Trusted medical expertise in seconds.

Access 1,000+ clinical and preclinical articles. Find answers fast with the high-powered search feature and clinical tools.

Try free for 5 days
Evidence-based content, created and peer-reviewed by physicians. Read the disclaimer.

Adrenal insufficiency

Last updated: August 10, 2021

Summarytoggle arrow icon

Adrenal insufficiency is the decreased production of adrenocortical hormones (glucocorticoids, mineralocorticoids, and adrenal androgens) and is classified as primary, secondary, or tertiary. Primary adrenal insufficiency (Addison disease) is caused by a disorder of the adrenal glands. The most frequent cause of primary adrenal insufficiency in the US by far is autoimmune adrenalitis, which can occur sporadically or as a manifestation of polyglandular autoimmune syndromes. Secondary adrenal insufficiency is the result of decreased production of ACTH (adrenocorticotropic hormone) and tertiary adrenal insufficiency is the result of decreased production of CRH (corticotropin-releasing hormone) by the hypothalamus. Decreased levels of ACTH or CRH are seen following sudden cessation of prolonged glucocorticoid therapy and in pituitary/hypothalamic diseases. Patients with long-standing adrenal insufficiency can present with postural hypotension, nausea, vomiting, weight loss, anorexia, lethargy, depression, and/or chronic hyponatremia. There may also be a loss of libido as a result of hypoandrogenism. Patients with primary adrenal insufficiency tend to additionally develop hyperpigmentation of the skin, mild hyperkalemia, and metabolic acidosis. Serum cortisol levels that remain low even after the administration of exogenous ACTH (ACTH stimulation test) confirm the diagnosis of primary adrenal insufficiency. Glucocorticoid replacement therapy with hydrocortisone is required for all forms of adrenal insufficiency. The dose of glucocorticoids should be increased during periods of stress (e.g., surgery, trauma, infections) in order to prevent adrenal crisis, which is a severe, acute type of adrenal insufficiency that manifests with shock, fever, impaired consciousness, and severe abdominal pain. Adrenal crisis is life-threatening and should be treated immediately with high doses of hydrocortisone and intravenous fluids.

Recommendations in this article are consistent with the 2016 Endocrine Society clinical practice guidelines for the diagnosis and treatment of primary adrenal insufficiency. [1]

Adrenal insufficiency is a failure of the adrenal glands to produce adequate amounts of adrenocortical hormones. It can be primary, secondary, or tertiary.

Primary adrenal insufficiency (Addison disease)

Primary adrenal insufficiency can be caused by abrupt destruction of the adrenal gland (acute adrenal insufficiency; e.g., due to massive adrenal hemorrhage) or by its gradual progressive destruction or atrophy (chronic adrenal insufficiency; e.g., due to autoimmune conditions, infection).

Secondary adrenal insufficiency

Secondary adrenal insufficiency is caused by conditions that decrease ACTH production (impaired hypothalamic-pituitary-adrenal axis).

Tertiary adrenal insufficiency

Tertiary adrenal insufficiency is caused by conditions that decrease CRH production.

  • The most common cause is sudden discontinuation of chronic glucocorticoid therapy.
  • Rarer causes include hypothalamic dysfunction (e.g., due to trauma, mass, hemorrhage, or anorexia): CRHACTHcortisol release

Secondary and tertiary adrenal insufficiency are far more common than primary adrenal insufficiency!

For basic information on the adrenal gland and its functions, see “Hormones of the adrenal cortex.”

Primary adrenal insufficiency (Addison disease)

Damage to the adrenal gland leads to the deficiency in all three hormones produced by the adrenal cortex: androgen, cortisol, and aldosterone.

Secondary adrenal insufficiency

Tertiary adrenal insufficiency

References:[12]

Hormonal changes

Clinical features Laboratory findings Primary adrenal insufficiency Secondary adrenal insufficiency Tertiary adrenal insufficiency

Hypoaldosteronism

  • Absent
  • Absent

Hypocortisolism

  • Weight loss, anorexia
  • Fatigue, lethargy, depression
  • Muscle aches
  • Weakness
  • Gastrointestinal complaints (e.g., nausea, vomiting, diarrhea)
  • Sugar cravings
  • (Orthostatic) hypotension
Hypoandrogenism
  • Loss of libido
  • Loss of axillary and pubic hair
Elevated ACTH
  • Absent
  • Absent

Most cases of adrenal insufficiency are subclinical and only become apparent during periods of stress (e.g., surgery, trauma, infections), when the cortisol requirement is higher!

Primary adrenal insufficiency Pigments the skin. Secondary adrenal insufficiency Spares the skin. Tertiary adrenal insufficiency is due to Treatment (cortisol).

References:[13]

Approach

Endocrine testing for adrenal insufficiency [17]

Morning cortisol

Morning ACTH

ACTH stimulation test

Primary adrenal insufficiency

No increase in serum cortisol after stimulation

Secondary/tertiary adrenal insufficiency

Increase in serum cortisol after stimulation

Longstanding secondary/tertiary adrenal insufficiency [18]

No (or very little) increase in serum cortisol after stimulation

Maintain a low threshold for adrenal insufficiency screening (especially in patients with nonspecific symptoms), as up to 50% of patients present with adrenal crisis, often due to missed or delayed diagnosis. [19]

Routine laboratory studies

Endocrine studies

Screening for hypoaldosteronism and hypoandrogenism [1]

The following parameters should be measured in patients with primary adrenal insufficiency.

Other dynamic endocrine studies

These can be performed in consultation with an endocrinologist, e.g., if previous tests have been inconclusive.

Additional evaluation

The following tests are used to investigate underlying causes.

Primary adrenal insufficiency [1]

The most common cause of primary adrenal insufficiency in high-income countries is autoimmune adrenalitis. [17]

Secondary/tertiary adrenal insufficiency [17]

The most common cause of tertiary adrenal insufficiency is exogenous glucocorticoid administration. [12]

Approach

Glucocorticoid replacement therapy with hydrocortisone is required in all forms of adrenal insufficiency.

Steroid replacement

Glucocorticoids [1]

Mineralocorticoids [1]

Androgens [1]

Consider treatment in anatomically female patients with low libido, depressive symptoms, and low energy levels.

  • Agent: DHEA [1]
  • Considerations
    • DHEA is not an FDA-approved drug, but is available as an OTC supplement.
    • Results of studies investigating the positive effects of DHEA have been mixed and data on long-term outcomes is lacking. [1]
    • Discontinue after 6 months if there is no positive effect.

Treatment of the underlying cause and associated conditions

Stress-dose steroids [29][30]

Steroid doses should be increased to prevent adrenal crisis in at-risk patients, e.g., in acute illness, surgery, or trauma (see also “Precipitating factors” in “Adrenal crisis”).

  • Inpatient steroid doses are adjusted according to the level of stress.
  • Patients who do not require hospitalization can be taught self-treatment plans, known as sick day rules.

If the dose of glucocorticoids is not increased during periods of stress, the patient may develop an adrenal crisis!

Inpatient stress-dose steroids [1][29]

Adhere to any preexisting protocol/care plan by the patient's endocrinologist. The following recommendations can apply to all patients on adrenosuppressive doses of glucocorticoids.

  • Febrile illness: : Double the usual oral dose until recovery; consider IV route if the patient is vomiting.
  • Critically ill patients: IV hydrocortisone [31]
  • Perioperative patients

Outpatient sick day rules [1] [19]

The following rules should be taught to patients with primary adrenal insufficiency so that they can self-administer glucocorticoids in times of illness/physiological stress:

Adrenal crisis is an acute, severe glucocorticoid deficiency that requires immediate emergency treatment.

Precipitating factors

In order to prevent the development of secondary and tertiary adrenal insufficiency, prolonged steroid therapy should be tapered slowly rather than stopped abruptly.

Signs and symptoms [19]

Diagnosis [12][19][32]

Consider adrenal crisis in patients with severe hypotension refractory to fluid resuscitation and/or vasopressors.

Adrenal crisis can be life-threatening, so treatment with high doses of hydrocortisone should be started immediately, without waiting for diagnostic confirmation of hypocortisolism!

Management [1][19]

The 5 S’s of adrenal crisis treatment are Salt (0.9% saline), Sugar (50% dextrose), Steroids (100 mg hydrocortisone IV once, then 200 mg over 24 hours), Support (normal saline to correct hypotension and electrolyte abnormalities), and Search (for the underlying disorder).

  • Establish IV access with two large-bore peripheral IV lines.
  • Administer hydrocortisone IV/IM.
  • Fluid resuscitation with 1 L of normal (isotonic) saline in the first hour
  • Treat hypoglycemia with IV dextrose.
  • Identify and treat the underlying cause (e.g., sepsis).
  • Consider early endocrinology consult.
  • Monitor vitals, blood glucose, and urine output every 1–2 hours.
  • Continue IV fluids to maintain blood pressure and urine output.
  • Continue substitution of hydrocortisone through boluses or continuous IV infusion.
  • Consider higher-level monitoring, e.g., ICU, if there is ongoing hemodynamic compromise.

References:[39][40]

  1. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2016; 101 (2): p.364-389. doi: 10.1210/jc.2015-1710 . | Open in Read by QxMD
  2. Tritos NA. Adrenal Hemorrhage. Adrenal Hemorrhage. New York, NY: WebMD. http://emedicine.medscape.com/article/126806. Updated: March 3, 2017. Accessed: March 13, 2017.
  3. Adrenal hemorrhage. https://radiopaedia.org/articles/adrenal-haemorrhage. Updated: March 1, 2019. Accessed: June 7, 2019.
  4. Laura H. Rosenberger, MD, Philip W. Smith, MD, Robert G. Sawyer, MD, John B. Hanks, MD, Reid B. Adams, MD, and Traci L. Hedrick, MD. Bilateral adrenal hemorrhage: The unrecognized cause of hemodynamic collapse associated with heparin-induced thrombocytopenia. Critical Care Medicine. 2011 .
  5. Provenzale JM, Ortel TL, Nelson RC. Adrenal hemorrhage in patients with primary antiphospholipid syndrome: imaging findings.. American Journal of Roentgenology. 1995 .
  6. Eric Jordan1, Liina Poder, Jesse Courtier, Victor Sai. Imaging of Nontraumatic Adrenal Hemorrhage. American Journal of Roentgenology. 2012 .
  7. Zainab Fatima, Usman Tariq, Amina Khan, Muhammad Saad Sohail, Abu Baker Sheikh, Shimron I Bhatti, and Kamran Munawar. A Rare Case of Bilateral Adrenal Hemorrhage. Cureus Journal of Medical Science. 2018 .
  8. Vasileios Charalampakis, Dimitrios Stamatiou, Eelco de Bree, Manousos Christodoulakis, and Odysseas Zoras. Spontaneous adrenal hemorrhage. Report of two cases and review of pathogenesis, diagnosis and management. Journal of Surgical Case Reports. 2018 .
  9. Nicholas R Zessis, Jennifer L Nicholas and Stephen I Stone. Severe bilateral adrenal hemorrhages in a newborn complicated by persistent adrenal insufficiency. Endocrinology, Diabetes & Metabolism Case Reports. 2018 .
  10. Gregory S. Kelly, ND. Nutritional and Botanical Interventions to Assist with the Adaptation to Stress. Alternative Medicine Review. 1999 .
  11. Granata A, Tirabassi G, Pugni V, Arnaldi G, Boscaro M, Carani C, Balercia G.. Sexual dysfunctions in men affected by autoimmune Addison's disease before and after short-term gluco- and mineralocorticoid replacement therapy.. The Journal of Sexual Medicine. 2013 .
  12. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014; 383 (9935): p.2152-2167. doi: 10.1016/s0140-6736(13)61684-0 . | Open in Read by QxMD
  13. Nieman LK. Clinical manifestations of adrenal insufficiency in adults. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/clinical-manifestations-of-adrenal-insufficiency-in-adults.Last updated: November 4, 2016. Accessed: February 19, 2017.
  14. Struja T, Briner L, Meier A, et al. Diagnostic accuracy of basal cortisol level to predict adrenal insufficiency in cosyntropin testing: results from an observational cohort study with 804 patients. Endocr Pract. 2017; 23 (8): p.949-961. doi: 10.4158/ep171861.or . | Open in Read by QxMD
  15. Michels A, Michels N. Addison disease: early detection and treatment principles.. Am Fam Physician. 2014; 89 (7): p.563-8.
  16. Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing's syndrome, adrenal insufficiency, and congenital adrenal hyperplasia.. Compr Physiol. 2014; 4 (2): p.739-69. doi: 10.1002/cphy.c130035 . | Open in Read by QxMD
  17. Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015; 3 (3): p.216-226. doi: 10.1016/s2213-8587(14)70142-1 . | Open in Read by QxMD
  18. Oelkers W. Adrenal Insufficiency. N Engl J Med. 1996; 335 (16): p.1206-1212. doi: 10.1056/nejm199610173351607 . | Open in Read by QxMD
  19. Puar THK, Stikkelbroeck NMML, Smans LCCJ, Zelissen PMJ, Hermus ARMM. Adrenal Crisis: Still a Deadly Event in the 21st Century. Am J Med. 2016; 129 (3): p.339.e1-339.e9. doi: 10.1016/j.amjmed.2015.08.021 . | Open in Read by QxMD
  20. Shenker Y, Skatrud JB. Adrenal Insufficiency in Critically Ill Patients. Am J Respir Crit Care Med. 2001; 163 (7): p.1520-1523. doi: 10.1164/ajrccm.163.7.2012022 . | Open in Read by QxMD
  21. Oster H, Challet E, Ott V, et al. The Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids. Endocr Rev. 2016; 38 (1): p.3-45. doi: 10.1210/er.2015-1080 . | Open in Read by QxMD
  22. Neary N, Nieman L. Adrenal insufficiency: etiology, diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes. 2010; 17 (3): p.217-223. doi: 10.1097/med.0b013e328338f608 . | Open in Read by QxMD
  23. Fleseriu M, Gassner M, Yedinak C, Chicea L, Delashaw J, Loriaux D. 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 (1): p.64-70. doi: 10.4158/ep09153.or . | Open in Read by QxMD
  24. Suliman AM, Smith TP, Labib M, Fiad TM, McKenna TJ. The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Clin Endocrinol (Oxf). 2002; 56 (4): p.533-539. doi: 10.1046/j.1365-2265.2002.01509.x . | Open in Read by QxMD
  25. Ospina NS, Al Nofal A, Bancos I, et al. ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2016; 101 (2): p.427-434. doi: 10.1210/jc.2015-1700 . | Open in Read by QxMD
  26. Li X, Goswami R, Yang S, Li Q. Aldosterone/direct renin concentration ratio as a screening test for primary aldosteronism: A meta-analysis. J Renin Angiotensin Aldosterone Syst. 2016; 17 (3). doi: 10.1177/1470320316657450 . | Open in Read by QxMD
  27. 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 (7): p.2350-2354. doi: 10.1210/jcem.83.7.4980 . | Open in Read by QxMD
  28. Angulo MA, Butler MG, Cataletto ME. Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. J Endocrinol Invest. 2015; 38 (12): p.1249-1263. doi: 10.1007/s40618-015-0312-9 . | Open in Read by QxMD
  29. Liu MM, Reidy AB, Saatee S, Collard CD. Perioperative Steroid Management. Anesthesiology. 2017; 127 (1): p.166-172. doi: 10.1097/aln.0000000000001659 . | Open in Read by QxMD
  30. Woodcock T, Barker P, Daniel S, et al. Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency. Anaesthesia. 2020; 75 (5): p.654-663. doi: 10.1111/anae.14963 . | Open in Read by QxMD
  31. Coursin DB. Corticosteroid Supplementation for Adrenal Insufficiency. JAMA. 2002; 287 (2): p.236. doi: 10.1001/jama.287.2.236 . | Open in Read by QxMD
  32. C Betterle, F Lazzarotto, and F Presotto. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg?. Clinical and Experimental Immunology. 2004 .
  33. Eystein S. Husebye, Mark S. Anderson, and Olle Kämpe. Autoimmune Polyendocrine Syndromes. The New England Journal of Medicine. 2018 .
  34. Autoimmune Polyendocrine Syndrome Type II. https://rarediseases.org/rare-diseases/autoimmune-polyendocrine-syndrome-type-ii/. Updated: January 1, 2007. Accessed: April 21, 2020.
  35. Dineen R, Thompson CJ, Sherlock M. Adrenal crisis: prevention and management in adult patients. Ther Adv Endocrinol Metab. 2019; 10 : p.204201881984821. doi: 10.1177/2042018819848218 . | Open in Read by QxMD
  36. Tucci V, Sokari T. The Clinical Manifestations, Diagnosis, and Treatment of Adrenal Emergencies. Emerg Med Clin North Am. 2014; 32 (2): p.465-484. doi: 10.1016/j.emc.2014.01.006 . | Open in Read by QxMD
  37. Karet FE. Mechanisms in hyperkalemic renal tubular acidosis.. J Am Soc Nephrol. 2009; 20 (2): p.251-4. doi: 10.1681/ASN.2008020166 . | Open in Read by QxMD
  38. Chrousos GP, Kino T, Charmandari E. Evaluation of the Hypothalamic-Pituitary-Adrenal Axis Function in Childhood and Adolescence. Neuroimmunomodulation. 2009; 16 (5): p.272-283. doi: 10.1159/000216185 . | Open in Read by QxMD
  39. Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I). Crit Care Med. 2017; 45 (12): p.2078-2088. doi: 10.1097/ccm.0000000000002737 . | Open in Read by QxMD
  40. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018; 378 (9): p.809-818. doi: 10.1056/nejmoa1705716 . | Open in Read by QxMD
  41. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. McGraw-Hill Education ; 2015
  42. 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 (4): p.1326-1333. doi: 10.1210/jc.2006-1791 . | Open in Read by QxMD
  43. Galbois A, Rudler M, Massard J, et al. Assessment of adrenal function in cirrhotic patients: Salivary cortisol should be preferred. J Hepatol. 2010; 52 (6): p.839-845. doi: 10.1016/j.jhep.2010.01.026 . | Open in Read by QxMD
  44. Hägg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency. Clin Endocrinol (Oxf). 1987; 26 (2): p.221-226. doi: 10.1111/j.1365-2265.1987.tb00780.x . | Open in Read by QxMD