – etomidate, ketoconazole, metyrapone
  • Secondary adrenal insufficiency (central insufficiency)
    • Drug induced (eg, corticosteroids)
    • Hypopituitarism
      • Postpartum hemorrhage – Sheehan syndrome
      • Pituitary radiation
      • Pituitary surgery
      • Acute interruption of prolonged corticosteroids
      • Pituitary infiltrative disease – sarcoidosis, granulomatosis with polyangiitis
      • Traumatic brain injury
    • Lymphocytic hypophysitis – may be part of autoimmune polyendocrine syndrome


  • Primary – combined glucocorticoid and mineralocorticoid deficiency
  • Secondary – glucocorticoid deficiency

Clinical Presentation

  • Insidious onset of fatigue, weakness, anorexia, nausea and emesis
  • Cutaneous hyperpigmentation – diffuse tan, brown or bronzing
    • Does not occur in secondary insufficiency
  • Orthostatic hypotension
  • Diarrhea, abdominal pain
  • Acute presentation may occur in patients with mild adrenal insufficiency who are stressed (eg, critical illness, surgery)
    • Hypotension which is unresponsive to fluids
    • Mainly attributable to mineralocorticoid deficiency
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Cortisol by LC-MS/MS, Serum or Plasma 2003250
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Adrenocorticotropic Hormone 0070010
Method: Quantitative Chemiluminescent Immunoassay


Some types of synthetic ACTH are not detected by this assay

11-Deoxycortisol Quantitative by HPLC-MS/MS, Serum or Plasma 0092331
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

21-Hydroxylase Antibody 0070265
Method: Quantitative Radioimmunoassay


Husebye ES, Allolio B, Arlt W, Badenhoop K, Bensing S, Betterle C, Falorni A, Gan EH, Hulting A, Kasperlik-Zaluska A, Kämpe O, Løvås K, Meyer G, Pearce SH. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med. 2014; 275(2): 104-15. PubMed

General References

Al-Aridi R, Abdelmannan D, Arafah BM. Biochemical diagnosis of adrenal insufficiency: the added value of dehydroepiandrosterone sulfate measurements. Endocr Pract. 2011; 17(2): 261-70. PubMed

Betterle C, Morlin L. Autoimmune Addison's disease. Endocr Dev. 2011; 20: 161-72. PubMed

Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014; 383(9935): 2152-67. PubMed

Grossman AB. Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010; 95(11): 4855-63. PubMed

Majeroni BA, Patel P. Autoimmune polyglandular syndrome, type II. Am Fam Physician. 2007; 75(5): 667-70. PubMed

Michels A, Michels N. Addison disease: early detection and treatment principles. Am Fam Physician. 2014; 89(7): 563-8. PubMed

Wallace I, Cunningham S, Lindsay J. The diagnosis and investigation of adrenal insufficiency in adults. Ann Clin Biochem. 2009; 46(Pt 5): 351-67. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

La'ulu SL, Roberts WL. Performance characteristics of the Architect cortisol immunoassay. Clin Chim Acta. 2008; 388(1-2): 219-21. PubMed

Medical Reviewers

Last Update: July 2017